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 Mechanobiology
From Molecular Sensing to Disease

Edited by
GLEN L. NIEBUR, PHD
Director
Bioengineering Graduate Program
University of Notre Dame, Notre Dame
Indiana
United States
Professor
Aerospace and Mechanical Engineering
University of Notre Dame

]
Mechanobiology ISBN: 978-0-12-817931-4
Copyright Ó 2020 Elsevier Inc. All rights reserved.

No part of this publication may be reproduced or transmitted in any form or by any means, electronic or
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This book and the individual contributions contained in it are protected under copyright by the Publisher (other
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To Marcia and Max
List of Contributors

Daniel P. Ahern, MCh, MRCSI, PhD Joseph S. Butler, PhD, FRCS

Candidate Clinical Associate Professor
Trinity Centre for Biomedical Engineering School of Medicine
Trinity Biomedical Sciences Institute Trinity College Dublin
Trinity College Consultant Surgeon
Dublin, Ireland National Spinal Injuries Unit
Department of Mechanical and Manufacturing Department of Trauma & Orthopaedic Surgery
Engineering Mater Misericordiae University Hospital
School of Engineering Dublin, Ireland
Trinity College Dublin
Dublin, Ireland Weitao Chen
Department of Mathematics
Department of Surgery
University of California
School of Medicine
Riverside, CA, United States
Trinity College Dublin
Dublin, Ireland Center for Quantitative Modeling in Biology
University of California
Mark Alber Riverside, CA, United States
Department of Mathematics
University of California David T. Corr
Riverside, CA, United States Biomedical Engineering Department
Rensselaer Polytechnic Institute
Center for Quantitative Modeling in Biology
Troy, NY, United States
University of California
Riverside, CA, United States
Matthew E. Dolack
School of Medicine Department of Mechanical and Nuclear Engineering
University of California The Pennsylvania State University
Riverside, CA, United States University Park, PA, United States
Department of Bioengineering
University of California Henry J. Donahue, PhD
Riverside, CA, United States Alice T. and William H. Goodwin Jr.
Professor and Distinguished Chair
Johana Barrientos Department of Biomedical Engineering
Department of Biological Sciences Virginia Commonwealth University
Wright State University Richmond, VA, United States
Dayton, OH, United States
Michael P. Duffy, MSc, PhD
Michael T.K. Bramson Candidate
Biomedical Engineering Department Department of Biomedical Engineering
Rensselaer Polytechnic Institute Columbia University
Troy, NY, United States New York, NY, United States

vii
viii LIST OF CONTRIBUTORS

Michael A. Friendman, PhD Ethylin Wang Jabs

Department of Biomedical Engineering Department of Genetics and Genomic Sciences
Virginia Commonwealth University Icahn School of Medicine at Mount Sinai
Richmond, VA, United States New York, NY, United States

Diego A. Garzón-Alvarado Reuben H. Kraft

Biomimetics Laboratory Department of Mechanical and Nuclear Engineering
Instituto de Biotechnología The Pennsylvania State University
Universidad Nacional de Colombia University Park, PA, United States
Bogotá, Colombia Department of Biomedical Engineering
Numerical Methods and Modeling Research Group The Pennsylvania State University
Universidad Nacional de Colombia University Park, PA, United States
Bogotá, Colombia
Chanyoung Lee
Damian C. Genetos, PhD Coulter Department of Biomedical Engineering
Associate Professor Georgia Institute of Technology/Emory University
Anatomy, Physiology, and Cell Biology Atlanta, GA, United States
UC Davis
Davis, CA, United States Jiun Liou, Jr., PhD
School of Veterinary Medicine Department of Bioengineering
Baton Rouge, LA, United States Swanson School of Engineering
University of Pittsburgh
M. Goelzer, MS Pittsburgh, PA, United States
Department of Mechanical and Biomedical
Engineering Jing Liu, PhD
Boise State University Department of Physics
Boise, ID, United States Indiana University-Purdue University Indianapolis
Indianapolis, IN, United States
David A. Hoey, PhD
Associate Professor Maureen E. Lynch, PhD
Biomedical Engineering University of Colorado Boulder
Trinity Centre for Biomedical Engineering Boulder, CO, United States
Trinity Biomedical Sciences Institute
Trinity College Arsalan Marghoub
Dublin, Ireland Department of Mechanical Engineering
University College London
Department of Mechanical and Manufacturing
London, United Kingdom
Engineering
School of Engineering
Kaitlin P. McCreery, BS
Trinity College Dublin
University of Colorado Boulder
Dublin, Ireland
Boulder, CO, United States
Advanced Materials and Bioengineering Research
Centre Megan R. Mc Fie, MSc, PhD
Trinity College Dublin & RCSI Candidate
Dublin, Ireland School of Engineering and Materials Science
Queen Mary University of London
Minyi Hu, PhD London, United Kingdom
Stony Brook University
Stony Brook, NY, United States Mehran Moazen
Department of Mechanical Engineering
University College London
London, United Kingdom
 LIST OF CONTRIBUTORS ix

Corey P. Neu, PhD Clare L. Thompson, PhD

University of Colorado Boulder Postdoctoral Researcher
Boulder, CO, United States School of Engineering and Materials Science
Queen Mary University of London
Glen L. Niebur, PhD London, United Kingdom
Professor
Tissue Mechanics Laboratory W.R. Thompson, PhD
Bioengineering Graduate Program and Department of Department of Physical Therapy
Aerospace and Mechanical Engineering Indiana University
University of Notre Dame Bloomington, IN, United States
Notre Dame, IN, United States
G. Uzer, PhD
Yi-Xian Qin, PhD Senior Author
Stony Brook University Department of Mechanical and Biomedical
Stony Brook, NY, United States Engineering
Boise State University
Joan T. Richtsmeier Boise, ID, United States
Department of Anthropology
The Pennsylvania State University Sarah K. Van Houten
University Park, PA, United States Biomedical Engineering Department
Rensselaer Polytechnic Institute
Ying Ru Troy, NY, United States
Department of Genetics and Genomic Sciences
Icahn School of Medicine at Mount Sinai Jonathan P. Vande Geest, PhD
New York, NY, United States Department of Bioengineering
Swanson School of Engineering
Benjamin Seelbinder, MS McGowan Institute for Regenerative Medicine
University of Colorado Boulder Department of Ophthalmology
Boulder, CO, United States School of Medicine
Louis J. Fox Center for Vision Restoration
Jason A. Shar, BS University of Pittsburgh
Department of Mechanical and Materials Engineering Pittsburgh, PA, United States
Wright State University
Dayton, OH, United States Vijay Velagala
Department of Chemical and Biomolecular
Jason E. Shoemaker, PhD Engineering
Department of Chemical and Petroleum Engineering University of Notre Dame
Swanson School of Engineering Notre Dame, IN, United States
Department of Computational and Systems Biology Bioengineering Graduate Program
School of Medicine University of Notre Dame
McGowan Institute for Regenerative Medicine Notre Dame, IN, United States
University of Pittsburgh
Pittsburgh, PA, United States Jeremiah J. Zartman
Department of Chemical and Biomolecular
Philippe Sucosky, PhD Engineering
Department of Mechanical and Materials Engineering University of Notre Dame
Wright State University Notre Dame, IN, United States
Dayton, OH, United States
Bioengineering Graduate Program
University of Notre Dame
Notre Dame, IN, United States
Preface: Mechanobiology, why not?

HISTORY OF MECHANOBIOLOGY Roux. Wolff published his monograph “Das Gesetz der
Mechanobiology is, in some ways, a new field. The first Transformation der Knochen” (“The Law of Bone
reference to the term mechanobiology in the US govern- Remodeling”)5,6 in 1892, and Roux published “Der
ment’s PubMed database was by Marjolein van der Kampf Der Theile im Organismus” (“The Challenges to
Meulen in 1993.1 Indeed, the term mechanobiology was the Parts in the Organism”) in which he proposed the
coined specifically for this paper at a meeting of the idea of functional adaptation to external stimuli in
Stanford-Palo Alto Bone Remodeling club. The group 1881.4 In 1885, Roux published a second treatise on
had realized that biomechanical neither was the correct developmental mechanics (“Die Entwicklungsmecha-
description for the phenomenon they were describing nik; ein neuer Zweig der biologischen Wissenschaft” or
nor was it sufficient to use the adjective “mechanical” to “Developmental mechanics: a new branch of biological
modify biological terms.2 They noted science”).7,8
The term mechanobiological is used to emphasize Before the emergence of the term mechanobiology, a
that the mechanical effects we are modeling are also significant amount of research was described by the
dependent upon a biological response.1 ubiquitously applied misnomer “Wolff’s law for .”,
Within a few years, a number of papers from labo- which was used to describe the concept of tissue adap-
ratories at Stanford and the Palo Alto VA adopted the tation or healing under the influence of mechanical
term. It came into more widespread use throughout the loads in tendons, ligaments,9e11 and skin,12 among
1990s. One of the seminal definitions of the term other tissues.13
appeared in the article “Why Mechanobiology?” published “Wolff’s law” has certainly seen its share of criticism
in the Journal of Biomechanics in 2001.3 In this article the for its simplicity, conflation of differing processes, over-
authors laid out the central precept of mechanobiology reliance on mechanics relative to hormonal and nutri-
for the skeleton: tional factors, and incorrect understanding of
mechanics.14,15 Similarly, Roux’s writings intermixed
The premise of mechanobiology is that these biological pro- concepts of heredity and adaptation, using examples of
cesses are regulated by signals to cells generated by me- ducks and cows. However, one must remember that the
chanical loading, a concept dating back to Roux.4 The existence of cells had only been known for a few decades
relevant questions include how external and muscle loads are at the time, Charles Darwin was a contemporary, and the
transferred to the tissues, how the cells sense these loads, and discovery of DNA was far in the future. In this context,
how the signals are translated into the cascade of biochem- these researchers established concepts and asked ques-
ical reactions to produce cell expression or differentiation. tions that remain at the heart of mechanobiology today,
Ultimately, we want to predict growth and differentiation in even if their initial hypotheses have been superseded and
augmented with newly discovered biological structures
quantitative terms, based on a given force exerted on a given
and phenomena over time.
tissue matrix populated by cells.3
Much of the early work in mechanobiology focused
This definition has been readily adapted to other on the musculoskeletal system, formalizing the ideas
tissues by changing “muscle loading” to a variety of force and incorporating growing knowledge of cellular pro-
generators and “tissue matrix populated by cells” with cesses. Advanced mechanical analysis, made possible by
any number of tissues or even cells themselves. At the the finite element method, provided a means to calculate
same time that a new field was being defined, the authors the spatial distribution of the mechanical signal, which
noted that it was in some ways a very old field. The un- was correlated to locations of bone formation or
derlying principles of mechanobiology were outlined a resorption or to changes in the local density of the
century earlier in the work by Julius Wolff and Wilhelm bone.16e18 Similarly, cartilage19 and tendon20e22

xi
xii PREFACE: MECHANOBIOLOGY, WHY NOT?

adaptation and remodeling were simulated using algo- Mechanobiology is now studied as an inherently
rithms that incorporated mechanical cues. Cardiovas- multiscale phenomenon. Starting from the cell scale, the
cular mechanobiology research also grew, leveraging role of mechanotransduction in sensing the presence or
similar computational methods but applying differing localized motions of surrounding cells or ECM is the first
theories of cellular response and remodeling.23 As stage in the mechanobiological cascade. At this level, it is
computational power has grown, cell and molecular essential to understand how forces are transmitted to the
level knowledge has been incorporated into simulations physiologic structures that connect the cells to the ECM
to include the local cell density, the density of local or to other cellsdthe integrins and the adherens,
signaling molecules, and nutrient diffusion.24,25 respectivelydas well as the cytoskeleton and cell mem-
brane, and how they are transduced into biochemical
actions within the cell. Forces on these structures can
MECHANOBIOLOGY ACROSS LENGTH induce gene translation, post-translational modification
SCALES of proteins, or upregulation of secondary messengers
At the largest length scales, mechanobiology has been that drive protein translation and cell differentiation
used to explain how activities of daily living and envi- through both autocrine and paracrine signaling. This
ronment affect the composition, geometry, or healing of signaling may alter local cell phenotypes, cell signaling,
the tissue. For example, multiple mechanobiological further ECM production and degradation, or the orga-
models have attempted to predict the shape and scaling nization of ECM molecules.
of bones with respect to mechanical loading26,27 or to
investigate rehabilitation regimens that can best rees-
tablish normal function.28 WHY NOT MECHANOBIOLOGY?
At the tissue scale the focus is often on the changes in Most cells contain the machinery necessary to sense and
extracellular matrix (ECM) properties. In these models respond to loads, even if other factors may dominate
the cell populations can often aggregate as concentra- their function. While mechanical loading is obviously an
tions. The interactions of cells with the matrix are essential part of the function of musculoskeletal and
quantified by the local strain or fluid flow. The choice of cardiovascular tissues, almost all tissues are subjected to
constitutive model has proven to be important in many some mechanical forces and deformation. Both epithe-
instances, with fiber-reinforced or poroelastic de- lial and endothelial surfaces can be subjected to fluid
scriptions improving the fidelity of calculations of the flows and stretching. Even baseline respiration in
mechanical behavior. The mechanobiological processes mammals causes cyclic motion and pressure changes in
are hypothesized to alter the mechanical properties by the thoracic and abdominal cavities, which would
defining rate laws for any or all of the constitutive pa- induce mechanical stress in the organs. For example,
rameters that depend on the number and the state of the mechanobiology plays a role in liver regeneration30 and
various cells. Nutrients or signaling molecules can also normal kidney function.31,32 Interestingly, molecules
be described by concentrations. Their diffusion and involved in mechanosensing in the kidneyd
convection are typically governed by classical laws, but yes-associated protein (YAP) and transcriptional coac-
additional production and consumption laws must also tivator with PDZ-binding motif (TAZ)dalso play a role
be postulated based on the cell populations present. in bone mechanobiology33,34 and many other cell line-
In parallel with these macroscopic phenomenological ages.35 Identification of this and other molecular targets
models, novel methods were being developed to deter- may provide a link to mechanobiological functions in
mine whether cells actually sense and respond to me- other tissues and organ systems.
chanical cues. Flow chambers, stretched surfaces, Over the past 25 years, mechanobiology has grown
patterned surfaces, and materials of varying mechanical into a distinct field with research centers, journals, and
properties were all used to determine whether cells conferences dedicated to its study. It is a uniquely
altered gene or protein expression in response to me- interdisciplinary field that rests at an interface between
chanical cues. Lower and upper bounds of shearing engineering, biology, materials science, and physics. It
stresses, stretches, and pressures have since been estab- relies on many other new and growing fields such as
lished for mechanobiological response of a range of cell bioinformatics, gene editing, and high-resolution imag-
phenotypes. In a seminal paper, Engler and colleagues29 ing to achieve its aims. Mechanobiology is now firmly
showed that culturing stem cells on materials with established in the biology and bioengineering lexicon,
differing constitutive properties alters their differentia- and in 2018, 308 articles indexed in the PubMed data-
tion fate. base specifically used one of the terms mechanobiology
 PREFACE: MECHANOBIOLOGY, WHY NOT? xiii

or mechanobiological in the abstract or title. There is an powerful experimental platforms for mechanobiology,
excellent textbook on mechanobiology,36 and courses especially when coupled with genetically engineered cell
are offered at many universities. A multisite National sources37 or small molecule activators or inhibitors of
Science Foundation is highly active, and there are other pathways of interest. Underlying biological mechanisms
institutes and centers at universities throughout the can be further probed by cell culture using reporter cells
world. to quantify the mechanics of individual cells.
New technologies, including animal models, organ-/ The final two chapters consider modeling of mecha-
tissue-on-a-chip, and engineered tissues, coupled with nobiology in development and tissue morphogenesis.
gene editing and cellular level probes, have opened Computational modeling can provide the best approach
endless possibilities for mechanobiology research. It is to develop and test hypotheses in mechanobiology.
now much easier to probe the mechanical response of Multiphysics modeling software allows researchers to
systems and to understand how they are coupled to both explore the interactions of mechanics, transport, and
health and disease. As such, we have entered the era of growth and to explore scenarios that lead to experi-
“why not mechanobiology.” mentally testable hypotheses. Development provides a
unique model with which to study mechanobiology
because the tissue and organ morphology can change
rapidly, and the effects of interventions are easily
OVERVIEW observed. Researchers have studied the mechanobiology
In the first five chapters of this book, mechanobiological of development using animal38,39 and even human
effects in different tissues are reviewed and discussed. As models.40,41
mechanobiology has taken root in various fields, the
theories and methods have evolved independently. It is Glen L. Niebur
often valuable to look across fields to understand new Tissue Mechanics Laboratory, Bioengineering Graduate
potential pathways and molecules that may play similar Program, Department of Aerospace and Mechanical
or differing roles in other systems. Across these chapters, Engineering, University of Notre Dame, IN, USA
we can see the recurring themes of understanding the
mechanical environment of the tissue and how that is
translated to the cells. Many themes are repeated across REFERENCES
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 SECTION I MECHANOBIOLOGICAL BASIS OF DISEASES

CHAPTER 1.1

Osteocyte Mechanobiology in Aging

and Disease
HENRY J. DONAHUE, PHD • MICHAEL J. FRIENDMAN, PHD •
DAMIAN GENETOS, PHD

1. INTRODUCTION necessary to serve the functions of other organs.6 As

Advances in healthcare enable longer lives, although the such, postnatal changes in bone mass, diameter,
proportion of quality living years has not kept pace.1,2 length, etc. were attributed to variations in hormonal
Thus a longer lifespan frequently engenders adverse ef- milieu or serum ion concentration, rather than a
fects, including loss of muscle mass and function (i.e., response to the mechanical loading environment.7
sarcopenia), idiopathic or senile osteoporosis, reduc- Motivated by serendipitous observations on the rela-
tions in joint mobility, and osteoarthritis. These disor- tionship between trabecular alignment in the femoral
ders promote physical inactivity, which reduces bone neck and the estimated principal stress directions
mass, microarchitecture, and strength, to increase frac- therein,8 skeletal adaptation as a consequence of me-
ture risk. Although fractures may be successfully chanical loading gained support and acceptance. Skel-
repaired, the adverse effects, such as decreased mobility etal adaptation to the mechanical environment may
and loss of independence, increase postfracture be most easily observed in conditions of disuse:
morbidity and mortality. In the United States, musculo- decreasing externally applied loadsdthrough casting,
skeletal diseases affect half of the persons aged 18 years limb immobilization, or microgravitydreduces bone
or older and three of four people over the age of 65 mass via periosteal and endosteal resorption.
years.3 Because women are at a greater risk of osteopo- Conversely, dynamically applied external loads in-
rotic fracture, osteoporosis diagnosis and treatment crease bone mass through concerted reductions in
often focus on women; however, mortality rates due osteoclastogenesis, conversion of bone-lining cells to
to fractures are greater in men within 1 year post frac- osteoblasts, and osteoblast formation and activation.9
ture.4 Moreover, the incidence of osteoporosis and in- Many bones are naturally curved, owing to the com-
creases in skeletal fragility are exacerbated by lifestyle bined influences of chondral growth and bone
choices, including type 2 diabetes, smoking, and low modeling.8 Applied loads transiently exacerbate their
physical activity. The current frequency of osteoporotic inherent curvature, generating compressive and tensile
fractures, projected future fracture rate, and associated stress gradients perpendicular to the bone surface. The
socioeconomic burden5 demand a means to reduce, if differential stresses promote site-specific bone resorption
not eliminate, osteoporosis. However, this is unlikely (at areas of tension) and formation (at compressive sites)
without a thorough understanding of the cellular pro- to reduce the magnitude of the applied strain. Yet any
cesses that contribute to, and are dysregulated by, aging compression or tension does not, nor should it, elicit a
and disease (Fig. 1.1.1). mechanoadaptive response. Rather than simply respond
to any nonzero strain, Frost proposed that time-averaged
2. MECHANICAL LOADING EFFECTS ON mechanical strains within or on a bone elicit a skeletal
BONE: MECHANOTRANSDUCTION response if they occur above or below a specific strain
Historically the skeleton was considered a mineral threshold.10 Analogous to using a thermostat to establish
reservoir, storing calcium and phosphorus until the temperature of a house, the mechanostat is a

Mechanobiology. https://doi.org/10.1016/B978-0-12-817931-4.00001-7
Copyright © 2020 Elsevier Inc. All rights reserved. 1
2 SECTION I Mechanobiological Basis of Diseases

FIG. 1.1.1 (A) Depiction of osteocyte morphology, lacunocanalicular organization, and interaction with other
osteocytes, surface osteoblasts, bone marrow, and the vasculature. From S.L. Dallas, M. Prideaux, L.F.
Bonewald, The osteocyte: an endocrine cell . and more, Endocr. Rev., 34 (2013), pp. 658e690. (B) Scanning
electron microscopic image of an acid-etched resin embedded murine osteocyte demonstrating its numerous
and tortuous canalicular network. From Lynda F. Bonewald, Osteocyte Biology In Robert Marcus, David
Feldman,... Jane A. Cauley Eds. Osteoporosis (Fourth Edition), (2013), pp. 209e234. (C) Mechanisms whereby
osteocytes regulate remodeling within and throughout a bone. From Sakhr, A. Murshid, The role of osteocytes
during experimental orthodontic tooth movement: A review, Archives of Oral Biology, 73, (2017), pp. 25e33,
2017.

theoretic set point that must be surpassed or unmet skeletal response to externally applied load include the
before initiating structurally appropriate alterations to nature of the strain (dynamic vs. static) and the time
bone mass and architecture. In this model, strains below over which it is applied.9
a set point promote osteoclast formation and bone Mechanotransduction refers to the complex interac-
resorption in order to reduce bone mass, thereby mini- tions whereby tissue-level strains are converted to local-
mizing the metabolic cost of unnecessary mass, and ized biophysical signals that ultimately promote skeletal
strains above the set point increase bone mass and the adaptation; per Duncan and Turner, it consists of four
strength to prevent pathologic fractures. Feedbackdin unique stages12:
the form of increased bone cross section that reduces (1) Mechanocoupling: Conversion of tissue-level loads
bone straindthereby limits the adaptive response.11 into localized mechanical signals perceived by
Beyond strain magnitude, other critical determinants of mechanosensitive cells.
 CHAPTER 1.1 Osteocyte Mechanobiology in Aging and Disease 3

(2) Biochemical coupling: Transduction of localized Because of their frequency and localization
mechanical signals into biochemical responses in throughout bone, osteocytes are currently considered
mechanosensitive cells. the primary mechanosensory cell within a bone. Based
(3) Signal transmission: From mechanosensory cell to on in vitro studies of osteoblast mechanosensitivity, os-
effector cell. teoblasts (and, by inference, osteocytes) require
(4) Effector cell response: Initiation of tissue-level >5000 mε in order to elicit second messenger activation
response. and gene transcription,18,19 the magnitude of which in-
Within this model, the strain induced by bone duces pathologic fracture. Therefore it has been pro-
bending during physical activity or exercise, approxi- posed that osteocytes possess an ability to amplify the
mately 400e3000 microstrain (mε), induces a plethora applied tissue-level strain into a localized strain suffi-
of biophysical signals within the bone tissue, consisting cient to elicit osteocyte activation.20 In this model, cana-
of interstitial fluid flow, direct mechanical strain, hydro- licular tethering elements, such as integrins and the
static pressure, and electrokinetic effects on bone hyaluronan-rich glycocalyx, connect the osteocyte cell
cells.13,14 Rapid responses (0 se1 min) to biophysical membrane to the extracellular matrix,21e24 which gen-
forces include the generation or liberation of second erates drag forces across the canalicular cell process to
messengers such as Ca2þ, cyclic AMP, diacylglycerol, amplify the tissue-level strain to a level sufficient to
and inositol triphosphate. Over the course of minutes induce an osteocytic response.
to hours, such messengers subsequently promote the Tremendous efforts have identified potential and
synthesis and secretion of autocrine/paracrine factors functional biochemical coupling mechanisms in bone.
(e.g., NO, prostaglandin [PG] E2, and ATP), kinase acti- Thus there are several mechanisms by which osteocytes
vation, cytoskeletal rearrangement, transcription factor may detect mechanical signals, and it is likely that most,
(nuclear factor [NF]-kB, b-catenin) activity, and gene if not all, of these mechanisms contribute to mechano-
transcription and translation. Concomitantly, gap junc- transduction in osteocytes.
tional intercellular communication (GJIC) and juxta- a) Integrins. Integrins are heteromeric membrane-
crine signaling amplifies the local signal among spanning proteins composed of a- and b-chains.
effector cells for initiation of appropriate tissue-level re- Integrins bind focal adhesion kinase (FAK) and
sponses (Fig. 1.1.2).15e17 transmit force to ERK, Src, and RhoA, leading to
stress fiber formation.25 Fluid-flow-induced shear

FIG. 1.1.2 (A) Mechanistic model for osteocyte mechanocoupling, wherein fluid shear stress and/or tissue
deformation promotes integrin engagement, ion channel activation and opening, and cytoskeletal alignment.
From M. Prideaux, D.M. Findlay, G.J. Atkins, Osteocytes: The master cells in bone remodeling, Curr Opin
Pharmacol 28 (2016), pp. 24-30. (B) Proposed influence of mechanical loading or disuse influences bone
modeling via sclerostin, osteoprotegerin, and Rankl. OPG, osteoprotegerin. T. Moriishi, R. Fukuyama, M. Ito, M.
Myazaki, Y. Kawai, H. Komori, T. Komori, Osteocyte Network: a Negative Regulatory System for Bone Mass
Augmented by the Induction of Rankl in Osteoblasts and Sost in Osteocytes at Unloading, PLoS ONE (2012).
4 SECTION I Mechanobiological Basis of Diseases

stress causes conformational changes in integrins mechanotransduction, but there has only been one
that likely activate downstream signaling.26 study describing their role in osteocyte mechano-
Furthermore, recent evidence suggests that pan- transduction: Miyauchi38 demonstrated that
nexin 1, which is implicated as an ATP-releasing gadolinium chloride blocked hypoosmotic stretch-
channel; the ATP-gated purinergic receptor P2RX7; induced increases in intracellular Ca2þ (Ca2þi) in
and the low-voltage transiently opened T-type cal- rat osteocytes, as well as inhibiting expression of the
cium channel Cav3.2 co-localize with b3 integrin pore-forming a1c subunit of the Cav1.2 calcium
attachment foci on osteocyte processes, suggesting a channel.
specialized mechanotransduction complex at these Similar to the case with gadolinium-sensitive
sites.27 Thus integrins are well positioned to stretch-activated channels, there are limited studies
contribute to osteocyte mechanotransduction not on the role of TRP channels in osteocyte mecha-
only through mechanocoupling of direct substrate notransduction. However, in a comprehensive
strain into an intracellular response but also as a study Lyons et al. demonstrated that TRPV4 was a
node that integrates multiple mechanocoupling critical component of the mechanism by which
mechanisms. fluid-flow-induced shear stress increases cytosolic
b) Cilia. Over the past several years, the role of cilia in Ca2þ levels, which then reduces sclerostin expres-
osteocyte mechanotransduction has begun to sion.39 As sclerostin inhibits bone formation, these
emerge. Cilia are long antennalike structures that results suggest that osteocytic TRPV is involved in
have been implicated in mechanotransduction in the bone anabolic effects of mechanical signals.
several cell types including osteocytes. It has been d) Gap junctions. Abundant in vitro data suggest that
demonstrated that lengthening primary cilia en- GJIC, largely through gap junction composed of
hances cellular mechanosensitivity. Osteocytic cells Cx43, plays a critical role in mechanotransduction
designed to have longer cilia displayed greater in bone. In vitro experiments, largely with osteo-
increased expression of COX-2 and osteopontin blasts, demonstrate that gap-junction-deficient cell
messenger RNA in response to fluid flow than did ensembles are less responsive to mechanical sig-
cells with normal length cilia.28 Furthermore, Lee nals40 and that mechanically induced signals travel
et al. demonstrated that the primary cilium function from bone cell to bone cell via gap junctions.41 This
as a mechanical and calcium signaling nexus in suggests that gap junctions sensitize bone to me-
osteocytes. Additionally, removal of polycystins chanical signals. However, in vivo studies do not
(Pkd1 and 2 in osteoblasts and osteocytes) or support the concept. For instance, bone from mice
ciliary proteins (Kif3a) impairs specifically deficient in osteoblast and osteocyte
mechanotransduction.29e31 However, while abun- Cx43 (Gja1) is actually more responsive to the
dant data suggest a role for cilia in osteocyte anabolic effects of mechanical loading42,43 and less
mechanotransduction, the biochemical coupling responsive to the catabolic effects of unloading.44,45
linking cilia movement to osteoanabolism remains The mechanism underlying these rather counterin-
elusive. Furthermore, cilia are located on cell bodies tuitive results is not known. However, a nonca-
rather than on dendritic processes, the more ideal nonical function of Cx43, that of a molecule that
location of mechanosensors in osteocytes. binds b-catenin, has been proposed.46,47
c) Membrane Channels. Osteocytic cells express Gap junction hemichannels may also play a role in
gadolinium-sensitive stretch-activated channels, bone mechanotransduction. Mechanical signals,
transient receptor potential (TRP) channels, and including fluid-flow-induced shear stress, increase
voltage-sensitive calcium channels.32e36 Brown the release of ATP48 and PGE249 via Cx43 hemi-
et al. elegantly demonstrated that Cav3.2 T-type channels and, in the case of PGE2 release, this may
voltage-sensitive calcium channels mediate shear- involve activated AKT kinase.50 However, one study
stress-induced cytosolic calcium in osteocytes has demonstrated that, at least in osteoblasts, fluid-
through a mechanism involving endoplasmic re- flow-induced PGE2 release occurs in Cx43-deficient
ticulum calcium dynamics,37 and Thompson et al. osteoblasts and is dependent on the expression of
found that the auxiliary a2d1 subunit of the Cav3.2 pannexin 1.51 Similarly, Genetos et al.48 found that
channel complex is involved in osteocytic stretch- osteocytes transfected with Cx43 small interfering
activated release of ATP. Regarding gadolinium- RNA were still capable of PGE2 release in response
sensitive stretch-activated channels, there is to purinoceptor activation, supporting a mecha-
considerable evidence for their role in osteoblast nism wherein ATP is released via Cx43 or
 CHAPTER 1.1 Osteocyte Mechanobiology in Aging and Disease 5

pannexins, which subsequently binds to purino- Unloading of bones because of disuse, weight loss,
ceptors to induce PGE2 secretion. or exposure to microgravity during spaceflight causes
Initial consideration of bone mechanobiology focused relatively rapid decreases in bone mass and mineraliza-
on the effects of diverse biophysical forces on osteoblast tion. Humans in space suffer bone loss of 0.5%e1.5%
or osteoclast function, as these are the primary effectors of bone mineral density (BMD) per month from expo-
of bone adaptation. Furthermore, osteocyte isolation pro- sure to microgravity, even when using a light exercise
cedures were time-consuming, and the ignorance or un- program of 3e4 days per week.63,64 Unloading from
availability of osteocyte markers prevented procurement immobilization also causes similar amounts of bone
of pure populations. The development of fluorescent re- loss in human and animal studies on Earth.56,65e67
porter mice and improved primary osteocyte enrichment Bones exposed to extended periods of unloading have
approaches have overcome this burden, enabling investi- increased numbers of empty lacunae and lacunae size,
gators to directly assay the effects of biophysical forces on increased porosity, and increased endosteal resorption.
osteocytes. Although osteocytes recapitulate many of the These changes make bone more susceptible to fracture
biophysical load-induced responses as observed in osteo- and less sensitive to changes in mechanical loading.
blasts, for example, rapid and transient increases in Ca2þi; Noting variations in lacunar shape, Marotti68 pro-
release of PGs, nitric oxide, and ATP; and OPG/RANKL, posed that osteocytes secrete an inhibitory factor that
there exist fundamental differences between osteoblastic limits bone deposition by nearby osteoblasts; this hy-
and osteocytic responses to in vitro mechanical loading. pothesis was refined by Martin,69 whose model pre-
For example, fewer primary osteocytes than primary oste- dicted tonic suppression bone-lining cell activation by
oblasts responded to shear stresses of 1.2e2.4 Pa by the said inhibitory factor. Furthermore, the funda-
mobilizing Ca2þi.52 Similarly, the molecular mecha- mental necessity of osteocytes for mechanosensing is
nisms whereby localized biophysical signals are trans- observed in their absence: targeted deletion of osteo-
duced into intracellular responses can alter as a cytes increases porosity and microdamage and de-
function of osteolineage state, with osteoblasts reliant creases bone formation, strength, and
on Cav1.2 calcium channels, and osteocytes reliant on mechanosensitivity.70 Sclerostin (product of the Sost
Cav3.2 calcium channels, to mobilize Ca2þi.53 Further, gene), an inhibitor of Wnt signaling expressed primarily
osteocyte-specific responses to mechanical load are in osteocytes, represents such an osteocyte-expressed in-
observed in the context of osteocyte-specific or -enriched hibitor of bone formation. Nonsense mutations in Sost
proteins, which are mechanoregulated in osteocytes, but produce the sclerosing bone dysplasia sclerosteosis,71
not mechanoregulated in osteoblasts. and a related syndrome, van Buchem disease, results
from the deletion of a noncoding distal enhancer.72e74
Murine models of Sost or ECR5 deletion phenocopy the
3. EVIDENCE FOR OSTEOCYTE-DIRECTED high bone mass phenotype observed in humans,75,76
SKELETAL RESPONSES enabling thorough evaluation of the molecular mecha-
Exercise has many long-lasting benefits to bone, nisms of Sost transcriptional regulation. The mechanical
including increasing bone volume, bone strength, and environment reciprocally influences sclerostin expres-
bone tissue quality.54e57 Bones respond to dynamic, re- sion, which decreases in limbs of loaded animals and
petitive loading with increased periosteal bone forma- increases following disuse.77,78 Load-induced changes
tion, bone mineralization, and tissue quality. This in Sost expression are required for skeletal adaptation:
response strengthens the areas of bone tissue exposed transgenic mice that increase Sost expression in response
to the highest amounts of loading.58 Periosteal bone to loading, rather than the natural downregulation that
formation increases linearly with increasing applied occurs after load, are incapable of an osteoadaptive
strain,59 loading frequency, and daily loading cycles.9 response,79 and pharmacologic or genetic inhibition
However, bone becomes desensitized to prolonged of Sost function protects mice from disuse-induced
loading, after approximately 40 high-magnitude bone loss.80,81 Mechanoregulated Sost expression ap-
loading cycles per day.60 Effects of increasing loading pears independent of the ECR5 enhancer, as, despite be-
on bone are also dependent on age and skeletal devel- ing mechanosensitive in vitro, ECR5/ mice
opment. Exercising when young and still undergoing demonstrate equivalent bone formation or loss
skeletal development offers the greatest benefits to compared to wild-type mice in response to loading or
bone mass and bone strength.61 Benefits to bone mass unloading, respectively.82 In contrast, the inhibitory ef-
from exercise decrease throughout adulthood such fect of parathyroid hormone (PTH) (1-34) requires
that, in the elderly, exercise only helps to attenuate ECR5.83
bone loss from aging.62 Osteocytes also have the ability to regulate bone
resorption by secreting receptor activator of NF-kB
6 SECTION I Mechanobiological Basis of Diseases

ligand (RANKL). RANKL is also secreted by chondrocytes the transcription factor b-catenin. Mice lacking b-catenin
and osteoblastic cells and is required for differentiation in osteocytes do not fully develop bones and die prema-
of osteoclast progenitor cells into osteoclasts.84 Osteo- turely,86 and heterozygous b-catenin osteocyte cKO mice
cytes also secrete osteoprotegerin (OPG) that works as reveal decreased trabecular bone volume and fail to lose
a decoy receptor,85,86 binding to RANKL and preventing cortical bone in response to unloading.100 Furthermore,
its osteoclastogenic effects. RANKL and OPG are closely constitutively active b-catenin in osteocytes has an
regulated, and the RANKL/OPG ratio is used as an indi- osteoanabolic effect resulting from the increasing bone
cator of osteoclastogenic activity.87 Osteocyte apoptosis formation and osteoblast differentiation.101 Yet, other
induces RANKL and decreases OPG expression in neigh- factors that exert osteotropic effects, beyond Wnt
boring osteocytes, thereby promoting pro-resorptive signaling, are capable of activating b-catenin signaling
adaptation.88 Thus reciprocal modulation of OPG and and eliciting osteoanabolic effects: load-induced b-cate-
RANKL by osteocytes provides a means to target bone, nin signaling in osteocytes is also driven through auto-
damaged from overuse, for replacement and subse- crine PGE2 function102 and PTH independent of
quent reduction of fracture risk.89,90 Lrp5,103e105 as well as fibroblast growth factor
In addition to regulating bone tissue remodeling, os- signaling.106
teocytes possess the capacity to remodel the perilacunar Osteocytes release many factors that work together to
area in which they reside. Perilacunar remodeling al- regulate bone remodeling. Communication between
lows for more rapid mobilization or storage of minerals neighboring osteocytes and the extracellular environment
from bone, as the osteocytes’ perilacunar networks is crucial for osteocytes to release and propagate these sig-
contain far more surface area of mineralized tissue nals in response to changes in mechanical loading. For
than the periosteal and endosteal bone surfaces. example, skeletal response to increases in mechanical
Enlarged lacunae, indicative of perilacunar bone resorp- loading is independent of osteocyte density in areas of
tion, are observed in patients with mineral metabolism maximum loading, supporting the concept that signal
disorders,91 in rats exposed to unloading during space- propagation from a modest few mechanoactivated osteo-
flight,92 in hibernating animals,93 and in lactating ani- cytes is necessary to promote skeletal adaptation.
mals.94,95 Perilacunar remodeling is activated through Membrane-bound connexins help osteocytes to propa-
tumor growth factor (TGF)-b96 or PTH95,97 signaling gate signals released in response to mechanical loading.
and, thus, is sensitive to both changes in both the hu- Mechanical loading increases expression and activation
moral milieu (PTH) and factors released from bone ma- of connexin 43, allowing for greater release of signals
trix during resorption (TGF-b, PTH-related protein such as PGE2 that affect bone metabolism. Deletion of
[PTHrP]). Furthermore, changes in lacuna size from per- connexin 43 in osteocytes causes early onset osteopenia,
ilacunar remodeling affect fluid-flow-induced shear weak bones, and high porosity, properties usually seen in
stress forces sensed by osteocytes.98 Thus conditions older bones or following increased osteocyte
that change the lacuna size can also change the mecha- apoptosis.107,108 This change in phenotype is not seen
nosensitivity of the bone. in osteocytes with normal connexin 43 hemichannels
To limit osteocytic influence on bone remodeling to and defective connexin 43 gap junctions,109 suggesting
a few scant proteinsesclerostin, OPG, and RANKLeor hemichannels play a predominant role in the response
via perilacunar remodeling minimizes the tremendous to changes in mechanical loading. Connexin 43-
influence that osteocytes have on skeletal development deficient osteocytes are more responsive to increases in
and repair. Dickkopf-1 (Dkk1) functions similar to scle- mechanical loading, increasing production of PGE2 and
rostin to inhibit bone formation by inhibiting activation decreasing Sost expression to a greater extent than in
of the Wnt pathway. However, the absence of Dkk1 does wild-type osteocytes.110 Connexin 43-deficient osteocytes
not influence bone mass and strength to the extent are less responsive to unloading, although these bones
observed in SostKO mice: neither osteocytic Dkk1 cKO already have signs of bone loss seen after wild-type bones
mice nor mice in which Dkk1 is systemically neutralized are exposed to microgravity.44,45 Yet, while cell-cell
by an antibody reveal a robust skeletal response to these communication, or release of paracrine factors, is attrib-
interventions, in contrast to the dramatic skeletal pheno- uted to Cx43 function in bones, evidence indicates that
type in animals deprived of sclerostin expression or func- the Cx43 carboxy terminus, independent of gap junction
tion. Instead, absence of Dkk1 expression or function signaling, is obligate for normal skeletal development.47
increases sclerostin expression, indicating a compensa- Alternately, direct cell-cell interactions, rather than
tory mechanism between the two Wnt antagonists.99 secretion of soluble factors, reveal tremendous influ-
Osteoanabolic effects of Wnt signaling appear to require ence on skeletal form and function; this is observed,
 CHAPTER 1.1 Osteocyte Mechanobiology in Aging and Disease 7

for example, in the context of Notch signaling, which is many studies designed to interrogate the effect of chro-
activated by direct interactions between a Notch ligand nologic age on osteoanabolic response to loading. Yet,
and a Notch receptor in neighboring cells. Notch rather than suggest failures in various models, the
signaling imparts osteolineage-specific effects on the inability to answer such a facile question may underlie
skeleton: in osteoprogenitors or immature osteoblasts, the complexity of organism aging viz. redundancy in
activation of Notch signaling through overexpression mechanoresponsive or mechanoadaptive mechanisms.
of the Notch1 intracellular domain (NICD) reduces Indeed, rather than posit a specific defective signaling
osteoblast differentiation, whereas in osteocytes the pathway in osteocytes as the cause for primary osteopo-
same model increases cancellous bone volume through rosis, it is necessary to consider osteoporosis as the
increased bone formation and reduced bone resorp- result of changes in the interaction of osteocytes with
tion.111 Notch activation in osteocytes promotes Wnt their matrix, osteocyte abundance, the hormonal
signaling through reductions in expression of the Wnt milieu, and cell-autonomous deficits in osteocyte func-
antagonists Sost and Dkk1; mice expressing constitu- tion (Fig. 1.1.3).
tively active b-catenin show increased Notch receptor
expression,101 and osteocytic Notch activation pro- 4.1. Osteocyte Number
motes Wnt signaling, creating a positive feedback be- The ability to perceive biophysical signals and transduce
tween Notch and Wnt signaling.112 them to tissue-level responses is predicated upon the
presence of an osteocyte, such that alterations in osteo-
cyte number may contribute to osteoporosis. Indeed, re-
4. OSTEOCYTES, ductions in osteocyte number and lacuna are observed
MECHANOTRANSDUCTION, AND AGING in human specimens and murine models, although
The existence of skeletal involution with increasing this highly depends on the anatomic location and
chronologic age is without dispute, but attributing type of bone (cortical vs. trabecular). For example, oste-
this tissue-level response to deficits in specific cells, or ocyte lacunar density decreases exponentially with
specific signaling mechanisms, is nigh impossible advancing chronologic age in human mid-diaphyseal
owing to the rich diversity of changes in, for example, cortical bone in specimens from both men and
the hormonal milieu, attenuation of cell function, and women,119 whereas lacunar number in iliac trabecular
increases in the inflammatory environment. Murine bone decreases linearly120; yet it was reported that in
models of inbred mice can identify quantitative trait the femoral head trabecular bone, there is no decrease
loci to map genes that influence BMD or other parame- in osteocyte density until 70 years of age, after which
ters113 or adaptation to mechanical loading,114 either a sharp decline in osteocyte lacunar density appears.121
confirming candidate genes or identifying novel genes Osteocyte density is also a function of distance from
for susceptibility to osteoporosis. Similarly, human ge- the bone/haversian surfacesdthat is, as a function of
netic diseases can reveal novel genes involved in causing bone agedwith superficial osteocytes (<25 mm from
osteoporosis (e.g., LRP5 or CYP17), but such variants surfaces) resistant to age-related decreases in osteocyte
that have a large effect are rare, whereas common allelic density, whereas osteocyte density in deep bones
variants have a small effect.115 Provided the evidence (>45 mm from surfaces) decreases with age in both
for skeletal adaptation to a changing mechanical envi- men and women.122 Osteocyte density in both superfi-
ronment, the question whether age influences the ca- cial and deep bones is reduced in vertebral iliac trabec-
pacity of an osteoanabolic response to age, seemingly ular bone from individuals with osteoporotic
a simple question to resolve with murine models, has fractures,119,123 and the endosteal cortex appears more
inconsistent results. For example, Rubin et al.116 re- sensitive to age-dependent osteocyte loss than the peri-
ported that greater strain was required for the initiation osteal cortex.124 As osteocytes are mechanosensory
of an osteoanabolic response in the ulna of aged (19- cells, their reduction secondary to aging removes a
month-old) turkeys versus younger (9-month-old) tur- means through which skeletal integrity may be interro-
keys, whereas Järvinen et al.117 found no overt effect of gated and improved.
age on the influence of treadmill-running on the
femoral neck, and Brodt and Silva118 reported 4.2. Changes in Osteocyte
enhanced endocortical response to axial tibial compres- Microenvironment
sion in aged mice. Stark differences in animal models, The mechanosensory role of osteocytes is grounded in
age ranges, experiment duration, and method of me- localized biophysical signals that are engendered during
chanical stimulus prevent direct comparison among locomotion or exercise. As described earlier, such signals
8 SECTION I Mechanobiological Basis of Diseases

FIG. 1.1.3 Age-related changes in osteocyte networks. (A) Scanning electron microscopic images of
acid-etched resin embedded human bone sections, revealing decreased osteonal width, osteocyte
frequency, and canaliculi in aged bone. From L.M. Tiede-Lewis, S.L. Dallas, Changes in the osteocyte
lacunocanalicular network with aging, Bone 122 (2019), pp. 101-113. (B) A model for osteocyte-mediated
effects of age on bone quality and fragility. From B. Busse, D. Djonic, P. Milanovic, M. Hahn, K. Püschel, R.O.
Ritchie, M. Djuric, M. Amling, Decrease in the osteocyte lacunar density accompanied by hypermineralized
lacunar occlusion reveals failure and delay of remodeling in aged human bone, Aging Cell 9 (2010), pp. 1065-
1075From B. Busse, D. Djonic, P. Milanovic, M. Hahn, K. Püschel, R.O. Ritchie, M. Djuric, M. Amling, Decrease
in the osteocyte lacunar density accompanied by hypermineralized lacunar occlusion reveals failure and delay of
remodeling in aged human bone, Aging Cell 9 (2010), pp. 1065-1075. (C) Alterations in osteocyte
microenvironment via perilacunar remodeling associated with pharmacotherapy, disease, and age. From L.F.
Bonewald. (2011) Osteocyte Mechanosensation and Transduction. In: Noda M. (eds) Mechanosensing Biology.
Springer, Tokyo, 2011, pp. 141-155.

include the shear stresses of interstitial fluid flow across canaliculi and thereby generating a “wall,” a “sink,” or
the plasma membrane of osteocyte dendrites and cell a “reservoir” to mitigate interstitial fluid flow and
body, microperturbations in osteocyte plasma mem- mass transport within bone.125 Thus microdamage
brane integrity, and tethering of osteocyte dendritic pro- effectively decreases the concentration of osteotropic
cesses to the canalicular wall.21,23 Thus it is axiomatic agents, from the vasculature or osteocytes within the
that age-related alterations to the microenvironment in LCN to osteocytes distal from the microdamage.
which an osteocyte resides would subsequently alter Furthermore, compromised transport and exchange of
the biophysical signals experienced by an osteocyte. nutrients in response to microdamage would decrease
The integrity of the lacunocanalicular network osteocyte viability, as is observed in vivo.126 Occlusion
(LCN) is diminished by microdamage, severing of the LCN can also occur with aging, a process termed
 CHAPTER 1.1 Osteocyte Mechanobiology in Aging and Disease 9

micropetrosis by Frost, wherein osteocyte death promotes The osteocyte morphology appears to depend on the
occlusion of lacunae with hypermineralized calcium anatomic location, age, hormonal status, and mechani-
phosphate, which could further cause deteriorations cal loading environment. In humans and rodents, oste-
in canalicular fluid flow.124 Even in the absence of ocyte morphology changes from relatively flattened to
lacunar occlusion, microstructural changes in the LCN more spherical.135,136 Similarly, osteocytes within ro-
negatively impact fluid flow in response to loading. dents demonstrate an elongated morphology, whereas
Strain amplification within osteocyte lacunae is influ- calvarial osteocytes are more spherical.137 Differences
enced by pericellular lacunar tissue modulus, with pre- in osteocyte morphology may result from the mechan-
dicted maximum perilacunar strain increasing as the ical loading environment: the long axis of fibular osteo-
modulus of the perilacunar matrix decreases; cytes align parallel to the principal loading direction,
conversely, maximum perilacunar strain decreased as whereas calvarial osteocytes do not appear to align
perilacunar matrix modulus increased.127 Furthermore, with any loading direction. In human osteonal bone,
microstructural changes, such as increases in vascular osteocyte lacunae are aligned with collagen fiber
porosity, reductions in trabecular number, and in- orientation,138e140 suggesting that osteocyte orienta-
creases in trabecular separation, in response to ovariec- tion within a lacuna occurs during the osteoblast-to-
tomy fundamentally reduce load-induced interstitial osteocyte transition.141 Hormonal cues also influence
fluid flow,128 indicating that changes in micro- and osteocyte morphology: for instance, compared to virgin
nanostructural properties of bone can negatively mice, the lacunar volume of lactating mice is increased,
influence osteocyte mechanosensation. Estrogen defi- indicating perilacunar remodeling,133 and exercise-
ciency influences strain distribution across osteocytes induced changes in PTH secretion promote changes in
more than osteoblasts, exerting acute increases yet sus- lacunar volume.134
tained decreases on applied strain129 resulting from To date, that osteocyte morphology influences
changes in tissue stiffness and mineral content.130 mechanosensation and downstream effects on remod-
Thus localized changes in mineral density, tissue eling, bone strength, etc. is inferred from changes in
composition, and even LCN tortuosity immediately sur- bone material and structural properties. Direct demon-
rounding the osteocyte130,131 may serve as a means to stration of altered osteocyte morphology to a given me-
sensitize or diminish osteocyte mechanoresponsiveness chanical load is light, although Bacabac et al.142
via osteocytic perilacunar remodeling. Indeed, Hesse demonstrated that round, partially adherent MLO-Y4
et al.132 used synchrotron radiation phase-contrast osteocytes were more mechanosensitive than flat,
nanoecomputed tomography to reveal a gradient of adherent osteocytes. Nonetheless, with the possible
bone tissue mass density that decreases from the pore- exception of hormonal influence on osteocyte
matrix interface into the tissue. Hemmatian et al.133 morphology, whether changes in osteocyte morphology
used virgin or lactating mice to evaluate the influence are the cause, or the consequence, of changes in bone
of perilacunar remodeling on the activation of b-cate- health requires more careful and considerate
nin, as a marker of mechanotransduction, and found investigation.
that load-induced stabilization of b-catenin was greater
in the lactating mouse than in the virgin mouse, sug- 4.3. Cell-Autonomous Alteration of
gesting that increased lacunar volume enhances the Osteocyte Function
response to mechanical loading. Although lacunar vol- The reductions in bone mass, density, and microarchi-
ume was interrogated as a marker of perilacunar remod- tecture that are observed as a result of aging are pro-
eling, other aspects of the lacuna-matrix interface, such posed to result, in part, from decreased
as mineral-matrix ratio and carbon-phosphate ratio, mechanosensing. Although there is sufficient evidence
were not studied. Conversely, exercise induces perilacu- (detailed earlier) that applied strains or interstitial fluid
nar remodeling; Gardinier et al.134 reported that perila- flows can be reduced secondary to increases in vascular
cunar remodeling occurs during exercise, with porosity or lacunocanalicular tortuosity, there is little
alterations in mineral-matrix or carbonate-phosphate direct evidence regarding whether osteoblasts or osteo-
ratio observed within 0e5 mm from osteocyte lacunae cytes per se are less capable of perceiving a given load.
yet disappearing with greater radial distance from Donahue et al.143 observed a modest decrease in the
lacunae. Thus there appears to be a finely regulated percent of aged rat osteoblastic cells that responded to
interaction between lacunocanalicular properties as oscillatory fluid flow with an increase in cytosolic
both a predictor of osteocyte mechanosensation and Ca2þ levels. Sterck et al.144 evaluated the influence of
the result of osteocyte mechanoresponsiveness. donor cell age on mechanically induced responses,
10 SECTION I Mechanobiological Basis of Diseases

finding that PGE2 and PGI2 release increased with bone is not derived from bone cells, instead it results
donor cell age, and Bakker et al.145 reported that pulsa- from the clonal plasma cell malignant neoplasm, which
tile fluid flow is able to induce the synthesis and release subsequently causes osteolytic bone lesions in >80% of
of second messengers (nitric oxide, PGE2) from osteo- patients with myeloma.153 Osteolytic bone lesions are
porotic or osteoarthritic donors. Similarly, relative in- also observed in breast and lung cancers that have
creases in cytosolic Ca2þ levels and cfos transcription metastasized to the skeleton, and mixed osteoblastic/
in fluid flow across osteoblasts are no different in osteolytic lesions are most commonly observed in met-
response to loading in osteoblasts from young versus astatic prostate cancer (PCa). Complications of skeletal
senescent mice, whereas absolute changes are affected metastasis, termed skeletal related events (SREs),
as a function of age.146 include pathologic fracture, hypercalcemia, spinal cord
Thus rather than the decreased capacity of osteocytes compression, and chronic pain. Beyond the debilitating
to perceive a given stimulus, it is perhaps more likely impact on quality of life, the incidence of SREs nega-
that other age-related changes in cell function tively predicts survival: 5-year survival rates for PCa
contribute to loss of bone with age. For example, there are 56% after skeletal metastasis, but the survival rate
is a loss of osteoprogenitors with age as mesenchymal plummets to <1% with metastasis and an SRE.154 The
stem cells shift toward adipogenesis, increased osteo- events involved in cancer metastasis to the skeleton
blast apoptosis reduces the duration of bone-forming involve disseminated tumor cells (1) colonizing the
capacity, and increased marrow adiposity enhances sup- bone microenvironment and (2) adapting to the new
pression of bone formation through reductions in environment, avoiding immune surveillance, and
osteoblastogenesis and mineralization.147 entering a state of dormancy; (3) reactivating in
Alternately, senescence of osteoblasts or osteocytes response to as-yet-unknown cues, thereafter prolifer-
can contribute to tissue dysfunction.148 Markers of cell ating and forming micrometastases; and (4) growing
senescence, including gene transcripts (p16Ink4, uncontrollably, independent of the microenvironment
Cdkn1a/p21, and p53), telomere shortening, and (reviewed in Ref. 155) (Fig. 1.1.4).
senescence-associated secretory phenotype, are Provided that osteocytes are sentinels against remod-
observed in osteoblasts and osteocytes from older eling, and the proclivity and propensity for cancer to
(24 months) mice relative to young (6 months) mice, subvert normal homeostatic processes, it is logical to
with greater age-related increases observed in osteocytes suggest that tumor colonization, dormancy, and activa-
relative to osteoblasts.149 Senescence is no longer an un- tion involve, if not require, altered osteocyte function.
avoidable consequence of aging, as genetic150 and phar- The most direct way to alter osteocyte function is to pro-
macologic151,152 approaches to reduce or eliminate mote their death, and osteocyte death is implicated in
senescent cell populations revert age-related pathologic disseminated tumor cell colonization and adaptation:
conditions. Indeed, genetic or pharmacologic ablation increased frequency of apoptotic osteocytes is observed
of senescent cells in old mice increases bone mass and in individuals with MM156 and selective depletion of
strength resulting from decreased endocortical bone osteocytes supports MM colonization of bone and tu-
resorption and increased endocortical bone forma- mor growth.157 Whether the oppositedmaintaining
tion.148 That bone resorption was reduced after senes- osteocyte viability pharmacologically or through other
cent cell ablation without concomitantly reducing meansdreduces tumor burden is under active investi-
bone formation is in contrast to current antiresorptive gation. Bisphosphonates reduce osteoclast formation,
therapies (bisphosphonates, anti-RANKL antibody, or but also exert antiapoptotic effects on osteocytes
estrogen), which reduce both bone formation and in vitro158 and in animal models of osteoporosis159,160
resorption. Because the currently identified senolytic through a molecular mechanism involving Cx43 hemi-
agents are already FDA-approved, and a monthly channels and ERK1/2.161 Provided that bisphospho-
dosing of senolytics was sufficient to reverse changes nates differentially influence apoptosis in osteocytes
due to age, such approaches portend their use in the versus osteoclasts, an unresolved question is to what
treatment of age-related bone loss. extent the beneficial effects of bisphosphonates for indi-
viduals with MM is related to osteocyte survival rather
than reduced osteoclast activity. The discovery of
5. OSTEOCYTES AND DISEASE bisphosphonates, which maintain osteocyte viability
5.1. Cancer without influencing osteoclast activity,162e164 provides
The skeleton is a common site for metastasis of other an opportunity to evaluate such a scenario. Other
cancers: multiple myeloma (MM) also begins in the agents that promote osteocyte viability, such as the
 CHAPTER 1.1 Osteocyte Mechanobiology in Aging and Disease 11

FIG. 1.1.4 Proposed model for osteocyte interaction with cancer cells. Red arrows indicate direct effects on
cancer cells, whereas green arrows indicate indirect effects mediated via osteoblasts or osteoclasts. From M.
Zhang, J. Dai, E.T. Keller, Multiple Roles of Osteocytes in Bone-Associated Cancers, Reference Module in
Biomedical Sciences 2019, 10.1016/B978-0-12-801238-3.11246-2

proteasome inhibitor bortezomib165 and PTH (1-34), in patients with MM and correlate with advanced dis-
are under investigation as a means of minimizing the ease172 and the Sost expression is increased in response
skeletal impact of MM or skeletal complications to to MM-osteocyte interactions,171 suggesting that
radiotherapy.166,167 manipulation of Sost expression or function may pro-
Communication between osteocytes and neigh- vide a means to reduce MM tumor burden and impact.
boring cells is also subverted during tumor metastasis Indeed, Sost deletion or pharmacologic inhibition of
to bone and growth therein, which has recently been sclerostin reduced MM-induced osteolysis and bone
elegantly reported in the context of MM signaling loss, although it did not decrease tumor volume,173
through Notch receptors and breast cancer communica- providing a promising opportunity to mitigate the skel-
tion through connexin 43 gap junctions. Compelling etal sequelae of MM.
evidence demonstrates that MM colonization of bone Osteocyte functiondor, minimally, markers of oste-
and adaptation therein involves reciprocal interactions ocyte functiondis also implicated in tumor burden and
between MM cells and osteocytes. Notch signaling is growth in PCa that has metastasized to the skeleton.
enhanced in MM cells,168e170 and direct coculture of Prostate carcinoma stimulates bone formation, both
MM cells with MLO-A5 osteocytes promotes osteocyte through the secretion of pro-osteogenic factors such as
apoptosis via Notch signaling.171 As in other studies, Wnts and through osteomimicry, wherein cancer tumor
osteocyte apoptosis increased osteoclastogenesis cells can secrete matrix, mineral, and osteotropic fac-
through enhanced Rankl expression and reductions in tors, as well as respond to osteotropic factors. For
Opg. Furthermore, MM cells increase Sost expression example, expression of the Wnt antagonist Dkk1 is
and decrease Wnt signaling in osteocytes, leading to re- observed in focal lesions of MM cells,174 sclerostin is
ductions in osteoblastogenesis. Reciprocally, Notch secreted by breast cancer cells,175 and increased b-cate-
activation in MM cells by osteocytes promotes MM nin levels are observed in individuals with PCa.176,177
cell proliferation. Serum sclerostin levels are increased Functionally, overexpressing Sost, but not Dkk1, in
12 SECTION I Mechanobiological Basis of Diseases

osteolytic PC3 cells reduces osteolysis in xenograft- (Gja1D130-136), which reduces both GJIC and hemichan-
derived tumor lesions,178 whereas increasing Wnt nel activity, relative to control animals. In contrast, tu-
signaling in mixed osteolytic/osteoblast C4-2B PCa mor growth in osteocytic Gja1R76W mice, which can
cells, through knockdown Dkk1, shifts tumor pheno- form hemichannels but not participate in GJIC, was
type toward osteolysis.179 Similarly, osteocyte-derived phenotypically similar to wild-type animals. Further-
GDF15, a member of the TGF-b superfamily, promotes more, the inhibitory effect of zolendronate on tumor
PCa metastasis to the skeleton.180 growth was absent in osteocytic Gja1 cKO or Gja1D130-
136
Disseminated tumor cell adaptation to the bone mice but not Gja1R76W animals, indicating a specific
microenvironment also subverts gap junctions. Con- inhibitory role of osteocytic Cx43 hemichannel-
nexins are considered antitumorigenic, as loss of con- mediated ATP release in tumor metastasis and growth
nexin 43 expression is a marker for breast tumors,181 in the skeleton.185
and connexin expression and intercellular communica-
tion are reduced during tumorigenesis, whereas trans- 5.2. Vascular Health
fection of cancer cells with connexins reduces cell A consequence of multicellular growth is the insuffi-
proliferation.182 Connexins exert multipronged influ- ciency of simple diffusion to provide sufficient oxygen
ences on tumor growth via GJIC, hemichannels, and for host respiration; oxygen delivery, as well as nutrient
channel-independent connexin function. Wang provision and waste removal, is provided by the
et al.183 found that Ca2þi-dependent transcription fac- vascular system. Bone development, homeostasis, and
tor activation of NFAT and MEF2 was enriched in breast repair are each exquisitely coupled to the vasculature
carcinomas that have metastasized to bones. Such ob- (reviewed in Ref. 186). Furthermore, blood vessels pro-
servations were recapitulated in both in vivo and vide the necessary conduit for calcium and phosphate,
ex vivo models of bone metastasis, such that inhibition liberated from the matrix, to reach target tissues for ho-
of calcium signaling with dominant-negative calci- meostatic function. A sufficient vasculature is funda-
neurin or calmodulin-dependent protein (CaM) kinase mental to osteogenesis, but vessel function is often
II function eliminated tumor colonization of bone. compromised by calcification as a consequence of aging
Cx43 expression was greater in skeletally metastatic and lifestyle. Calcification may occur throughout the
breast carcinomas, correlated with calcium-dependent vascular tree, with distinct molecular origins and path-
transcription factor enrichment, and established cal- ologic consequences. For example, calcification of
cium flux from osteogenic to tumor cells; reducing medial arteries increases vessel stiffness and decreases
Cx43 expression or inhibiting GJIC with carbenoxolone compliance, thereby impairing Windkessel physiology
reduced bone colonization and skeletal tumor burden. and increasing vessel pressure and cardiac work-
This association between connexins, GJIC, and calcium- load.187,188 Similarly, calcification of atherosclerotic
dependent transcription factor enrichment was not plaques reduces vessel lumen size and increases tissue
unique to breast carcinoma, as prostate carcinoma ischemia and thromboembolic events,188 whereas
and PCa cell lines demonstrated equivalent interactions aortic valve calcification reduces valve leaflet mobility
between calcium signaling, Cx43 expression, and tumor and impairs leaflet closing, promotes left ventricular hy-
burden. Notably, mesenchymal stem cells, but not oste- pertrophy, and results in aortic valve regurgitation.189
ocytes, were capable of altering calcium signaling in tu- Ectopic calcification within the vasculature and cardiac
mor cells, further suggesting that unique bone valves was long considered to be a passive, degenerative
microenvironments contribute to tumor cell coloniza- process. However, the biochemical and structural similar-
tion and survival. The influence of connexins on tumor ity of these ectopic calcifications to orthotopic bone
cell adaptation to the skeletal microenvironment is not hinted that an active process may be involved (Fig.
restricted to GJIC, as connexin hemichannels are also 1.1.5).190e192 This was initially confirmed in the study
implicated as mediators of tumor fate. Osteocytic hemi- by Boström et al.,193 wherein the potent osteogenic
channel opening in response to fluid shear stress48 or morphogen BMP-2 (then known as BMP-2a) immuno-
the bisphosphonate alendronate184 promotes the localized within human atherosclerotic lesions. Because
release of cytosolic ATP, which reduces the migratory ca- BMP-2 stimulates orthotopic calcification by increasing
pacity of breast cancer cells and reduces tumor growth. matrix synthesis, this finding suggested an active, cell-
The antitumor effect of osteocytic Cx43 appears mediated process for vessel calcification. Further studies
restricted to hemichannels: growth of mammary carci- revealed the presence of Wnts, osteoblast-related tran-
noma cells in the skeleton is greater in mice lacking scription factors Runx2194 and Msx2,195 and matrix ves-
osteocytic Gja1 or expressing dominant-negative Cx43 icles within arterial calcifications,196,197 suggesting that a
 CHAPTER 1.1 Osteocyte Mechanobiology in Aging and Disease 13

FIG. 1.1.5 Osteogenic networks implicated in vessel wall calcification. A.S.A. Bardeesi, J. Gao, K. Zhang, S.
Yu, M. Wei, P. Liu, H. Huang, A novel role of cellular interactions in vascular calcification, J Transl Med
(2017) 15: 95. https://doi.org/10.1186/s12967-017-1190-z AGE, advanced glycation end product; BMP, bone
morphogenetic protein; DKK-1, dickkopf-1; DMP-1, dentin matrix protein 1; FGF23, fibroblast growth factor
23; IGF-1, insulinlike growth factor 1; M-CSF, macrophage colony-stimulating factor; MEPE, matrix
extracellular phosphoglycoprotein; OB, osteoblast; OC, osteoclast; OCy, osteocyte; OPG, osteoprotegerin;
PGE2, prostaglandin E2; RANKL, receptor activator of nuclear factor kB ligand; SFRP-1, secreted frizzled-
related protein 1.

subpopulation of cells within the vessel wall are capable heterogeneous group of valve interstitial cells contains
of active mineralization processes described in chondro- mesenchymal precursors with osteogenic and chondro-
cytes and osteoblasts.188,193 Altering Wnt signaling, genic potential.200,201
through the overexpression of the Wnt antagonist sclero-
stin or the addition of recombinant sclerostin, attenuates
angiotensin-II-induced atherosclerosis.198 A similar oste- 6. CONCLUSIONS AND FUTURE
ogenic mechanism is involved in cardiac valve calcifica- DIRECTIONS
tion, wherein the Wnt/Lrp5/b-catenin signaling Although clearly the most abundant cell in bone, osteo-
pathway actively promotes calcium deposition. Caira cytes have been understudied until the past decades,
et al.199 revealed increased Lrp5 and osteogenic marker owing largely to technical reasons. However, recent ad-
gene expression in calcified aortic valves compared vances in cell isolation, the characterization of specific
with control valves. These results may at least partially gene transcripts in osteocytes, and the use of novel mu-
explain the increased risk of cardiovascular disease in in- rine models of altered osteocyte gene expression have
dividuals receiving antisclerostin antibody to treat osteo- revealed the central role that osteocytes play in surpris-
porosis. However, serum sclerostin levels are higher in ingly diverse areas of bone, and possibly host, meta-
individuals with cardiovascular disease, emphasizing bolism. Osteocytes not only are the orchestrator of
the complicated nature of sclerostin function in nonbone osteoblast and osteoclast activity in response to mechan-
tissue. ical, hormonal, or cytokine signals but also clearly play a
For active ectopic calcification to occur, these ectopic central role in bone cancer, vascular disease, and age-
sites must contain osteoblast(-like) cells. Both the related bone loss. However, there remain clear gaps in
vasculature and cardiac valves contain resident progen- our understanding of osteocyte biology. For example,
itor cells capable of osteogenic differentiation. Boström osteocyte function in osteoimmunology is poorly under-
et al.193 isolated a subpopulation of aortic medial cells, stood, the interactions of osteocytes with the peripheral
termed calcifying vascular cells (CVCs), that express and central nervous systems have only been
osteoblastic markers and are capable of osteogenic dif- suggested, and the role of osteocytes in development,
ferentiation in vitro. A similar effector cell, the adventi- maintenance, and activation of stem cell niches under
tial myofibroblast (pericyte), has been implicated in health and disease is unresolved. Furthermore, the role
medial artery calcification, as occurs in diabetic patients. that genetic variability plays in osteocyte biology and
Both CVCs and adventitial myofibroblasts express the how osteocytes may be exploited to regenerate lost
smooth muscle cell markers SM22 and a-SMA, which bone tissue and mass after injury or aging have not
are routinely used as the basis for confirmation of the been explored. These are just some of the gaps in osteo-
SMC phenotype for ex vivo cultures. Similarly, the cyte biology whose questions we avidly await answers.
14 SECTION I Mechanobiological Basis of Diseases

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had received the usual notes from the Treasury, begging them to be
in their places and to vote against Mr. Fox’s motion. It was asserted
by Mr. Hastings, that, early in the morning of the very day on which
the debate took place, Dundas called on Pitt, woke him, and was
closeted with him many hours. The result of this conference was a
determination to give up the late Governor-General to the vengeance
of the Opposition. It was impossible even for the most powerful
minister to cany all his followers with him in so strange a course.
Several persons high in office, the Attorney-General, Mr. Grenville,
and Lord Mulgrave, divided against Mr. Pitt. But the devoted
adherents who stood by the head of the government without asking
questions were sufficiently numerous to turn the scale. A hundred
and nineteen members voted for Mr. Fox’s motion; seventy nine
against it. Dundas silently followed Pitt.
That good and great man, the late William Wilberforce, often
related the events of this remarkable night. He described the
amazement of the House, and the bitter reflections which were
muttered against the Prime Minister by some of the habitual
supporters of government. Pitt himself appeared to feel that his
conduct required some explanation. He left the treasury bench, sat
for some time next to Mr. Wilberforce, and very earnestly declared
that he had found it impossible, as a man of conscience, to stand
any longer by Hastings. The business, he said, was too bad. Mr.
Wilberforce, we are bound to add, fully believed that his friend was
sincere, and that the suspicions to which this mysterious affair gave
rise were altogether unfounded.
Those suspicions, indeed, were such as it is painful to mention.
The friends of Hastings, most of whom, it is to be observed,
generally supported the administration, affirmed that the motive of
Pitt and Dundas was jealousy. Hastings was personally a favourite
with the King. He was the idol of the East India Company and of its
servants. If he were absolved by the Commons, seated among the
Lords, admitted to the Board of Control, closely allied with the
strong-minded and imperious Thurlow, was it not almost certain that
he would soon draw to himself the entire management of Eastern
affairs? Was it not possible that he might become a formidable rival
in the cabinet? It had probably got abroad that very singular
communications had taken place between Thurlow and Major Scott,
and that, if the First Lord of the Treasury was afraid to recommend
Hastings for a peerage, the Chancellor was ready to take the
responsibility of that step on himself. Of all ministers, Pitt was the
least likely to submit with patience to such an encroachment on his
functions. If the Commons impeached Hastings, all danger was at an
end. The proceeding, however it might terminate, would probably
last some years. In the mean time, the accused person would be
excluded from honours and public employments, and could scarcely
venture even to pay his duty at court. Such were the motives
attributed by a great part of the public to the young minister, whose
ruling passion was generally believed to be avarice of power.
The prorogation soon interrupted the discussions respecting
Hastings. In the following year, those discussions were resumed. The
charge touching the spoliation of the Begums was brought forward
by Sheridan, in a speech which was so imperfectly reported that it
may be said to be wholly lost, but which was, without doubt, the
most elaborately brilliant of all the productions of his ingenious
mind. The impression which it produced was such as has never been
equalled. He sat down, not merely amidst cheering, but amidst the
loud clapping of hands, in which the Lords below the bar and the
strangers in the gallery joined. The excitement of the House was
such that no other speaker could obtain a hearing; and the debate
was adjourned. The ferment spread fast through the town. Within
four and twenty hours, Sheridan was offered a thousand pounds for
the copyright of the speech, if he would himself correct it for the
press. The impression made by this remarkable display of eloquence
on severe and experienced critics, whose discernment may be
supposed to have been quickened by emulation, was deep and
permanent. Mr. Windham, twenty years later, said that the speech
deserved all its fame, and was, in spite of some faults of taste, such
as were seldom wanting either in the literary or in the parliamentary
performances of Sheridan, the finest that had been delivered within
the memory of man. Mr. Fox, about the same time, being asked by
the late Lord Holland what was the best speech ever made in the
Home of Commons, assigned the first place, without hesitation, to
the great oration of Sheridan on the Oude charge.
When the debate was resumed, the tide ran so strongly against
the accused that his friends were coughed and scraped down. Pitt
declared himself for Sheridan’s motion; and the question was carried
by a hundred and seventy-five votes against sixty-eight.
The Opposition, flushed with victory and strongly supported by the
public sympathy, proceeded to bring forward a succession of charges
relating chiefly to pecuniary transactions. The friends of Hastings
were discouraged, and, having now no hope of being able to avert
an impeachment, were not very strenuous in their exertions. At
length the House, having agreed to twenty articles of charge,
directed Burke to go before the Lords, and to impeach the late
Governor-General of High Crimes and Misdemeanours. Hastings was
at the same time arrested by the Serjeant-at-arms and carried to the
bar of the Peers.
The session was now within ten days of its close. It was,
therefore, impossible that any progress could be made in the trial till
the next year. Hastings was admitted to bail; and further
proceedings were postponed till the Houses should re-assemble.
When Parliament met in the following winter, the Commons
proceeded to elect a committee for managing the impeachment.
Burke stood at the head; and with him were associated most of the
leading members of the Opposition. But when the name of Francis
was read a fierce contention arose. It was said that Francis and
Hastings were notoriously on bad terms, that they had been at feud
during many years, that on one occasion their mutual aversion had
impelled them to seek each other’s lives, and that it would be
improper and indelicate to select a private enemy to be a public
accuser. It was urged on the other side with great force, particularly
by Mr. Windham, that impartiality, though the first duty of a judge,
had never been reckoned among the qualities of an advocate; that
in the ordinary administration of criminal justice among the English,
the aggrieved party, the very last person who ought to be admitted
into the jury-box, is the prosecutor; that what was wanted in a
manager was, not that he should be free from bias, but that he
should be able, well informed, energetic, and active. The ability and
information of Francis were admitted; and the very animosity with
which he was reproached, whether a virtue or a vice, was at least a
pledge for his energy and activity. It seems difficult to refute these
arguments. But the inveterate hatred borne by Francis to Hastings
had excited general disgust. The House decided that Francis should
not be a manager. Pitt voted with the majority, Dundas with the
minority.
In the mean time, the preparations for the trial had proceeded
rapidly; and on the thirteenth of February, 1788, the sittings of the
Court commenced. There have been spectacles more dazzling to the
eye, more gorgeous with jewellery and cloth of gold, more attractive
to grown-up children, than that which was then exhibited at
Westminster; but, perhaps, there never was a spectacle so well
calculated to strike a highly cultivated, a reflecting, an imaginative
mind. All the various kinds of interest which belong to the near and
to the distant, to the present and to the past, were collected on one
spot and in one hour. All the talents and all the accomplishments
which are developed by liberty and civilisation were now displayed,
with every advantage that could be derived both from co-operation
and from contrast. Every step in the proceedings carried the mind
either backward, through many troubled centuries, to the days when
the foundations of our constitution were laid; or far away, over
boundless seas and deserts, to dusky nations living under strange
stars, worshipping strange gods, and writing strange characters from
right to left. The High Court of Parliament was to sit, according to
forms handed down from the days of the Plantagenets, on an
Englishman accused of exercising tyranny over the lord of the holy
city of Benares, and over the ladies of the princely house of Oude.
 The place was worthy of such a trial. It was the great hall of
William Rufus, the hall which had resounded with acclamations at
the inauguration of thirty kings, the hall which had witnessed the
just sentence of Bacon and the just absolution of Somers, the hall
where the eloquence of Strafford had for a moment awed and
melted a victorious party inflamed with just resentment, the hall
where Charles had confronted the High Court of Justice with the
placid courage which has half redeemed his fame. Neither military
nor civil pomp was wanting. The avenues were lined with
grenadiers. The streets were kept clear by cavalry. The peers, robed
in gold and ermine, were marshalled by the heralds under Garter
King-at-arms. The judges in their vestments of state attended to
give advice on points of law. Near a hundred and seventy lords,
three fourths of the Upper House as the Upper House then was,
walked in solemn order from their usual place of assembling to the
tribunal. The junior Baron present led the way, George Eliott, Lord
Heathfield, recently ennobled for his memorable defence of Gibraltar
against the fleets and armies of France and Spain. The long
procession was closed by the Duke of Norfolk, Earl Marshal of the
realm, by the great dignitaries, and by the brothers and sons of the
King. Last of all came the Prince of Wales, conspicuous by his fine
person and noble bearing. The grey old walls were hung with
scarlet. The long galleries were crowded by an audience such as has
rarely excited the fears or the emulations of an orator. There were
gathered together, from all parts of a great, free, enlightened, and
prosperous empire, grace and female loveliness, wit and learning,
the representatives of every science and of every art. There were
seated round the Queen the fairhaired young daughters of the
House of Brunswick. There the Ambassadors of great Kings and
Commonwealths gazed with admiration on a spectacle which no
other country in the world could present. There Siddons, in the
prime of her majestic beauty, looked with emotion on a scene
surpassing all the imitations of the stage. There the historian of the
Roman Empire thought of the days when Cicero pleaded the cause
of Sicily against Verres, and when, before a senate which still ret
ained some show of freedom, Tacitus thundered against the
oppressor of Africa. There were seen side by side the greatest
painter and the greatest scholar of the age. The spectacle had
allured Reynolds from that easel which has preserved to us the
thoughtful foreheads of so many writers and statesmen, and the
sweet smiles of so many noble matrons. It had induced Parr to
suspend his labours in that dark and profound mine from which he
had extracted a vast treasure of erudition, a treasure too often
bulled in the earth, too often paraded with injudicious and inelegant
ostentation, but still precious, massive, and splendid. There
appeared the voluptuous charms of her to whom the heir of the
throne had in secret plighted his faith. There too was she, the
beautiful mother of a beautiful race, the Saint Cecilia, whose delicate
features, lighted up by love and music, art has rescued from the
common decay. There wore the members of that brilliant society
which quoted, criticized, and exchanged repartees, under’ the rich
peacock-hangings of Mrs. Montague. And there the ladies whose
lips, more persuasive than those of Fox himself, had carried the
Westminster election against palace and treasury, shone around
Georgi-ana Duchess of Devonshire.
The Serjeants made proclamation. Hastings advanced to the bar,
and bent his knee. The culprit was indeed not unworthy of that great
presence. He had ruled an extensive and populous country, had
made laws and treaties, had sent forth armies, had set up and pulled
down princes. And in his high place he had so borne himself, that all
had feared him, that most had loved him, and that hatred itself
could deny him no title to glory, except virtue. He looked like a great
man, and not like a bad man. A person small and emaciated, yet
deriving dignity from a carriage which, while it indicated deference
to the court, indicated also habitual self-possession and self-respect,
a high and intellectual forehead, a brow pensive, but not gloomy, a
mouth of inflexible decision, a face pale and worn, but serene, on
which was written, as legibly as under the picture in the council-
chamber at Calcutta, Mens aequa in arduis; such was the aspect
with which the great Proconsul presented himself to his judges.
 His counsel accompanied him, men all of whom were afterwards
raised by their talents and learning to the highest posts in their
profession, the bold and strong-minded Law, afterwards Chief
Justice of the King’s Bench; the more humane and eloquent Dallas,
afterwards Chief Justice of the Common Pleas; and Plomer who,
near twenty years later, successfully conducted in the same high
court the defence of Lord Melville, and subsequently became Vice-
chancellor and Master of the Rolls.
But neither the culprit nor his advocates attracted so much notice
as the accusers. In the midst of the blaze of red drapery, a space
had been fitted up with green benches and tables for the Commons.
The managers, with Burke at their head, appeared in full dress. The
collectors of gossip did not fail to remark that even Fox, generally so
regardless of his appearance, had paid to the illustrious tribunal the
compliment of wearing a bag and sword. Pitt had refused to be one
of the conductors of the impeachment; and his commanding,
copious, and sonorous eloquence was wanting to that great muster
of various talents. Age and blindness had unfitted Lord North for the
duties of a public prosecutor; and his friends were left without the
help of his excellent sense, his tact, and his urbanity. But, in spite of
the absence of these two distinguished members of the Lower
House, the box in which the managers stood contained an array of
speakers such as perhaps had not appeared together since the great
age of Athenian eloquence. There were Fox and Sheridan, the
English Demosthenes and the English Hyperides. There was Burke,
ignorant, indeed, or negligent of the art of adapting his reasonings
and his style to the capacity and taste of his hearers, but in
amplitude of comprehension and richness of imagination superior to
every orator, ancient or modern. There, with eyes reverentially fixed
on Burke, appeared the finest gentleman of the age, his form
developed by every manly exercise, his face beaming with
intelligence and spirit, the ingenious, the chivalrous, the high-souled
Windham. Nor, though surrounded by such men, did the youngest
manager pass unnoticed. At an age when most of those who
distinguish themselves in life are still contending for prizes and
fellowships at college, He had won for himself a conspicuous place in
parliament. No advantage of fortune or connection was wanting that
could set off to the height his splendid talents and his unblemished
honour. At twenty-three he had been thought worthy to be ranked
with the veteran statesmen who appeared as the delegates of the
British Commons, at the bar of the British nobility. All who stood at
that bar, save him alone, are gone, culprit, advocates, accusers. To
the generation which is now in the vigour of life, he is the sole
representative of a great age which has passed away. But those
who, within the last ten years, have listened with delight, till the
morning sun shone on the tapestries of the House of Lords, to the
lofty and animated eloquence of Charles Earl Grey, are able to form
some estimate of the powers of a race of men among whom he was
not the foremost.
The charges and the answers of Hastings were first read. The
ceremony occupied two whole days, and was rendered less tedious
than it would otherwise have been by the silver voice and just
emphasis of Cowper, the clerk of the court, a near relation of the
amiable poet. On the third day Burke rose. Four sittings were
occupied by his opening speech, which was intended to be a general
introduction to all the charges. With an exuberance of thought and a
splendour of diction which more than satisfied the highly raised
expectation of the audience, he described the character and
institutions of the natives of India, recounted the circumstances in
which the Asiatic empire of Britain had originated, and set forth the
constitution of the Company and of the English presidencies. Having
thus attempted to communicate to his hearers an idea of Eastern
society, as vivid as that which existed in his own mind, he proceeded
to arraign the administration of Hastings as systematically conducted
in defiance of morality and public law. The energy and pathos of the
great orator extorted expressions of unwonted admiration from the
stern and hostile Chancellor, and, for a moment, seemed to pierce
even the resolute heart of the defendant. The ladies in the galleries,
unaccustomed to such displays of eloquence, excited by the
solemnity on the occasion, and perhaps not unwilling to display their
taste and sensibility, were in a state of uncontrollable emotion.
Handkerchiefs were pulled out; smelling bottles were handed round;
hysterical sobs and screams were heard: and Mrs. Sheridan was
carried out in a fit. At length the orator concluded. Raising his voice
till the old arches of Irish oak resounded, “Therefore,” said he, “hath
it with all confidence been ordered, by the Commons of Great
Britain, that I impeach Warren Hastings of high crimes and
misdemeanours. I impeach him in the name of the Commons’ House
of Parliament, whose trust he has betrayed. I impeach him in the
name of the English nation, whose ancient honour he has sullied. I
impeach him in the name of the people of India, whose rights he
has trodden under foot, and whose country he has turned into a
desert. Lastly, in the name of human nature itself, in the name of
both sexes, in the name of every age, in the name of every rank, I
impeach the common enemy and oppressor of all!”
When the deep murmur of various emotions had subsided, Mr. Fox
rose to address the Lords respecting the course of proceeding to be
followed. The wish of the accusers was that the Court would bring to
a close the investigation of the first charge before the second was
opened. The wish of Hastings and of his counsel was that the
managers should open all the charges, and produce all the evidence
for the prosecution, before the defence began. The Lords retired to
their own House to consider the question. The Chancellor took the
side of Hastings. Lord Loughborough, who was now in opposition,
supported the demand of the managers. The division showed which
wav the inclination of the tribunal leaned. A majority of near three to
one decided in favour of the course for which Hastings contended.
When the Court sat again, Mr. Fox, assisted by Mr. Grey, opened
the charge respecting Cheyte Sing, and several days were spent in
reading papers and hearing witnesses. The next article was that
relating to the Princesses of Onde. The conduct of this part of the
case was intrusted to Sheridan. The curiosity of the public to hear
him was unbounded. His sparkling and highly finished declamation
lasted two days; but the Hall was crowded to suffocation during the
whole time. It was said that fifty guineas had been paid for a single
ticket. Sheridan, when he concluded, contrived, with a knowledge of
stage effect which his father might have envied, to sink back, as if
exhausted, into the arms of Burke, who hugged him with the energy
of generous admiration.
June was now far advanced. The session could not last much
longer; and the progress which had been made in the impeachment
was not very satisfactory. There were twenty charges. On two only
of these had even the case for the prosecution been heard; and it
was now a year since Hastings had been admitted to bail.
The interest taken by the public in the trial was great when the
Court began to sit, and rose to the height when Sheridan spoke on
the charge relating to the Begums. From that time the excitement
went down fast. The spectacle had lost the attraction of novelty. The
great displays of rhetoric were over. What was behind was not of a
nature to entice men of letters from their books in the morning, or to
tempt ladies who had left the masquerade at two to be out of bed
before eight. There remained examinations and cross-examinations.
There remained statements of accounts. There remained the reading
of papers, filled with words unintelligible to English cars, with lacs
and crores, zemindars and aumils, sunnuds and perwannahs,
jaghires and nuzzurs. There remained bickerings, not always carried
on with the best taste or with the best temper, between the
managers of the impeachment and the counsel for the defence,
particularly between Mr. Burke and Mr. Law. There remained the
endless marches and countermarches of the Peers between their
House and the Hall: for as often as a point of law was to be
discussed, their Lordships retired to discuss it apart; and the
consequence was, as a Peer wittily said, that the judges walked and
the trial stood still.
It is to be added that, in the spring of 1788, when the trial
commenced, no important question, either of domestic or foreign
policy, occupied the public mind. The proceeding in Westminster
Hall, therefore, naturally attracted most of the attention of
Parliament and of the country. It was the one great event of that
season. But in the following year the King’s illness, the debates on
the Regency, the expectation of a change of ministry, completely
diverted public attention from Indian affairs; and within a fortnight
after George the Third had returned thanks in St. Paul’s for his
recovery, the States-General of France met at Versailles, In the midst
of the agitation produced by these events, the impeachment was for
a time almost forgotten.
The trial in the Hall went on languidly. In the session of 1788,
when the proceedings had the interest of novelty, and when the
Peers had little other business before them, only thirty-five days
were given to the impeachment. In 1789, the Regency Bill occupied
the Upper House till the session was far advanced. When the Kino;
recovered the circuits were beginning. The judges left town; the
Lords waited for the return of the oracles of jurisprudence; and the
consequence was that during the whole year only seventeen days
were given to the case of Hastings. It was clear that the matter
would be protracted to a length unprecedented in the annals of
criminal law.
In truth, it is impossible to deny that impeachment, though it is a
fine ceremony, and though it may have been useful in the
seventeenth century, is not a proceeding from which much good can
now be expected. Whatever confidence may be placed in the
decision of the Peers on an appeal arising out of ordinary litigation, it
is certain that no man has the least confidence in their impartiality,
when a great public functionary, charged with a great state crime, is
brought to their bar. They are all politicians. There is hardly one
among them whose vote on an impeachment may not be confidently
predicted before a witness has been examined; and, even if it were
possible to rely on their justice, they would still be quite unfit to try
such a cause as that of Hastings. They sit only during half the year.
They have to transact much legislative and much judicial business.
The law-lords, whose advice is required to guide the unlearned
majority, are employed daily in administering justice elsewhere. It is
impossible, therefore, that, during a busy session, the Upper House
should give more than a few days to an impeachment.
To expect that their Lordships would give up partridge-shooting, in
order to bring the greatest delinquent, to speedy justice, or to
relieve accused innocence by speedy acquittal, would be
unreasonable indeed. A well constituted tribunal, sitting regularly six
days in the week, and nine hours in the day, would have brought the
trial of Hastings to a close in less than three months. The Lords had
not finished their work in seven years.
The result ceased to be matter of doubt, from the time when the
Lords resolved that they would be guided by the rules of evidence
which are received in the inferior courts of the realm. Those rules, it
is well known, exclude much information which would be quite
sufficient to determine the conduct of any reasonable man, in the
most important transactions of private life. These rules, at every
assizes, save scores of culprits whom judges, jury, and spectators,
firmly believe to be guilty. But when those rules were rigidly applied
to offences committed many years before, at the distance of many
thousands of miles, conviction was, of course, out of the question.
We do not blame the accused and his counsel for availing
themselves of every legal advantage in order to obtain an acquittal.
But it is clear that an acquittal so obtained cannot be pleaded in bar
of the judgment of history.
Several attempts were made by the friends of Hastings to put a
stop to the trial. In 1780 they proposed a vote of censure upon
Burke, for some violent language which he had used respecting the
death of Nuncomar and the connection between Hastings and
Impey. Burke was then unpopular in the last degree both with the
House and with the country. The asperity and indecency of some
expressions which he had used during the debates on the Regency
had annoyed even his warmest friends. The vote of censure was
carried; and those who had moved it hoped that the managers
would resign in disgust. Burke was deeply hurt. But his zeal for what
he considered as the cause of justice and mercy triumphed over his
personal feelings. He received the censure of the House with dignity
and meekness, and declared that no personal mortification or
humiliation should induce him to flinch from the sacred duty which
he had undertaken.
In the following year the Parliament was dissolved; and the friends
of Hastings entertained a hope that the new House of Commons
might not be disposed to go on with the impeachment. They began
by maintaining that the whole proceeding was terminated by the
dissolution. Defeated on this point, they made a direct motion that
the impeachment, should be dropped; but they were defeated by
the combined forces of the Government and the Opposition. It was,
however, resolved that, for the sake of expedition, many of the
articles should be withdrawn. In truth, had not some such measure
been adopted, the trial would have lasted till the defendant was in
his grave.
At length, in the spring of 1795, the decision was pronounced,
near eight years after Hastings had been brought by the Serjeant-at-
arms of the Commons to the bar of the Lords. On the last day of this
great procedure the public curiosity, long suspended, seemed to be
revived. Anxiety about the judgment there could be none; for it had
been fully ascertained that there was a great majority for the
defendant. Nevertheless many wished to see the pageant, and the
Hall was as much crowded as on the first day. But those who, having
been present on the first day, now bore a part in the proceedings of
the last, were few; and most of those few were altered men.
As Hastings himself said, the arraignment had taken place before
one generation, and the judgment was pronounced by another. The
spectator could not look at the woolsack, or at the red benches of
the Peers, or at the green benches of the Commons, without seeing
something that reminded him of the instability of all human things,
of the instability of power and tame and life, of the more lamentable
instability of friendship. The great seal was borne before Lord
Loughborough, who, when the trial commenced, was a fierce
opponent of Mr. Pitt’s government, and who was now a member of
that government, while Thurlow, who presided in the Court when it
first sat, estranged from all his old allies, sat scowling among the
junior barons. Of about a hundred and sixty nobles who walked in
the procession on the first day, sixty had been laid in their family
vaults. Still more affecting must have been the sight of the
managers’ box. What had become of that fair fellowship, so closely
bound together by public and private ties, so resplendent with every
talent and accomplishment? It had been scattered by calamities
more bitter than the bitterness of death. The great chiefs were still
living, and still in the full vigour of their genius. But their friendship
was at an end. It had been violently and publicly dissolved, with
tears and stormy reproaches. If those men, once so dear to each
other, were now compelled to meet for the purpose of managing the
impeachment, they met as strangers whom public business had
brought together, and behaved to each other with cold and distant
civility. Burke had in his vortex whirled away Windham. Fox had
been followed by Sheridan and Grey.
Only twenty-nine Peers voted. Of these only six found Hastings
guilty on the charges relating to Cheyte Sing and to the Begums. On
other charges, the majority in his favour was still greater. On some
he was unanimously absolved. He was then called to the bar, was
informed from the woolsack that the Lords had acquitted him, and
was solemnly discharged. He bowed respectfully and retired.
We have said that the decision had been fully expected. It was
also generally approved. At the commencement of the trial there had
been a strong and indeed unreasonable feeling against Hastings. At
the close of the trial there was a feeling equally strong and equally
unreasonable in his favour. One cause of the change was, no doubt,
what is commonly called the fickleness of the multitude, but what
seems to us to be merely the general law of human nature. Both in
individuals and in masses violent excitement is always followed by
remission, and often by reaction. We are all inclined to depreciate
whatever we have overpraised, and, on the other hand, to show
undue indulgence where we have shown undue rigour. It was thus in
the case of Hastings. The length of his trial, moreover, made him an
object of compassion. It was thought, and not without reason, that,
even if he was guilty, he was still an ill-used man, and that an
impeachment of eight years was more than a sufficient punishment.
It was also felt that, though, in the ordinary course of criminal law, a
defendant is not allowed to set off his good actions against his
crimes, a great political cause should be tried on different principles,
and that a man who had governed an empire during thirteen years
might have done some very reprehensible things, and yet might be
on the whole deserving of rewards and honours rather than of fine
and imprisonment. The press, an instrument neglected by the
prosecutors, was used by Hastings and his friends with great effect.
Every ship, too that arrived from Madras or Bengal, brought a cuddy
full of his admirers. Every gentleman from India spoke of the late
Governor-General as having deserved better, and having been
treated worse, than any man living. The effect of this testimony
unanimously given by all persons who knew the East was naturally
very great. Retired members of the Indian services, civil and military,
were settled in all corners of the kingdom. Each of them was, of
course, in his own little circle, regarded as an oracle on an Indian
question, and they were, with scarcely one exception, the zealous
advocates of Hastings. It is to be added, that the numerous
addresses to the late Governor-General, which his friends in Bengal
obtained from the natives and transmitted to England, made a
considerable impression. To these addresses we attach little or no
importance. That Hastings was beloved by the people whom he
governed is true; but the eulogies of pundits, zemindars,
Mahommedan doctors, do not prove it to be true. For an English
collector or judge would have found it easy to induce any native who
could write to sign a panegyric on the most odious ruler that ever
was in India. It was said that at Benares, the very place at which the
acts set forth in the first article of impeachment had been
committed, the natives had erected a temple to Hastings, and this
story excited a strong sensation in England. Burke’s observations on
the apotheosis were admirable. He saw no reason for astonishment,
he said, in the incident which had been represented as so striking.
He knew something of the mythology of the Brahmins. He knew that
as they worshipped some gods from love, so they worshipped others
from fear. He knew that they erected shrines, not only to the
benignant deities of light and plenty, but also to the fiends who
preside over smallpox and murder; nor did he at all dispute the claim
of Mr. Hastings to be admitted into such a Pantheon. This reply has
always struck us as one of the finest that ever was made in
Parliament. It is a grave and forcible argument, decorated by the
most brilliant wit and fancy.
Hastings was, however, safe. But in every thing except character,
he would have been far better off if, when first impeached, he had at
once pleaded guilty, and paid a fine of fifty thousand pounds. He
was a ruined man. The legal expenses of his defence had been
enormous. The expenses which did not appear in his attorney’s bill
were perhaps larger still. Great sums had been paid to Major Scott.
Great sums had been laid out in bribing newspapers, rewarding
pamphleteers, and circulating tracts. Burke, so early as 1790,
declared in the House of Commons that twenty thousand pounds
had been employed in corrupting the press. It is certain that no
controversial weapon, from the gravest reasoning to the coarsest
ribaldry, was left unemployed. Logan defended the accused
Governor with great ability in prose. For the lovers of verse, the
speeches of the managers were burlesqued in Simpkin’s letters. It is,
we are afraid, indisputable that Hastings stooped so low as to court
the aid of that malignant and filthy baboon John Williams, who
called himself Anthony Pasquin. It was necessary to subsidise such
allies largely. The private hoards of Mrs. Hastings had disappeared.
It is said that the banker to whom they had been intrusted had
failed. Still if Hastings had practised strict economy, he would, after
all his losses, have had a moderate competence; but in the
management of his private affairs he was imprudent. The clearest
wish of his heart had always been to regain Daylesford. At length, in
the very year in which his trial commenced, the wish was
accomplished; and the domain, alienated more than seventy years
before, returned to the descendant of its old lords. But the manor
house was a ruin; and the grounds round it had, during many years,
been utterly neglected. Hastings proceeded to build, to plant, to
form a sheet of water, to excavate a grotto; and, before he was
dismissed from the bar of the House of Lords, he had expended
more than forty thousand pounds in adorning his seat.
The general feeling both of the Directors and of the proprietors of
the East India Company was that he had great claims on them, that
his services to them had been eminent, and that his misfortunes had
been the effect of his zeal for their interest. His friends in Leadenhall
Street proposed to reimburse him the costs of his trial, and to settle
on him an annuity of five thousand pounds a year. But the consent
of the Board of Control was necessary; and at the head of the Board
of Control was Mr. Dundas, who had himself been a party to the
impeachment, who had, on that account, been reviled with great
bitterness by the adherents of Hastings, and who, therefore, was not
in a very complying mood. He refused to consent to what the
Directors suggested. The Directors remonstrated. A long controversy
followed. Hastings, in the mean time, was reduced to such distress,
that he could hardly pay his weekly bills. At length a compromise
was made. An annuity for life of four thousand pounds was settled
on Hastings; and in order to enable him to meet pressing demands,
he was to receive ten years’ annuity in advance. The Company was
also permitted to lend him fifty thousand pounds, to be repaid by
instalments without interest. The relief, though given in the most
absurd manner, was sufficient to enable the retired Governor to live
in comfort, and even in luxury, if he had been a skilful manager. But
he was careless and profuse, and was more than once under the
necessity of applying to the Company for assistance, which was
liberally given.
He had security and affluence, but not the power and dignity
which, when he landed from India, he had reason to expect. He had
then looked forward to a coronet, a red riband, a seat at the Council
Board, an office at Whitehall. He was then only fifty-two, and might
hope for many years of bodily and mental vigour. The case was
widely different when he left the bar of the Lords. He was now too
old a man to turn his mind to a new class of studies and duties. He
had no chance of receiving any mark of royal favour while Mr. Pitt
remained in power; and, when Mr. Pitt retired, Hastings was
approaching his seventieth year.
Once, and only once, after his acquittal, he interfered in polities;
and that interference was not much to his honour. In 1804 he
exerted himself strenuously to prevent Mr. Addington, against whom
Fox and Pitt had combined, from resigning the Treasury. It is difficult
to believe that a man so able and energetic as Hastings can have
thought that, when Bonaparte was at Boulogne with a great army,
the defence of our island could safely be intrusted to a ministry
which did not contain a single person whom flattery could describe
as a great statesman. It is also certain that, on the important
question which had raised Mr. Addington to power, and on which he
differed from both Fox and Pitt, Hastings, as might have been
expected, agreed with Fox and Pitt, and was decidedly opposed to
Addington, Religious intolerance has never been the vice of the
Indian service, and certainly was not the vice of Hastings. But Mr.
Addington had treated him with marked favour. Fox had been a
principal manager of the impeachment. To Pitt it was owing that
there had been an impeachment; and Hastings, we fear, was on this
occasion guided by personal considerations, rather than by a regard
to the public interest.
The last twenty-four years of his life were chiefly passed at
Daylesford. He amused himself with embellishing his grounds, riding
fine Arab horses, fattening prize-cattle, and trying to rear Indian
animals and vegetables in England. He sent for seeds of a very fine
custard-apple, from the garden of what had once been his own villa,
among the green hedgerows of Allipore. He tried also to naturalise in
Worcestershire the delicious leechee, almost the only fruit of Bengal
which deserves to be regretted even amidst the plenty of Covent
Garden. The Mogul emperors, in the time of their greatness, had in
vain attempted to introduce into Hindustan the goat of the table-
land of Thibet, whose down supplies the looms of Cashmere with
the materials of the finest shawls. Hastings tried, with no better
fortune, to rear a breed at Daylesford; nor does he seem to have
succeeded better with the cattle of Bootan, whose tails are in high
esteem as the best fans for brushing away the mosquitoes.
Literature divided his attention with his conservatories and his
menagerie. He had always loved books, and they were now
necessary to him. Though not a poet, in any high sense of the word,
he wrote neat and polished lines with great facility, and was fond of
exercising this talent. Indeed, if we must speak out, he seems to
have been more of a Trissotin than was to be expected from the
powers of his mind, and from the great part which he had played in
life. We are assured in these Memoirs that the first thing which he
did in the morning was to write a copy of verses. When the family
and guests assembled, the poem made its appearance as regularly
as the eggs and rolls; and Mr. Gleig requires us to believe that, if
from any accident Hastings came to the breakfast-table without one
of his charming performances in his hand, the omission was felt by
all as a grievous disappointment. Tastes differ widely. For ourselves,
we must say that, however good the breakfasts at Daylesford may
have been,—and we are assured that the tea was of the most
aromatic flavour, and that neither tongue nor venison-pasty was
wanting,—we should have thought the reckoning high if we had
been forced to earn our repast by listening every day to a new
madrigal or sonnet composed by our host. We are glad, however,
that Mr. Gleig has preserved this little feature of character, though
we think it by no means a beauty. It is good to be often reminded of
the inconsistency of human nature, and to learn to look without
wonder or disgust on the weaknesses which are found in the
strongest minds. Dionysius in old times, Frederic in the last century,
with capacity and vigour equal to the conduct of the greatest affairs,
united all the little vanities and affectations of provincial blue-
stockings. These great examples may console the admirers of
Hastings for the affliction of seeing him reduced to the level of the
Hayleys and Sewards.
 When Hastings had passed many years in retirement, and had
long outlived the common age of men, he again became for a short
time an object of general attention. In 1813 the charter of the East
India Company was renewed; and much discussion about Indian
affairs took place in Parliament. It was determined to examine
witnesses at the bar of the Commons; and Hastings was ordered to
attend. He had appeared at that bar once before. It was when he
read his answer to charges which Burke had laid on the table. Since
that time twenty-seven years had elapsed; public feeling had
undergone a complete change; the nation had now forgotten his
faults, and remembered only his services. The reappearance, too, of
a man who had been among the most distinguished of a generation
that had passed away, who now belonged to history, and who
seemed to have risen from the dead, could not but produce a
solemn and pathetic effect. The Commons received him with
acclamations, ordered a chair to be set for him, and, when he
retired, rose and uncovered. There were, indeed, a few who did not
sympathize with the general feeling. One or two of the managers of
the impeachment were present. They sate in the same seats which
they had occupied when they had been thanked for the services
which they had rendered in Westminster Hall: for, by the courtesy of
the House, a member who has been thanked in his place is
considered as having a right alwavs to occupy that place. These
gentlemen were not disposed to admit that they had employed
several of the best years of their lives in persecuting an innocent
man. They accordingly kept their seats, and pulled their hats over
their brows; but the exceptions only made the prevailing enthusiasm
more remarkable. The Lords received the old man with similar
tokens of respect. The University of Oxford conferred on him the
degree of’ Doctor of Laws; and, in the Sheldonian Theatre, the
undergraduates welcomed him with tumultuous cheering.
These marks of public esteem were soon followed by marks of
royal favour. Hastings was sworn of the Privy Council, and was
admitted to a long private audience of the Prince Regent, who
treated him very graciously. When the Emperor of Russia and the
King of Prussia visited England, Hastings appeared in their train both
at Oxford and in the Guildhall of London, and, though surrounded by
a crowd of princes and great warriors, was everywhere received with
marks of respect and admiration. He was presented by the Prince
Resent both to Alexander and to Frederic William; and his Royal
Highness went so far as to declare in public that honours far higher
than a seat in the Privy Council were due, and would soon be paid,
to the man who had saved the British dominions in Asia. Hastings
now confidently expected a peerage; but, from some unexplained
cause, he was again disappointed.
He lived about four years longer, in the enjoyment of good spirits,
of faculties not impaired to any painful or degrading extent, and of
health such as is rarely enjoyed by those who attain such an age. At
length, on the twenty-second of August, 1818, in the eighty-sixth
year of his age, he met death with the same tranquil and decorous
fortitude which he had opposed to all the trials of his various and
eventful life.
With all his faults,—and they were neither few nor small,—only
one cemetery was worthy to contain his remains. In that temple of
silence and reconciliation where the enmities of twenty generations
He buried, in the Great Abbey which has during many ages afforded
a quiet resting-place to those whose minds and bodies have been
shattered by the contentions of the Great Hall, the dust of the
illustrious accused should have mingled with the dust of the
illustrious accusers. This was not to be. Yet the place of interment
was not ill-chosen. Behind the chancel of the parish church of
Daylesford, in earth which already held the bones of many chiefs of
the house of Hastings, was laid the coffin of the Greatest man who
has ever borne that ancient and widely extended name. On that very
spot, probably, fourscore years before, the little Warren, meanly clad
and scantily fed, had played with the children of ploughmen. Even
then his young mind had revolved plans which might be called
romantic. Yet, however romantic, it is not likely that they had been
so strange as the truth. Not only had the poor orphan retrieved the
fallen fortunes of his line. Not only had he repurchased the old
lands, and rebuilt the old dwelling. He had preserved and extended
an empire. He had founded a polity. He had administered
government and war with more than the capacity of Richelieu. He
had patronised learning with the judicious liberality of Cosmo. He
had been attacked by the most formidable combination of enemies
that ever sought the destruction of a single victim: and over that
combination, after a struggle of ten years, he had triumphed. He
had at length gone down to his grave in the fulness of age in peace,
after so many troubles, in honour, after so much obloquy.
Those who look on his character without favour or malevolence
will pronounce that, in the two great elements of all social virtue, in
respect for the rights of others, and in sympathy for the sufferings of
others, he was deficient. His principles were somewhat lax. His heart
was somewhat hard. But though we cannot with truth describe him
either as a righteous or as a merciful ruler, we cannot regard without
admiration the amplitude and fertility of his intellect, his rare talents
for command, for administration, and for controversy, his dauntless
courage, his honourable poverty, his fervent zeal for the interests of
the state, his noble equanimity, tried by both extremes of fortune,
and never disturbed by either.
 FREDERIC THE GREAT. (1)
(Edinburgh Review, April, 1842.)

T
his work, which has the high honour of being introduced to
the world by the author of Loehiel and Hohenlinden, is not
wholly unworthy of so distinguished a chaperon. It professes,
indeed, to be no more than a compilation; but it is an exceedingly
amusing compilation, and we shall be glad to have more of it. The
narrative comes down at present only to the commencement of the
Seven Years’ War, and therefore does not comprise the most
interesting portion of Frederic’s reign.
It may not be unacceptable to our readers that we should take
this opportunity of presenting them with a slight sketch of the life of
the greatest king that has, in modern times, succeeded by right of
birth to a throne. It may, we fear, be impossible to compress so long
and eventful a story within the limits which we must prescribe to
ourselves. Should we be compelled to break off, we may perhaps,
when the continuation of this work appears, return to the subject.
The Prussian monarchy, the youngest of the great European
states, but in population and revenue the fifth among them, and in
art, science, and civilisation entitled to the third, if not to the second
place, sprang

(1) Frederic the Great and his Times. Edited, with an

Introduction, by Thomas Campbell., Esq. 2 vols. 8vo. London:
1842.

from a humble origin. About the beginning of the fifteenth

century, the marquisate of Brandenburg was bestowed by the
Emperor Sigismund on the noble family of Hohenzollern. In the
sixteenth century that family embraced the Lutheran doctrines. It
obtained from the King of Poland, early in the seventeenth century,
the investiture of the duchy of Prussia. Even after this accession of
territory, the chiefs of the house of Hohenzollern hardly ranked with
the Electors of Saxony and Bavaria. The soil of Brandenburg was for
the most part sterile. Even round Berlin, the capital of the province,
and round Potsdam, the favourite residence of the Margraves, the
country was a desert. In some places, the deep sand could with
difficulty be forced by assiduous tillage to yield thin crops of rye and
oats. In other places, the ancient forests, from which the conquerors
of the Roman empire had descended on the Danube, remained
untouched by the hand of man. Where the soil was rich it was
generally marshy, and its insalubrity repelled the cultivators whom its
fertility attracted. Frederic William, called the Great Elector, was the
prince to whose policy his successors have agreed to ascribe their
greatness. He acquired by the peace of Westphalia several valuable
possessions, and among them the rich city and district of
Magdeburg; and he left to his son Frederic a principality as
considerable as any which was not called a kingdom.
Frederic aspired to the style of royalty. Ostentatious and profuse,
negligent of his true interests and of his high duties, insatiably eager
for frivolous distinctions, he added nothing to the real weight of the
state which he governed: perhaps he transmitted his inheritance to
his children impaired rather than augmented in value; but he
succeeded in gaining the great object of his life, the title of King. In
the year 1700 he assumed this new dignity. He had on that occasion
to undergo all the mortifications which fall to the lot of ambitious
upstarts. Compared with the other crowned heads of Europe, he
made a figure resembling that which a Nabob or a Commissary, who
had bought a title, would make in the company of Peers whose
ancestors had been attainted for treason against the Plantagenets.
The envy of the class which Frederic quitted, and the civil scorn of
the class into which he intruded himself, were marked in very
significant ways. The Elector of Saxony at first refused to
acknowledge the new Majesty. Lewis the Fourteenth looked down on
his brother King with an air not unlike that with which the Count in
Molière’s play regards Monsieur Jourdain, just fresh from the
mummery of being made a gentleman. Austria exacted large
sacrifices in return for her recognition, and at last gave it
ungraciously.
Frederic was succeeded by his son, Frederic William, a prince who
must be allowed to have possessed some talents for administration,
but whose character was disfigured by odious vices, and whose
eccentricities were such as had never before been seen out of a
madhouse. He was exact and diligent in the transacting of business;
and he was the first who formed the design of obtaining for Prussia
a place among the European powers, altogether out of proportion to
her extent and population, by means of a strong military
organization. Strict economy enabled him to keep up a peace
establishment of sixty thousand troops. These troops were
disciplined in such a manner, that placed beside them, the household
regiments of Versailles and St. James’s would have appeared an
awkward squad. The master of such a force could not but be
regarded by all his neighbours as a formidable enemy and a valuable
ally.
But the mind of Frederic William was so ill regulated, that all his
inclinations became passions, and all his passions partook of the
character of moral and intellectual disease. His parsimony
degenerated into sordid avarice. His taste for military pomp and
order became a mania, like that of a Dutch burgomaster for tulips,
or that of a member of the Roxburghe Club for Caxtons. While the
envoys of the Court of Berlin were in a state of such squalid poverty
as moved the laughter of foreign capitals, while the food placed
before the princes and princesses of the blood-royal of Prussia was
too scanty to appease hunger, and so bad that even hunger loathed
it, no price was thought too extravagant for tall recruits. The
ambition of the King was to form a brigade of giants, and every
country was ransacked by his agents for men above the ordinary
stature. These researches were not confined to Europe. No head
that towered above the crowd in the bazaars of Aleppo, of Cairo, or
of Surat, could escape the crimps of Frederic William. One Irishman
more than seven feet high, who was picked up in London by the
Prussian ambassador, received a bounty of near thirteen hundred
pounds sterling, very much more than the ambassador’s salary. This
extravagance was the more absurd, because a stout youth of five
feet eight, who might have been procured for a few dollars, would in
all probability have been a much more valuable soldier. But to
Frederic William, this huge Irishman was what a brass Otho, or a
Vinegar Bible, is to a collector of a different kind.
It is remarkable, that though the main end of Frederic William’s
administration was to have a great military force, though his reign
forms an important epoch in the history of military discipline, and
though his dominant passion was the love of military display, he was
yet one of the most pacific of princes. We are afraid that his aversion
to war was not the effect of humanity, but was merely one of his
thousand whims. His feeling about his troops seems to have
resembled a miser’s feeling about his money. He loved to collect
them, to count them, to see them increase; but he could not find it
in his heart to break in upon the precious hoard. He looked forward
to some future time when his Patagonian battalions were to drive
hostile infantry before them like sheep: but this future time was
always receding; and it is probable that, if his life had been
prolonged thirty years, his superb army would never have seen any
harder service than a sham fight in the fields near Berlin. But the
great military means which he had collected were destined to be
employed by a spirit far more daring and inventive than his own.
Frederic, surnamed the Great, son of Frederic William, was born in
January, 1712. It may safely be pronounced that he had received
from nature a strong and sharp understanding, and a rare firmness
of temper and intensity of will. As to the other parts of his character,
it is difficult to say whether they are to be ascribed to nature, or to
the strange training which he underwent. The history of his boyhood
is painfully interesting. Oliver Twist in the parish workhouse, Smike
at Dotheboy’s Hall, were petted children when compared with this
wretched heir apparent of a crown. The nature of Frederic William
was hard and bad, and the habit of exercising arbitrary power had
made him frightfully savage. His rage constantly vented itself to right
and left in curses and blows. When his Majesty took a walk, every
human being fled before him, as if a tiger had broken loose from a
menagerie. If he met a lady in the street, he gave her a kick, and
told her to go home and mind her brats. If he saw a clergyman
staring at the soldiers, he admonished the reverend gentleman to
betake himself to study and prayer, and enforced this pious advice
by a sound caning, administered on the spot. But it was in his own
house that he was most unreasonable and ferocious. His palace was
hell, and he the most execrable of fiends, a cross between Moloch
and Puck. His son Frederic and his daughter Wilhelmina, afterwards
Margravine of Bareuth, were in an especial manner objects of his
aversion. His own mind was uncultivated. He despised literature. He
hated infidels, papists, and metaphysicians, and did not very well
understand in what they differed from each other. The business of
life, according to him, was to drill and to be drilled. The recreations
suited to a prince, were to sit in a cloud of tobacco smoke, to sip
Swedish beer between the puffs of the pipe, to play backgammon
for three halfpence a rubber, to kill wild hogs, and to shoot
partridges by the thousand. The Prince Royal showed little inclination
either for the serious employments or for the amusements of his
father. He shirked the duties of the parade: he detested the fume of
tobacco: he had no taste either for backgammon or for field sports.
He had an exquisite ear and performed skilfully on the flute. His
earliest instructors had been French refugees, and they had
awakened in him a strong passion for French literature and French
society. Frederic William regarded these tastes as effeminate and
contemptible, and by abuse and persecution, made them still
stronger. Things became worse when the Prince Royal attained that
time of life at which the great revolution in the human mind and
body takes place. He was guilty of some youthful indiscretions,
which no good and wise parent would regard with severity. At a later
period He was accused, truly or falsely, of vices from which history
averts her eyes, and which even Satire blushes to name, vices such
that, to borrow the energetic language of Lord Keeper Coventry, “the
depraved nature of man, which of itself carrieth man to all other sin,
abhorreth them.” But the offences of his youth were not
characterized by any degree of turpitude. They excited, however,
transports of rage in the King, who hated all faults except those to
which he was himself inclined, and who conceived that he made
ample atonement to Heaven for his brutality, by holding the softer
passions in detestation. The Prince Royal, too, was not one of those
who are content to take their religion on trust. He asked puzzling
questions, and brought forward arguments which seemed to savour
of something different from pure Lutheranism. The King suspected
that his son was inclined to be a heretic of some sort or other,
whether Calvinist or Atheist his Majesty did not very well know. The
ordinary malignity of Frederic William was bad enough. He now
thought malignity a part of his duty as a Christian man, and all the
conscience that he had stimulated his hatred. The flute was broken:
the French books were sent out of the palace: the Prince was kicked
and cudgelled, and pulled by the hair. At dinner the plates were
hurled at his head: sometimes he was restricted to bread and water:
sometimes he was forced to swallow food so nauseous that he could
not keep it on his stomach. Once his father knocked him down,
dragged him along the floor to a window, and was with difficulty
prevented from strangling him with the cord of the curtain. The
Queen, for the crime of not wishing to see her son murdered, was
subjected to the grossest indignities. The Princess Wilhelmina, who
took her brother’s part, was treated almost as ill as Mrs. Brownrigg’s
apprentices.
Driven to despair, the unhappy youth tried to run away. Then the
fury of the old tyrant rose to madness. The Prince was an officer in
the army: his flight was therefore desertion; and, in the moral code
of Frederic William, desertion was the highest of all crimes.
“Desertion,” says this royal theologian, in one of his half crazy
letters, “is from hell. It is a work of the children of the Devil. No child
of God could possibly be guilty of it.” An accomplice of the Prince, in
spite of the recommendation of a court martial, was mercilessly put
to death. It seemed probable that the Prince himself would suffer
the same fate. It was with difficulty that the intercession of the
States of Holland, of the Kings of Sweden and Poland, and of the
Emperor of Germany, saved the House of Brandenburg from the
stain of an unnatural murder. After months of cruel suspense,
Frederic learned that his life would be spared. He remained,
however, long a prisoner; but he was not on that account to be
pitied. He found in his gaolers a tenderness which he had never
found in his father; his table was not sumptuous, but he had
wholesome food in sufficient quantity to appease hunger: he could
read the Henriade without being kicked, and could play on his flute
without having it broken over his head.
When his confinement terminated he was a man. He had nearly
completed his twenty-first year, and could scarcely be kept much
longer under the restraints which had made his boyhood miserable.
Suffering had matured his understanding, while it had hardened his
heart and soured his temper. He had learnt self-command and
dissimulation: he affected to conform to some of his father’s views,
and submissively accepted a wife, who was a wife only in name,
from his father’s hand. He also served with credit, though without
any opportunity of acquiring brilliant distinction, under the command
of Prince Eugene, during a campaign marked by no extraordinary
events. He was now permitted to keep a separate establishment,
and was therefore able to indulge with caution his own tastes. Partly
in order to conciliate the King, and partly, no doubt, from inclination,
he gave up a portion of his time to military and political business,
and thus gradually acquired such an aptitude for affairs as his most
intimate associates were not aware that he possessed.
His favourite abode was at Rheinsberg, near the frontier which
separates the Prussian dominions from the Duchy of Mecklenburg.
Rheinsberg is a fertile and smiling spot, in the midst of the sandy
waste of the Marquisate. The mansion, surrounded by woods of oak
and beech, looks out upon a spacious lake. There Frederic amused
himself by laying out gardens in regular alleys and intricate mazes,
by building obelisks, temples, and conservatories, and by collecting
rare fruits and flowers. His retirement was enlivened by a few
companions, among whom he seems to have preferred those who,
by birth or extraction, were French. With these inmates he dined and
supped well, drank freely, and amused himself sometimes with
concerts, and sometimes with holding chapters of a fraternity which
he called the Order of Bayard; but literature was his chief resource.
His education had been entirely French. The long ascendency which
Lewis the Fourteenth had enjoyed, and the eminent merit of the
tragic and comic dramatists, of the satirists, and of the preachers
who had flourished under that magnificent prince, had made the
French language predominant in Europe. Even in countries which
had a national literature, and which could boast of names greater
than those of Racine, of Molière, and of Massillon, in the country of
Dante, in the country of Cervantes, in the country of Shakspeare and
Milton, the intellectual fashions of Paris had been to a great extent
adopted. Germany had not yet produced a single masterpiece of
poetry or eloquence. In Germany, therefore, the French taste
reigned without rival and without limit. Every youth of rank was
taught to speak and write French. That he should speak and write
his own tongue with politeness, or even with accuracy and facility,
was regarded as comparatively an unimportant object. Even Frederic
William, with all his rugged Saxon prejudices, thought it necessary
that his children should know French, and quite unnecessary that
they should be well versed in German. The Latin was positively
interdicted. “My son,” his Majesty wrote, “shall not learn Latin; and,
more than that, I will not suffer anybody even to mention such a
thing to me.” One of the preceptors ventured to read the Golden Bull
in the original with the Prince Royal. Frederic William entered the
room, and broke out in his usual kingly style.
“Rascal, what are you at there?”
“Please your Majesty,” answered the preceptor, “I was explaining
the Golden Bull to his Royal Highness.”
 “I’ll Golden Bull you, you rascal!” roared the Majesty of Prussia. Up
went the King’s cane; away ran the terri lied instructor; and
Frederic’s classical studies ended for ever. He now and then affected
to quote Latin sentences, and produced such exquisitely Ciceronian
phrases as these:—“Stante pede morire,”—“De gustibus non est
disputandus,”—“Tot verbas tot spondera.” Of Italian, he had not
enough to read a page of Metastasio with ease; and of the Spanish
and English, he did not, as for as we are aware, understand a single
word.
As the highest human compositions to which he had access were
those of the French writers, it is not strange that his admiration for
those writers should have been unbounded. His ambitious and eager
temper early prompted him to imitate what he admired. The wish,
perhaps, dearest his heart was, that he might rank among the
masters of French rhetoric and poetry. He wrote prose and verse as
indefetigably as if he had been a starving hack of Cave or Osborn;
but Nature, which had bestowed on him, in a large measure, the
talents of a captain and of an administrator, had withheld from him
those higher and rarer gifts, without which industry labors in vain to
produce immortal eloquence and song. And, indeed, had he been
blessed with more imagination, wit, and fertility of thought, than he
appears to have had, he would still have been subject to one great
disadvantage, which would, in all probability, have for ever
prevented him from taking a high place among men of letters. He
had not the full command of any language. There was no machine
of thought which he could employ with perfect ease, confidence, and
freedom. He had German enough to scold his servants, or to give
the word of command to his grenadiers; but his grammar and
pronunciation were extremely bad. He found it difficult to make out
the meaning even of the simplest German poetry. On one occasion a
version of Racine’s Iphigénie was read to him. He held the French
original in his hand; but was forced to own that, even with such
help, he could not understand the translation. Yet, though he had
neglected his mother tongue in order to bestow all his attention on
French, his French was, after all, the French of a foreigner. It was
necessary for him to have always at his beck some men of letters
from Paris to point out the solecisms and false rhymes of which, to
the last, he was frequently guilty. Even had he possessed the poetic
faculty, of which, as far as we can judge, he was utterly destitute,
the want of a language would have prevented him from being a
great poet. No noble work of imagination, as far as we recollect, was
ever composed by any man, except in a dialect which he had
learned without remembering bow or when, ana which he had
spoken with perfect ease before he had ever analysed its structure.
Romans of great abilities wrote Greek verses; but how many of
those verses have deserved to live? Many men of eminent genius
have, in modern times, written Latin poems; but, as for as we are
aware, none of those poems, not even Milton’s, can be ranked in the
first class of art, or even very high in the second. It is not strange,
therefore, that, in the French verses of Frederic, we can find nothing
beyond the reach of any man of good parts and industry, nothing
above the level of Newdigate and Seatonian poetry. His best pieces
may perhaps rank with the worst in Dodsley’s collection. In history,
he succeeded better. We do not, indeed, find, in any part of his
voluminous Memoirs, either deep reflection or vivid pointing. But the
narrative is distinguished by clearness, conciseness, good sense, and
a certain air of truth and simplicity, which is singularly graceful in a
man who, having done great things, sits down to relate them. On
the whole, however, none of his writings are so agreeable to us as
his Letters, particularly those which are written with earnestness,
and are not embroidered with verses.
It is not strange that a young man devoted to literature, and
acquainted only with the literature of France, should have looked
with profound veneration on the genius of Voltaire. “A man who has
never seen the sun,” says Calderon, in one of his charming
comedies, “cannot be blamed for thinking that no glory can exceed
that of the moon. A man who has seen neither moon nor sun,
cannot be blamed for talking of the unrivalled brightness of the
morning star.” Had Frederic been able to read Homer and Milton, or
even Virgil and Tasso, his admiration of the Henriade would prove
that he was utterly destitute of the power of discerning what is
excellent in art. Had he been familiar with Sophocles or Shakspeare,
we should have expected him to appreciate Zaire more justly. Had
he been able to study Thucydides and Tacitus in the original Greek
and Latin, he would have known that there were heights in the
eloquence of history far beyond the reach of the author of the Life of
Charles the Twelfth. But the finest heroic poem, several of the most
powerful tragedies, and the most brilliant and picturesque historical
work that Frederic had ever read were Voltaire’s. Such high and
various excellence moved the young prince almost to adoration. The
opinions of Voltaire on religious and philosophical questions had not
yet been fully exhibited to the public. At a later period, when an
exile from his country, and at open war with the Church, he spoke
out. But when Frederic was at Rheinsberg, Voltaire was still a
courtier; and, though He could not always curb his petulant wit, he
had as yet published nothing that could exclude him from Versailles,
and little that a divine of the mild and generous school of Grotius
and Tillotson might not read with pleasure. In the Henriade, in Zaire,
and in Alzire, Christian piety is exhibited in the most amiable form;
and, some years after the period of which we are writing, a Pope
condescended to accept the dedication of Mahomet. The real
sentiments of the poet, however, might be clearly perceived by a
keen eye through the decent disguise with which he veiled them,
and could not escape the sagacity of Frederic, who held similar
opinions, and had been accustomed to practice similar dissimulation.
The Prince wrote to his idol in the style of a worshipper; and
Voltaire replied with exquisite grace and address. A correspondence
followed, which may be studied with advantage by those who wish
to become proficients in the ignoble art of flattery. No man ever paid
compliments better than Voltaire. His sweetest confectionery had
always a delicate, yet stimulating flavour, which was delightful to
palates wearied by the coarse preparations of inferior artists. It was
only from his hand that so much sugar could be swallowed without
making the swallower sick. Copies of verses, writing desks, trinkets
of amber, were exchanged between the friends. Frederic confided his