Principles of Bone Biology - 4th Edition

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Principles of Bone Biology

Fourth Edition

Volume 2
Edited by
John P. Bilezikian
Division of Endocrinology, Department of Medicine
College of Physicians and Surgeons
Columbia University, New York, NY, United States

T. John Martin
St. Vincent’s Institute of Medical Research;
Department of Medicine at St. Vincent’s Hospital
The University of Melbourne
Melbourne, Australia

Thomas L. Clemens
Department of Orthopaedic Surgery
Johns Hopkins University School of Medicine;
Baltimore Veterans Administration Medical Center
Baltimore, MD, United States

Clifford J. Rosen
Maine Medical Center Research Institute
Scarborugh, ME, United States
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Dedication of Fourth Edition
to Lawrence G. Raisz

By the end of the 1970s, when the bone research community felt that it was ready for its own scientific society, Larry Raisz
was one of the leaders of the group that founded the American Society for Bone and Mineral Research (ASBMR). The
ASBMR had its first annual conference in 1979, with Larry serving as its second president. As the first editor of the
Journal of Bone and Mineral Research, for a decade, Larry set the highest scientific standards for quality and integrity.
That standard remains untarnished today.
Larry’s knowledge of the facts in our field was prodigious. His expertise and experience in basic elements of bone
biology were exceptional. He had great understanding and wisdom in interpretation of the clinical implications of basic
bone biology. But he always wanted to know more. At ASBMR and other annual meetings, it was always Larry who rose
to the microphone after a presentation to ask, not only the first question, but typically the best one! Remarkably, Larry
could translate basic bone biology to the clinical arena. Few in our field then or now could so smoothly integrate clinical
aspects of metabolic bone diseases with the burgeoning knowledge of underlying pathophysiological mechanisms. Adding
to these talents was a collegiality and an exuberant enthusiasm that pervaded all venues of Larry Raisz’s world. As
osteoporosis became more widely recognized to be a medical scourge, then and now, Larry quickly grasped the need to
speak about the burden of the disease and contributed to the international dialogue, raising awareness among us all. This
awareness was a major factor in the recognition among countries that we are dealing with a disease that needs greater
understanding at all levels. And, indeed, at all levels, Larry contributed so much.
These qualities made Larry Raisz a wonderfully effective coeditor of the first three editions of Principles of Bone
Biology. Much more than that, though, he was a pleasure to work with as a colleague and friend, exceptionally efficient and
with unfailing humor and optimism when faced with any adversity. Larry would share the highs and lows with you, but the
lows were rare and short lived.
We remember him constantly and dedicate to Lawrence G. Raisz, MD, this fourth edition of what he called “Big Gray.”

John P. Bilezikian
T. John Martin
Thomas L. Clemens
Clifford J. Rosen
List of Contributors

David Abraham Centre for Rheumatology and Connective George Bou-Gharios Institute of Ageing and Chronic
Tissue Diseases, University College London, London, Disease, University of Liverpool, Liverpool, United
United Kingdom Kingdom
Maria Almeida Division of Endocrinology and Metabo- Roger Bouillon Laboratory of Clinical and Experimental
lism, Center for Osteoporosis and Metabolic Bone Endocrinology, Department of Chronic Diseases,
Diseases, University of Arkansas for Medical Sciences, Metabolism and Aging, KU Leuven, Belgium
Little Rock, AR, United States; The Central Arkansas Mary L. Bouxsein Center for Advanced Orthopaedic
Veterans Healthcare System, Little Rock, AR, United Studies, Beth Israel Deaconess Medical Center, Bos-
States ton, MA, United States; Department of Orthopaedic
Elena Ambrogini Center for Osteoporosis and Metabolic Surgery, Harvard Medical School, Boston, MA, Uni-
Bone Diseases, University of Arkansas for Medical ted States; Endocrine Unit, Department of Medicine,
Sciences Division of Endocrinology and Metabolism, Massachusetts General Hospital, Boston, MA, United
Little Rock, AR, United States; Central Arkansas Vet- States
erans Healthcare System, Little Rock, AR, United Brendan F. Boyce Department of Pathology and Labo-
States ratory Medicine, University of Rochester School of
Andrew Arnold Center for Molecular Oncology and Medicine and Dentistry, Rochester, NY, United States
Division of Endocrinology and Metabolism, University Steven Boyd McCaig Institute for Bone and Joint Health,
of Connecticut School of Medicine, Farmington, CT, The University of Calgary, Calgary, AB, Canada
United States
Maria Luisa Brandi Department of Experimental and
Bence Bakos 1st Department of Medicine, Semmelweis Clinical Biomedical Sciences, University of Florence,
University Medical School, Budapest, Hungary Florence, Italy
Clemens Bergwitz Departments of Pediatrics and Internal David B. Burr Department of Anatomy and Cell Biology,
Medicine, Yale University School of Medicine, New Indiana Center for Musculoskeletal Health, Indiana
Haven, CT, United States University School of Medicine, Indianapolis, IN, Uni-
Daniel D. Bikle VA Medical Center and University of ted States
California San Francisco, San Francisco, California, Laura M. Calvi Department of Medicine and Wilmot
United States Cancer Center, University of Rochester Medical Center,
John P. Bilezikian Division of Endocrinology, Department Rochester, NY, United States
of Medicine, College of Physicians and Surgeons, Ernesto Canalis Departments of Orthopaedic Surgery and
Columbia University, New York, NY, United States Medicine, and the UConn Musculoskeletal Institute,
Neil Binkley University of Wisconsin School of Medicine UConn Health, Farmington, CT, United States
and Public Health, Madison, Wisconsin, United States Xu Cao Department of Orthopedic Surgery, Johns Hopkins
Alessandro Bisello Department of Pharmacology and University School of Medicine, Baltimore, MD, United
Chemical Biology, Laboratory for GPCR Biology, States
University of Pittsburgh School of Medicine, Pitts- Geert Carmeliet Laboratory of Clinical and Experimental
burgh, PA, United States Endocrinology, Department of Chronic Diseases,
L.F. Bonewald Indiana Center for Musculoskeletal Health, Metabolism and Ageing, KU Leuven, Leuven, Bel-
Departments of Anatomy and Cell Biology and Ortho- gium; Prometheus, Division of Skeletal Tissue Engi-
paedic Surgery, Indiana University, Indianapolis, IN, neering, KU Leuven, Leuven, Belgium
USA

xiii
xiv List of Contributors

Thomas O. Carpenter Departments of Pediatrics and Benoit de Crombrugghe The University of Texas M.D.
Internal Medicine, Yale University School of Medicine, Anderson Cancer Center, Houston, TX, United States
New Haven, CT, United States Hector F. DeLuca Department of Biochemistry, Uni-
Wenhan Chang Endocrine Research Unit, Department of versity of WisconsineMadison, Madison, Wisconsin,
Veterans Affairs Medical Center, Department of Med- United States
icine, University of California, San Francisco, CA, David W. Dempster Regional Bone Center, Helen Hayes
United States Hospital, West Haverstraw, NY, United States;
Shek Man Chim Regeneron Pharmaceuticals, Inc. Tarry- Department of Pathology and Cell Biology, College of
town, NY, United States Physicians and Surgeons, Columbia University, New
Shilpa Choudhary Department of Medicine and Muscu- York, NY, United States
loskeletal Institute, UConn Health, Farmington, CT, Matthew T. Drake Department of Endocrinology and
United States Kogod Center of Aging, Mayo Clinic College of
Sylvia Christakos Department of Microbiology, Bio- Medicine, Rochester, MN, United States
chemistry and Molecular Genetics, Rutgers, New Jersey Patricia Ducy Department of Pathology & Cell Biology,
Medical School, Newark, NJ, United States Columbia University, College of Physicians & Sur-
Yong-Hee Patricia Chun Department of Periodontics, geons, New York, NY, United States
University of Texas Health Science Center at San Frank H. Ebetino Department of Chemistry, University of
Antonio, San Antonio, TX, United States Rochester, Rochester, NY, United States; Mellanby
Cristiana Cipriani Department of Internal Medicine and Centre for Bone Research, Medical School, University
Medical Disciplines, Sapienza University of Rome, of Sheffield, United Kingdom
Italy Klaus Engelke Department of Medicine, FAU University
Roberto Civitelli Washington University in St. Louis, Erlangen-Nürnberg and Universitätsklinikum Erlangen,
Department of Medicine, Division of Bone and Mineral Erlangen, Germany; Bioclinica, Hamburg, Germany
Diseases, St. Louis, MO, United States Reinhold G. Erben Department of Biomedical Research,
Thomas L. Clemens Department of Orthopaedic Surgery, University of Veterinary Medicine Vienna, Vienna,
Johns Hopkins University School of Medicine, Balti- Austria
more, MD, United States; Baltimore Veterans Admin- David R. Eyre Department of Orthopaedics and Sports
istration Medical Center, Baltimore, MD, United States Medicine, University of Washington, Seattle, WA,
Michael T. Collins Skeletal Disorders and Mineral United States
Homeostasis Section, National Institute of Dental and Charles R. Farber Center for Public Health Genomics,
Craniofacial Research, National Institutes of Health, Departments of Public Health Sciences and Bio-
Bethesda, MD, United States chemistry and Molecular Genetics, University of
Caterina Conte Vita-Salute San Raffaele University, Virginia School of Medicine, Charlottesville, VA,
Milan, Italy; Division of Immunology, Transplantation United States
and Infectious Diseases, IRCCS San Raffaele Scientific Marina Feigenson Department of Developmental Biology,
Institute, Milan, Italy Harvard School of Dental Medicine, Boston, MA,
Mark S. Cooper The University of Sydney, ANZAC United States
Research Institute and Department of Endocrinology & Mathieu Ferron Institut de Recherches Cliniques de
Metabolism, Concord Hospital, Sydney, NSW, Australia Montréal, Montréal, QC, Canada
Jillian Cornish Department of Medicine, University of Pablo Florenzano Endocrine Department, School of
Auckland, Auckland, New Zealand Medicine, Pontificia Universidad Católica de Chile,
Serge Cremers Department of Pathology & Cell Biology Santiago, Chile
and Department of Medicine, Vagelos College of Francesca Fontana Washington University in St. Louis,
Physicians and Surgeons, Columbia University Irving Department of Medicine, Division of Bone and Mineral
Medical Center, United States Diseases, St. Louis, MO, United States
Bess Dawson-Hughes Jean Mayer USDA Human Nutri- Brian L. Foster Biosciences Division at College of Den-
tion Research Center on Aging at Tufts University, tistry at Ohio State University, Columbus, OH, United
Boston, Massachusetts, United States States
 List of Contributors xv

Peter A. Friedman Department of Pharmacology and Fadil M. Hannan Department of Musculoskeletal Biology,
Chemical Biology, Laboratory for GPCR Biology, Institute of Ageing and Chronic Disease, Faculty of
University of Pittsburgh School of Medicine, Pitts- Health & Life Sciences, University of Liverpool, Liv-
burgh, PA, United States erpool, United Kingdom; Academic Endocrine Unit,
Seiji Fukumoto Fujii Memorial Institute of Medical Sci- Radcliffe Department of Medicine, University of
ences, Institute of Advanced Medical Sciences, Oxford, Oxford Centre for Diabetes, Endocrinology and
Tokushima University, Tokushima, Japan Metabolism (OCDEM), Churchill Hospital, Oxford,
United Kingdom
Laura W. Gamer Department of Developmental Biology,
Harvard School of Dental Medicine, Boston, MA, Stephen E. Harris Department of Periodontics, University
United States of Texas Health Science Center at San Antonio, San
Antonio, TX, United States
Thomas J. Gardella Endocrine Unit, Department of
Medicine and Pediatric Nephrology, MassGeneral Iris R. Hartley Interinstitute Endocrine Training Program,
Hospital for Children, Massachusetts General Hospital Eunice Kennedy Shriver National Institute of Child
and Harvard Medical School, Boston, MA, United Health and Human Development, National Institutes of
States Health, Bethesda, MD, United States

Patrick Garnero INSERM Research Unit 1033-Lyos, Christine Hartmann Institute of Musculoskeletal Medi-
Lyon, France cine, Department of Bone and Skeletal Research,
Medical Faculty of the University of Münster, Münster,
Harry K. Genant Departments of Radiology and Medi- Germany
cine, University of California, San Francisco, CA,
United States Robert P. Heaney Creighton University, Omaha, NE,
United States
Francesca Giusti Department of Experimental and Clinical
Biomedical Sciences, University of Florence, Florence, Geoffrey N. Hendy Metabolic Disorders and Complica-
Italy tions, McGill University Health Center Research Insti-
tute, and Departments of Medicine, Physiology and
Andy Göbel Department of Medicine III, Technische Uni- Human Genetics, McGill University, Montreal, QC,
versität Dresden, Dresden, Germany; German Cancer Canada
Consortium (DKTK), Partner site Dresden and German
Cancer Research Center (DKFZ), Heidelberg, Germany Matthew J. Hilton Department of Orthopaedic Surgery,
Department of Cell Biology, Duke University School of
David Goltzman Calcium Research Laboratories and Medicine, Durham, NC, United States
Department of Medicine, McGill University and McGill
University Health Centre, Montreal, QC, Canada Lorenz C. Hofbauer Center for Regenerative Therapies
Dresden, Center for Healthy Aging and Division of
Jeffrey P. Gorski Department of Oral and Craniofacial Endocrinology, Diabetes, and Bone Diseases, Depart-
Sciences, School of Dentistry, and Center for Excel- ment of Medicine III, Technische Universität Dresden,
lence in Mineralized and Dental Tissues, University of Dresden, Germany
MissourieKansas City, Kansas City, MO, United States
Gill Holdsworth Bone Therapeutic Area, UCB Pharma,
James Griffith Department of Imaging and Interventional Slough, United Kingdom
Radiology, The Chinese University of Hong Kong,
Hong Kong, China Yi-Hsiang Hsu Department of Medicine, Beth Israel
Deaconess Medical Center and Harvard Medical
R. Graham G Russell Mellanby Centre for Bone School, Harvard School of Public Health, Hinda and
Research, Medical School, University of Sheffield, Arthur Marcus Institute for Aging Research, Hebrew
United Kingdom; Nuffield Department of Orthopaedics, SeniorLife, Boston, MA, United States
Rheumatology and Musculoskeletal Sciences, The
Oxford University Institute of Musculoskeletal Scien- David M. Hudson Department of Orthopaedics and Sports
ces, The Botnar Research Centre, Nuffield Orthopaedic Medicine, University of Washington, Seattle, WA,
Centre, Oxford, United Kingdom United States

Kurt D. Hankenson Department of Orthopaedic Surgery, Marja Hurley Department of Medicine, University of
University of Michigan Medical School, Ann Arbor, Connecticut School of Medicine, UConn Health,
MI, United States Farmington, CT, United States
xvi List of Contributors

Karl L. Insogna Departments of Pediatrics and Internal Yasuhiro Kobayashi Institute for Oral Science, Matsu-
Medicine, Yale University School of Medicine, New moto Dental University, Nagano, Japan
Haven, CT, United States Martin Konrad Department of General Pediatrics, Uni-
Robert L. Jilka Center for Osteoporosis and Metabolic versity Children’s Hospital Münster, Münster, Germany
Bone Diseases, University of Arkansas for Medical Paul J. Kostenuik Phylon Pharma Services, Newbury
Sciences Division of Endocrinology and Metabolism, Park, CA, United States; School of Dentistry, Uni-
Little Rock, AR, United States; Central Arkansas Vet- versity of Michigan, Ann Arbor, MI, United States
erans Healthcare System, Little Rock, AR, United States
Christopher S. Kovacs Faculty of Medicine, Memorial
Mark L. Johnson Department of Oral and Craniofacial University of Newfoundland, St. John’s, NL, Canada
Sciences, UMKC School of Dentistry, Kansas City,
MO, United States Richard Kremer Calcium Research Laboratories and
Department of Medicine, McGill University and McGill
Rachelle W. Johnson Vanderbilt Center for Bone Biology, University Health Centre, Montreal, QC, Canada
Department of Medicine, Division of Clinical Pharma-
cology, Nashville, TN, United States Venkatesh Krishnan Lilly Research Laboratories, Eli
Lilly & Company, Lilly Corporate Center, Indianapolis,
Glenville Jones Department of Biomedical and Molecular United States
Science, Queen’s University, Kingston, ON, Canada
Henry M. Kronenberg Endocrine Unit, Massachusetts
Stefan Judex Department of Biomedical Engineering, General Hospital, Harvard Medical School, Boston,
Bioengineering Building, State University of New York MA, United States
at Stony Brook, Stony Brook, NY, United States
Peter A. Lakatos 1st Department of Medicine, Semmel-
Harald Jüppner Endocrine Unit, Department of Medicine weis University Medical School, Budapest, Hungary
and Pediatric Nephrology, MassGeneral Hospital for
Children, Massachusetts General Hospital and Harvard Uri A. Liberman Department of Physiology and Phar-
Medical School, Boston, MA, United States macology, Sackler Faculty of Medicine, Tel Aviv
University, Tel-Aviv, Israel
Ivo Kalajzic Department of Reconstructive Sciences,
UConn Health, Farmington, CT, United States Joseph A. Lorenzo The Departments of Medicine and
Orthopaedics, UConn Health, Farmington, CT, United
Gérard Karsenty Department of Genetics and Develop- States
ment, Columbia University Medical Center, New York,
NY, United States Conor C. Lynch Department of Tumor Biology, Moffitt
Cancer Center, Tampa, FL, United States
Hua Zhu Ke Angitia Biopharmaceuticals Limited,
Guangzhou, China Karen M. Lyons Department of Orthopaedic Surgery/
Orthopaedic Hospital, University of California, Los
Sundeep Khosla Department of Medicine, Division of Angeles, CA, United States; Department of Molecular,
Endocrinology, Mayo Clinic College of Medicine, Cell, & Developmental Biology, University of Cal-
Rochester, MN, United States; The Robert and Arlene ifornia, Los Angeles, CA, United States
Kogod Center on Aging, Rochester, MN, United States
Y. Linda Ma Biotechnology and Autoimmunity Research,
Douglas P. Kiel Department of Medicine, Beth Israel Eli Lilly and Company, Indianapolis, IN, United States
Deaconess Medical Center and Harvard Medical
School, Harvard School of Public Health, Hinda and Christa Maes Laboratory of Skeletal Cell Biology and
Arthur Marcus Institute for Aging Research, Hebrew Physiology (SCEBP), Skeletal Biology and Engineering
SeniorLife, Boston, MA, United States Research Center (SBE), KU Leuven, Leuven, Belgium
J. Klein-Nulend Department of Oral Cell Biology, Michael Mannstadt Endocrine Unit, Massachusetts Gen-
Academic Centre for Dentistry Amsterdam (ACTA), eral Hospital, Harvard Medical School, Boston, MA,
University of Amsterdam and Vrije Universiteit United States
Amsterdam, Amsterdam Movement Sciences, Amster- Stavros Manolagas Division of Endocrinology and
dam, The Netherlands Metabolism, Center for Osteoporosis and Metabolic
Frank C. Ko Center for Advanced Orthopaedic Studies, Bone Diseases, University of Arkansas for Medical
Beth Israel Deaconess Medical Center, Boston, MA, Sciences, Little Rock, AR, United States; The Central
United States Arkansas Veterans Healthcare System, Little Rock, AR,
United States
 List of Contributors xvii

Robert Marcus Stanford University, Stanford, CA, United Nicola Napoli Unit of Endocrinology and Diabetes, Uni-
States versity Campus Bio-Medico, Rome, Italy; Division of
David E. Maridas Department of Developmental Biology, Bone and Mineral Diseases, Washington University in
Harvard School of Dental Medicine, Boston, MA, St Louis, St Louis, MO, United States
United States Tally Naveh-Many Minerva Center for Calcium and Bone
Pierre J. Marie UMR-1132 Inserm (Institut national de la Metabolism, Nephrology Services, Hadassah University
Santé et de la Recherche Médicale) and University Paris Hospital, Hebrew University School of Medicine, Jer-
Diderot, Sorbonne Paris Cité, Paris, France usalem, Israel
Francesca Marini Department of Experimental and Clin- Edward F. Nemeth MetisMedica, Toronto, ON, Canada
ical Biomedical Sciences, University of Florence, Thomas L. Nickolas Division of Nephrology, Department
Florence, Italy of Medicine, Columbia University Medical Center,
Jasna Markovac California Institute of Technology, New York, NY, United States
Pasadena, CA, United States Michael S. Ominsky Radius Health Inc., Waltham, MA,
T. John Martin St. Vincent’s Institute of Medical United States
Research, Melbourne, Australia; Department of Noriaki Ono Department of Orthodontics and Pediatric
Medicine at St. Vincent’s Hospital, The University of Dentistry, University of Michigan School of Dentistry,
Melbourne, Melbourne, Australia Ann Arbor, MI, United States
Brya G. Matthews Department of Molecular Medicine and David M. Ornitz Department of Developmental Biology,
Pathology, University of Auckland, Auckland, New Washington University School of Medicine, St. Louis,
Zealand MO, United States
Antonio Maurizi Department of Biotechnological and Nicola C. Partridge Department of Basic Science and
Applied Clinical Sciences, University of L’Aquila, Craniofacial Biology, New York University College of
L’Aquila, Italy Dentistry, New York, NY, United States
Sasan Mirfakhraee The University of Texas Southwestern Vihitaben S. Patel Department of Biomedical Engineering,
Medical Center, Department of Internal Medicine, Bioengineering Building, State University of New York
Endocrine Division, Dallas, TX, United Sates at Stony Brook, Stony Brook, NY, United States
Sharon M. Moe Division of Nephrology, Indiana University J. Wesley Pike Department of Biochemistry, University of
School of Medicine, Rodebush Veterans Administration WisconsineMadison, Madison, WI, United States
Medical Center, Indianapolis, IN, United States Carol Pilbeam Department of Medicine and Muscu-
David G. Monroe Department of Medicine, Division of loskeletal Institute, UConn Health, Farmington, CT,
Endocrinology, Mayo Clinic College of Medicine, United States
Rochester, MN, United States; The Robert and Arlene Lori Plum Department of Biochemistry, University of
Kogod Center on Aging, Rochester, MN, United States WisconsineMadison, Madison, Wisconsin, United States
Carolina A. Moreira Bone Unit of Endocrine Division of John T. Potts, Jr. Endocrine Unit, Department of
Federal University of Parana, Laboratory PRO, Section Medicine and Pediatric Nephrology, MassGeneral
of Bone Histomorphometry, Pro Renal Foundation, Hospital for Children, Massachusetts General Hospital
Curitiba, Parana, Brazil and Harvard Medical School, Boston, MA, United
Ralph Müller Institute for Biomechanics, ETH Zurich, States
Zurich, Switzerland J. Edward Puzas Department of Orthopaedics and Reha-
David S. Musson Department of Medicine, University of bilitation, University of Rochester School of Medicine
Auckland, Auckland, New Zealand and Dentistry, Rochester, NY, United States
Teruyo Nakatani Department of Basic Science and Cra- Tilman D. Rachner Department of Medicine III, Techni-
niofacial Biology, New York University College of sche Universität Dresden, Dresden, Germany; German
Dentistry, New York, NY, United States Cancer Consortium (DKTK), Partner site Dresden and
Dorit Naot Department of Medicine, University of Auck- German Cancer Research Center (DKFZ), Heidelberg,
land, Auckland, New Zealand Germany; Center for Healthy Aging and Division of
xviii List of Contributors

Endocrinology, Diabetes, and Bone Diseases, Techni- Clinton T. Rubin Department of Biomedical Engineering,
sche Universität Dresden, Dresden, Germany Bioengineering Building, State University of New York
Audrey Rakian Department of Applied Oral Sciences, The at Stony Brook, Stony Brook, NY, United States
Forsyth Institute, Cambridge, MA, United States; Karl P. Schlingmann Department of General Pediatrics,
Department of Oral Medicine, Infection, Immunity, University Children’s Hospital Münster, Münster,
Harvard School of Dental Medicine, Boston, MA, Germany
United States Ego Seeman Department of Endocrinology and Medicine,
Rubie Rakian Department of Applied Oral Sciences, The Austin Health, University of Melbourne, Melbourne,
Forsyth Institute, Cambridge, MA, United States; VIC, Australia; Mary MacKillop Institute for Health
Department of Oral Medicine, Infection, Immunity, Research, Australian Catholic University, Melbourne,
Harvard School of Dental Medicine, Boston, MA, VIC, Australia
United States Markus J. Seibel The University of Sydney, ANZAC
Nora E. Renthal Division of Endocrinology, Children’s Research Institute and Department of Endocrinology &
Hospital Boston, Boston, MA, United States Metabolism, Concord Hospital, Sydney, NSW, Australia
Julie A. Rhoades (Sterling) Department of Veterans Chris Sempos Vitamin D Standardization Program, Havre
Affairs, Nashville, TN, United States; Vanderbilt de Grace, MD, United States
Center for Bone Biology, Department of Medicine, Dolores M. Shoback Endocrine Research Unit, Depart-
Division of Clinical Pharmacology, Nashville, TN, ment of Veterans Affairs Medical Center, Department
United States; Department of Biomedical Engineering, of Medicine, University of California, San Francisco,
Nashville, TN, United States CA, United States
Mara Riminucci Department of Molecular Medicine, Caroline Silve Hôpital Bicêtre, Paris, France; Centre de
Sapienza University of Rome, Rome, Italy Référence des Maladies rares du Calcium et du Phos-
Scott J. Roberts Bone Therapeutic Area, UCB Pharma, phore and Filière de Santé Maladies Rares OSCAR,
Slough, United Kingdom AP-HP, Paris, France; Service de Biochimie et Génét-
Pamela Gehron Robey National Institute of Dental and ique Moléculaires, Hôpital Cochin, AP-HP, Paris,
Craniofacial Research, National Institutes of Health, France
Department of Health and Human Services, Bethesda, Justin Silver Minerva Center for Calcium and Bone
MD, United States Metabolism, Nephrology Services, Hadassah University
Michael J. Rogers Garvan Institute of Medical Research Hospital, Hebrew University School of Medicine, Jer-
and St Vincent’s Clinical School; University of New usalem, Israel
South Wales, Sydney, Australia Natalie A. Sims St. Vincent’s Institute of Medical
G. David Roodman Department of Medicine, Division of Research, Melbourne, Australia; Department of Medi-
Hematology and Oncology, Indiana University School cine at St. Vincent’s Hospital, The University of Mel-
of Medicine, and Roudebush VA Medical Center, bourne, Melbourne, Australia
Indianapolis, IN, United States Frederick R. Singer John Wayne Cancer Institute, Saint
Clifford J. Rosen Maine Medical Center Research Insti- John’s Health Center, Santa Monica, CA, United States
tute, Scarborugh, ME, United States Joseph P. Stains Department of Orthopaedics, University
Vicki Rosen Department of Developmental Biology, Har- of Maryland School of Medicine, Baltimore, MD,
vard School of Dental Medicine, Boston, MA, United United States
States Steve Stegen Laboratory of Clinical and Experimental
David W. Rowe Center for Regenerative Medicine and Endocrinology, Department of Chronic Diseases,
Skeletal Development, Department of Reconstructive Metabolism and Ageing, KU Leuven, Leuven, Bel-
Sciences, Biomaterials and Skeletal Development, gium; Prometheus, Division of Skeletal Tissue Engi-
School of Dental Medicine, University of Connecticut neering, KU Leuven, Leuven, Belgium
Health Center, Farmington, CT, United States Paula H. Stern Department of Pharmacology, Northwest-
Janet Rubin Endocrine Division, Department of Medicine, ern University Feinberg School of Medicine, Chicago,
University of North Carolina, Chapel Hill, NC, United IL, United States
States
 List of Contributors xix

Gaia Tabacco Division of Endocrinology, Department of Nobuyuki Udagawa Department of Biochemistry, Mat-
Medicine, College of Physicians and Surgeons, sumoto Dental University, Nagano, Japan
Columbia University, New York, NY, United States; Connie M. Weaver Purdue University, West Lafayette,
Endocrinology and Diabetes Unit, Department of IN, United States
Medicine, Campus Bio-Medico University of Rome,
Rome, Italy Marc N. Wein Endocrine Unit, Massachusetts General
Hospital, Harvard Medical School, Boston, MA, United
Istvan Takacs 1st Department of Medicine, Semmelweis States
University Medical School, Budapest, Hungary
Lee S. Weinstein Metabolic Diseases Branch, National
Naoyuki Takahashi Institute for Oral Science, Matsumoto Institute of Diabetes, Digestive, and Kidney Diseases,
Dental University, Nagano, Japan Bethesda, MD, United States
Donovan Tay Division of Endocrinology, Department of MaryAnn Weis Department of Orthopaedics and Sports
Medicine, College of Physicians and Surgeons, Medicine, University of Washington, Seattle, WA,
Columbia University, New York, NY, United States; United States
Department of Medicine, Sengkang General Hospital,
Singhealth, Singapore Michael P. Whyte Center for Metabolic Bone Disease and
Molecular Research, Shriners Hospitals for Children -
Anna Teti Department of Biotechnological and Applied St. Louis, St. Louis, MO, United States; Division of
Clinical Sciences, University of L’Aquila, L’Aquila, Bone and Mineral Diseases, Department of Internal
Italy Medicine, Washington University School of Medicine
Rajesh V. Thakker Academic Endocrine Unit, Radcliffe at Barnes-Jewish Hospital, St. Louis, MO, United States
Department of Medicine, University of Oxford, Oxford Bart O. Williams Program for Skeletal Disease and Center
Centre for Diabetes, Endocrinology and Metabolism for Cancer and Cell Biology, Van Andel Research
(OCDEM), Churchill Hospital, Oxford, United Institute, Grand Rapids, MI, United States
Kingdom
Xin Xu State Key Laboratory of Oral Diseases & National
Ryan E. Tomlinson Department of Orthopaedic Surgery, Clinical Research Center for Oral Diseases, Department
Thomas Jefferson University, Philadelphia, PA, United of Cariology and Endodontics, West China Hospital of
States Stomatology, Sichuan University, Chengdu, PR China
Francesco Tonelli Department of Experimental and Clin- Shoshana Yakar David B. Kriser Dental Center, Depart-
ical Biomedical Sciences, University of Florence, ment of Basic Science and Craniofacial Biology, New
Florence, Italy York University College of Dentistry New York, New
Dwight A. Towler The University of Texas Southwestern York, NY, United States
Medical Center, Department of Internal Medicine, Yingzi Yang Department of Developmental Biology,
Endocrine Division, Dallas, TX, United Sates Harvard School of Dental Medicine, Boston, MA,
Elena Tsourdi Department of Medicine III, Technische United States
Universität Dresden, Dresden, Germany; Center for Stefano Zanotti Departments of Orthopaedic Surgery and
Healthy Aging, Technische Universität Dresden, Medicine, and the UConn Musculoskeletal Institute,
Dresden, Germany UConn Health, Farmington, CT, United States
Chia-Ling Tu Endocrine Research Unit, Department of Hong Zhou The University of Sydney, ANZAC Research
Veterans Affairs Medical Center, Department of Med- Institute, Sydney, NSW, Australia
icine, University of California, San Francisco, CA,
United States
Preface to the Fourth Edition

The first edition of Principles of Bone Biology was published about 24 years ago, in 1996. Our field was ready then for a
compendium of the latest concepts in bone biology. Now, several decades and two editions later, we are pleased to
welcome you to the fourth edition of “Big Gray.” Since the third edition was published in 2008, our field has continued to
undergo sea changes of knowledge and insights. As a result of these advances since then, all chapters have undergone
major revisions. In addition, areas not previously covered in depth are featured, such as vascular and nerve interactions
with bone, interorgan communicants of bone, hematopoieticebone cell interactions, nonskeletal aspects of vitamin D and
RANK ligand, newly recognized signaling molecules and systems, and advances in methodological aspects of skeletal
research. Illustrative of the vibrancy of our field, over 50% of the authors in this edition are new to it. Our returning and
new authors are the very best.
We remember Larry Raisz. He, along with Gideon Rodan, constituted the triumvirate of coeditors for the first and
second editions. We dedicated the third edition to the memory of Gideon. We dedicate Principles of Bone Biology, fourth
edition, to the memory of Larry. In these front pages, we reprint our dedication to Gideon and remember Larry with a
separate dedication for this edition. We miss them both very much.
We want to acknowledge Jasna Markovac, who has served as our liaison to our authors and our publisher. Given the
nature of the times, this book would not have been completed without her dedication, perseverance, and single-minded
purpose not to let anything disrupt our publishing goals. She accomplished this feat with an even handedness and a
professionalism that was remarkable and remarkably effective. We are grateful to you, Jasna.
Finally, we are grateful to our authors, who have made this book what it is, namely a repository of knowledge and
concepts in bone biology and a resource for us all in the years to come.

John P. Bilezikian
T. John Martin
Thomas L. Clemens
Clifford J. Rosen

xxi
Chapter 1

Molecular and cellular regulation of

intramembranous and endochondral
bone formation during embryogenesis
Christine Hartmann1 and Yingzi Yang2
1
Institute of Musculoskeletal Medicine, Department of Bone and Skeletal Research, Medical Faculty of the University of Münster, Münster, Germany;
2
Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, United States

Chapter outline
Introduction 5 Systemic mediators 19
Intramembranous ossification 6 Local mediators 19
The axial skeleton 9 Growth factor signaling pathways 19
Somitogenesis 9 Transforming growth factor b and bone
Sclerotome differentiation 11 morphogenetic proteins 19
The limb skeleton 11 Parathyroid hormone-related protein and Indian
Overview of limb development 11 hedgehog 21
Proximaledistal axis 12 WNTs and b-catenin 23
Anterioreposterior axis 14 Fibroblast growth factors and their receptors 24
Dorsaleventral axis 14 C-type natriuretic peptide 25
Mesenchymal condensation and patterning of Notch signaling 25
the skeleton 14 Transcription factors 25
Endochondral bone formation 15 Epigenetic factors and microRNAs 26
Overview 15 The functional roles of the vasculature in
The growth plate 18 endochondral bone formation 27
Mediators of skeleton formation 19 References 27

Introduction
The skeletal system performs vital functions: support, movement, protection, blood cell production, calcium storage, and
endocrine regulation. Skeletal formation is also a hallmark that distinguishes vertebrate animals from invertebrates. In
higher vertebrates (i.e., birds and mammals), the skeletal system contains mainly bones and cartilage, as well as a
network of tendons and ligaments that connects them. During embryonic development, bones and cartilage are formed by
osteoblasts and chondrocytes, respectively, both of which are derived from common mesenchymal progenitor cells called
osteochondral progenitors. Skeletal development starts from mesenchymal condensation, during which mesenchymal
progenitor cells aggregate at future skeletal locations. As mesenchymal cells in different parts of the embryo are derived
from different cell lineages, the locations of initial skeletal formation determine which of the three mesenchymal cell
lineages contribute to the future skeleton. Neural crest cells from the branchial arches contribute to the craniofacial bone,
the sclerotome compartment of the somites gives rise to most of the axial skeleton, and lateral plate mesoderm forms the
limb mesenchyme, from which limb skeletons are derived.

Principles of Bone Biology. https://doi.org/10.1016/B978-0-12-814841-9.00001-4 5

Copyright © 2020 Elsevier Inc. All rights reserved.
6 PART | I Basic principles

How osteoblast cells are induced during bone development is a central question for understanding the organizational
principles underpinning a functional skeletal system. Abnormal osteoblast differentiation leads to a broad range of
devastating skeletal diseases. Therefore, it is imperative to understand the cellular and molecular mechanisms underlying
temporal and spatial controls of bone formation. Bone formation occurs by two essential processes: intramembranous
ossification and endochondral ossification during embryonic development. Osteochondral progenitors differentiate into
osteoblasts directly to form the membranous bone during intramembranous ossification, whereas during endochondral
ossification, they differentiate into chondrocytes instead to form a cartilage template of the future bone. Both ossification
processes are essential during the natural healing of bone fractures. In this chapter, we focus on current understanding of
the molecular regulation of endochondral and intramembranous bone formation and its implication in diseases.

Intramembranous ossification
Intramembranous ossification mainly occurs during formation of the flat bones of the skull, mandible, maxilla, and
clavicles. The mammalian cranium, or neurocranium, is the upper and back part of the skull. It protects the brain and
supports the sensory organs, such as the ear, and the viscerocranium, which supports the face. The neurocranium can be
divided into calvarium and chondrocranium, which grow to be the cranial vault that surrounds the brain and the skull base,
respectively. The calvarium is composed of flat bones: frontal bones, parietal bones, the interparietal part of the occipital
bone, and the squamous parts of the temporal bone (Jin et al., 2016). In mice, the calvarium consists of frontal bones,
parietal bones, interparietal bone, and squamous parts of the temporal bone, all going through intramembranous ossifi-
cation (Ishii et al., 2015). By lineage analysis in mouse models, frontal bones show a major contribution from neural crest
and a small contribution from head mesoderm, while parietal bones entirely originate from head mesoderm (Jiang et al.,
2002; Yoshida et al., 2008; Deckelbaum et al., 2012). Neural crestederived and head mesodermederived cells coalesce to
form calvarial bone primordia (Jiang et al., 2002; Yoshida et al., 2008). The mandible and maxilla are derived from the
neural crest cells originating in the mid- and hindbrain regions of the neural folds that migrate ventrally, while the clavicles
are formed from mesoderm.
The process starts from mesenchymal condensation and progresses through formation of the ossification center,
ossification expansion, trabecula formation, and compact bone formation and the development of the periosteum (Fig. 1.1).

FIGURE 1.1 Schematics of intramembranous cranial bone formation. See text for details.
 Molecular and cellular regulation of intramembranous and endochondral bone formation Chapter | 1 7

Condensation of mesenchymal progenitor cells is the first step for both intramembranous and endochondral ossification.
During intramembranous ossification, mesenchymal progenitor cells differentiate into osteoblasts instead of chondrocytes
as occurs during endochondral ossification. The osteoblasts that appear first in the condensation secrete bone matrix and
form the ossification center. The early osteoblasts secrete osteoid, uncalcified matrix, which calcifies soon after, while the
osteoblasts mature and terminally differentiate into osteocytes that are entrapped in the osteoid. As osteoblasts differentiate
into osteocytes, more mesenchymal progenitors surrounding the osteoid differentiate into new osteoblast cells at the
osteoid surface to expand the calcification center. Osteoid expansion around the capillaries results in a trabecular matrix of
the spongy bone, while osteoblasts on the superficial layer become the periosteum. The periosteum is a layer that also
contains mesenchymal progenitor cells, osteoblast differentiation of which contributes to the formation of a protective layer
of compact bone. The blood vessels along with other cells between the trabecular bone eventually form the red marrow.
Intramembranous ossification begins in utero during fetal development and continues on into adolescence. At birth, the
skull and clavicles are not fully ossified. Sutures and fontanelles are unossified cranial regions that allow the skull to
deform during passage through the birth canal. Sutures are joints between craniofacial bones, which are composed of two
osteogenic fronts with suture mesenchyme between them (Fig. 1.2). Fontanelles are the space between the skull bones
where the sutures intersect and are covered by tough membranes that protect the underlying soft tissues and brain. In
humans, cranial sutures normally fuse between 20 and 30 years of age and facial sutures fuse after 50 years of age (Badve
et al., 2013; Senarath-Yapa et al., 2012). Most sutures in mice remain patent throughout the animal’s lifetime. Sutures and
fontanelles allow the craniofacial bones to expand evenly as the brain grows, resulting in a symmetrically shaped head.
However, if any of the sutures close too early (fuse prematurely), in the condition called craniosynostosis, there may be no
growth in that area. This may force growth to occur in another area or direction, resulting in an abnormal head shape.
Apart from craniofacial bone development, intramembranous ossification also controls bone formation in the peri-
chondral and periosteal regions of the long bone, where osteoblasts directly differentiate from mesenchymal progenitor
cells. Yet, this requires a signal from the cartilaginous element. Furthermore, intramembranous ossification is an essential
mechanism underlying bone repair and regeneration in the following processes: fracture healing with rigid fixation;
distraction osteogenesis, a bone-regenerative process in which osteotomy followed by gradual distraction yields two
vascularized bone surfaces from which new bone is formed (Ai-Aql et al., 2008); and blastemic bone creation, which
occurs in children with amputations (Fernando et al., 2011).
Intramembranous ossification is tightly regulated at both molecular and cellular levels. Cranial malformations are often
progressive and irreversible, and some of them need aggressive surgical management to prevent or mitigate severe
impairment such as misshapen head or abnormal brain growth (Bronfin, 2001). For instance, craniosynostosis is a common
congenital disorder that affects 1 in 2500 live births. It is characterized by premature cranial suture fusion, which may
result in severe conditions such as increased intracranial pressure, craniofacial dysmorphism, disrupted brain development,
and mental retardation. Craniosynostosis is generally considered a developmental disorder resulting from a disrupted
balance of cellular proliferation, differentiation, and apoptosis within the suture (Senarath-Yapa et al., 2012; Levi et al.,
2012; Slater et al., 2008; Lattanzi et al., 2012; Ciurea and Toader, 2009). Surgical correction followed by reshaping of the
calvarial bones remains the only treatment available for craniosynostosis patients (Martou and Antonyshyn, 2011; Posnick
et al., 2010; Hankinson et al., 2010). In contrast to craniosynostosis, cleidocranial dysplasia (CCD) is caused by reduced
intramembranous bone formation, underdeveloped or absent clavicles (collarbones) as well as delayed maturation of the
skull, manifested by delayed suture closure and larger than normal fontanelles that are noticeable as “soft spots” on the
heads of infants (Farrow et al., 2018). Severe cases of CCD require surgical intervention. Identifying molecular pathways
that control intramembranous ossification is critically important in the mechanistic understanding of craniofacial bone
diseases and their targeted therapeutic development.

FIGURE 1.2 Schematics of cellular composition of the suture. In the suture, mesenchymal stem cells (MSCs) are located in the middle. They may first
become committed preosteoblasts and then finally mature osteoblasts.