International Journal of

Molecular Sciences

Editorial
Bone Development and Regeneration 2.0
Kazuo Yudoh *, Yodo Sugishita and Yuki Suzuki-Takahashi

Department of Frontier Medicine, Institute of Medical Science, St. Marianna University School of Medicine,
Kawasaki 216-8511, Japan; [email protected] (Y.S.); [email protected] (Y.S.-T.)
* Correspondence: [email protected]

Bone is an important tissue which is a structural body component, carrying out the
roles of mechanical stress response and organ/tissue protection. In addition, bone, as
an integral organ, not only regulates bone metabolism and regulates the hematopoietic
niche, but also acts as an endocrine organ to control some metabolic processes that are
independent of bone metabolism.
Bone homeostasis is regulated and maintained by the remodeling cycle of osteoblastic
bone formation and osteoclastic bone resorption [1,2]. When breaking the balance of bone
homeostasis, bone remodeling cannot maintain an invariant bone mass, consequently
leading to osteopenia and eventually osteoporosis [1–4]. Osteoporosis is an age-related
common disease that is characterized by low bone mass and bone microstructural destruc-
tion resulting from the downregulation of bone remodeling and bone homeostasis [1,3,4].
In comparison with other organs/tissues, bone shows a high regenerative and remodeling
potential throughout the human lifespan. Although bone tissue has a high regenerative
and remodeling potential, this gradually decreases with age. Indeed, with the continual
extension of life expectancy, aging-related bone mass loss and pathologies are increasing in
a gradual manner, which negatively influences the quality of daily living of an increasing
number of individuals. In particular, osteoporosis causes significant impacts on activities
of daily living (ADL), which are expected to be further accentuated in future by the contin-
uous increase in life expectancy. New scientific capabilities and perspectives are needed to
further understand the mechanism of bone homeostasis.
Regarding bone metabolism, several mechanisms and pathways, such as the wingless-
type (WNT)/beta-catenin, bone morphogenetic protein (BMP) 2 or parathyroid hormone
Citation: Yudoh, K.; Sugishita, Y.;
(PTH) signaling pathways, have been thoroughly studied over the last few decades. Among
Suzuki-Takahashi, Y. Bone
numerous regulatory factors in bone metabolism, mechanical stress is recognized as a
Development and Regeneration 2.0.
critically important factor in bone-associated cell differentiation/growth and their func-
Int. J. Mol. Sci. 2023, 24, 8761.
https://doi.org/10.3390/
tions, including those of osteoblasts, osteoclasts and osteocytes [5–7]. Recent studies
ijms24108761
have demonstrated that physiologic mechanical loading stimulates osteoblast differen-
tiation and resultant bone formation, and this is regulated by the molecular signaling
Received: 7 April 2023 pathway controlling osteocytes in response to mechanical stress [8–10]. Lin C. et al. demon-
Revised: 29 April 2023
strated that osteocyte-produced sclerostin (in response to mechanical loading) controls the
Accepted: 4 May 2023
bone-remodeling cycle (bone formation and resorption) as a master molecule in mechano-
Published: 15 May 2023
transduction [11]. Mechanical-stress-mediated bone metabolism is realized through the
interaction between two opponent mechanisms: (1) mechanical unloading accelerates scle-
rostin expression, which counteracts the Wnt/beta-catenin signaling pathway through the
Copyright: © 2023 by the authors.
interaction between osteocytes and osteoblasts, allowing the concurrent Wnt-noncanonical
Licensee MDPI, Basel, Switzerland. pathway in osteocytes to osteoclasts, and is directed at bone resorption; on the contrary,
This article is an open access article (2) mechanical loading decreases the expression of sclerostin, inducing the activation of
distributed under the terms and Wnt/beta-catenin signaling in osteocytes, consequently resulting in osteoblast differen-
conditions of the Creative Commons tiation and bone formation [11]. The interaction of osteoblasts with osteocytes through
Attribution (CC BY) license (https:// the osteocytic sclerostin-Wnt/beta-catenin signaling pathway is closely implicated in the
creativecommons.org/licenses/by/ mechanical-stress-mediated osteoblast differentiation following the acceleration of bone
4.0/). formation [8–12].

Int. J. Mol. Sci. 2023, 24, 8761. https://doi.org/10.3390/ijms24108761 https://www.mdpi.com/journal/ijms

Conversely, a recent report clearly indicates that physiologic mechanical stress directly
causes osteoblast differentiation and increased bone formation without a mechanism in-
volving the Wnt/beta-catenin signaling pathway connecting osteocytes and osteoblasts as
mentioned above [13]. Somemura S. et al. studied the interaction of the mechanical stress
response with glucose metabolism via the glucose transporter (Glut)-1 and energy sensor
sirtuin (Sirt)-1 in osteoblast energy metabolism [13]. They clearly revealed that both regula-
tors of energy metabolism, Glut-1 and Sirt-1, also function as master molecules of stress
responses against mechanical loading in osteoblasts. Mechanical loading to osteoblasts
changed the expression of Glut-1 and Sirt-1 following the activation of the osteogenic tran-
scription factor, Runx2, and resultant bone formation. Indeed, the inactivation of cell surface
Glut-1 by the inhibitor significantly reduced the mechanical-loading-induced changes in the
Sirt-1-to-Runx2 signaling pathway as well as bone formation activity, suggesting that the
activation of Glut1 is required for mechanical-stress-mediated osteoblast differentiation and
bone formation, via the signal transduction network between the energy sensor Sirt-1 and
the osteogenic transcription factor Runx2, in osteoblasts. The Glu-1-Sirt-1-Runx2 pathway
in osteoblasts may play some sort of role in mechanical-stress-mediated bone formation and
osteoblast differentiation, without the osteocytic sclerostin−Wnt/beta-catenin signaling
pathway. Mechanical loading may directly induce osteoblast differentiation and bone
formation through the signaling pathway of glucose metabolism, without a sclerostin–
Wnt/beta-catenin-dependent pathway through osteocyte-to-osteoblast contact. Indeed,
it has been indicated that glucose uptake induces the osteoblast differentiation and bone
formation potential by activating Runx2 activity in osteoblasts [14–17].
Attention has been attracted by recent findings that the nicotinamide adenine dinu-
cleotide (NAD)-dependent deacetylase Sirt-1 regulates many metabolic functions, such as
inflammatory response, apoptosis, cell cycle, DNA repair, genome stability, mitochondrial
function, cellular energy metabolism (adenosine triphosphate production) and cell re-
sponses to extrinsic stresses, including mechanical stress [18–23]. It has been also indicated
that Sirt-1 has two important roles—“regulation of cell energy metabolism” and “response
to cellular stresses (stress tolerance)”—which are involved in some metabolisms, and the
pathogenesis and pathology of a variety of diseases, including mechanical-stress-induced
degenerative diseases [24–26]. These findings provide evidence to support Sirt-1 activity
being a key factor which links the mechanical stress response to energy metabolism in
osteoblasts. In other words, the cell surface Glut-1-to-Sirt-1 pathway may have an impor-
tant role as a mechano-sensor in osteoblasts. Further understanding of the mechanisms
involved in the response of osteoblasts to mechanical stress is conducive to the elucidation
of bone metabolism and the pathophysiology of osteoporosis.
In particular, several factors and proteins are linked to the regulatory mechanisms
of bone development and growth, as well as bone regeneration and degeneration [27–30].
Saito M et al. indicated that 4.1 G, a plasma-membrane-associated cytoskeletal protein,
promotes primary ciliogenesis in the differentiating preosteoblasts and induction of cilia-
mediated osteoblast differentiation at the newborn stage [27]. Interestingly, it has been
demonstrated that LIM-homeodomain transcription factor (Lmx1b), which plays a key role
in body pattern formation during development, negatively regulates osteoblast differentia-
tion and function through regulation of Runx2 [28]. Although further studies are needed to
clarify the exact mechanism in bone biology, these papers will generate a representative
picture of the latest advances in bone research and serve as a road map for where the field
is headed.

Author Contributions: Conceptualization, K.Y., Y.S. and Y.S-T.; investigation, K.Y., Y.S. and Y.S.-T.;
resources, K.Y.; writing—original draft preparation, K.Y.; writing—review and editing, Y.S. and
Y.S.-T.; visualization, K.Y.; supervision, K.Y.; project administration, K.Y. All authors have read and
agreed to the published version of the manuscript.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.
Int. J. Mol. Sci. 2023, 24, 8761 3 of 4

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