Bone remodeling: Multiple cellular interactions required for coupling of bone formation and resorption.

The dynamic nature of the skeleton is achieved by a process called "remodeling" which involves the co-ordinated actions of osteoclasts, osteoblasts, osteocytes within the bone matrix and osteoblast-derived lining cells that cover the surface of bone. Remodeling commences with signals that initiate osteoclast formation followed by osteoclast-mediated bone resorption, a reversal period, and then a long period of bone matrix formation mediated by osteoblasts, followed by mineralisation of the matrix. This review will discuss each of these steps with particular emphasis on the communication pathways between each cell type involved and the roles of ephrins, sclerostin, RANKL and PTHrP.

[1]  P. Collin‐Osdoby,et al.  CCR1 Chemokines Promote the Chemotactic Recruitment, RANKL Development, and Motility of Osteoclasts and Are Induced by Inflammatory Cytokines in Osteoblasts , 2004, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[2]  R. Baron,et al.  The role(s) of Src kinase and Cbl proteins in the regulation of osteoclast differentiation and function , 2005, Immunological reviews.

[3]  P. Roberson,et al.  Increased bone formation by prevention of osteoblast apoptosis with parathyroid hormone. , 1999, The Journal of clinical investigation.

[4]  S. Vukicevic,et al.  Autoradiographic localization of osteogenin binding sites in cartilage and bone during rat embryonic development. , 1990, Developmental biology.

[5]  J. Wozney,et al.  Expression of bone morphogenetic protein messenger RNAs by normal rat and human prostate and prostate cancer cells , 1994, The Prostate.

[6]  M. Karsdal,et al.  Osteoclasts prefer aged bone , 2007, Osteoporosis International.

[7]  J P Gorski,et al.  Is all bone the same? Distinctive distributions and properties of non-collagenous matrix proteins in lamellar vs. woven bone imply the existence of different underlying osteogenic mechanisms. , 1998, Critical reviews in oral biology and medicine : an official publication of the American Association of Oral Biologists.

[8]  Wei Yao,et al.  Osteocytes as mechanosensors in the inhibition of bone resorption due to mechanical loading. , 2008, Bone.

[9]  M. Horowitz,et al.  B Lymphocytes and the Skeleton , 2007, Annals of the New York Academy of Sciences.

[10]  M. Horton,et al.  Immunohistochemical detection of parathyroid hormone-related protein in human fetal epithelia. , 1991, The Journal of clinical endocrinology and metabolism.

[11]  T. Martin,et al.  Osteoclast-derived activity in the coupling of bone formation to resorption. , 2005, Trends in molecular medicine.

[12]  T. Takano-Yamamoto,et al.  A three-dimensional distribution of osteocyte processes revealed by the combination of confocal laser scanning microscopy and differential interference contrast microscopy. , 2001, Bone.

[13]  S. Mochizuki,et al.  Identity of osteoclastogenesis inhibitory factor (OCIF) and osteoprotegerin (OPG): a mechanism by which OPG/OCIF inhibits osteoclastogenesis in vitro. , 1998, Endocrinology.

[14]  M. Karperien,et al.  Sclerostin Is an Osteocyte-expressed Negative Regulator of Bone Formation, But Not a Classical BMP Antagonist , 2004, The Journal of experimental medicine.

[15]  J. Chirgwin,et al.  Basic Mechanisms Responsible for Osteolytic and Osteoblastic Bone Metastases , 2006, Clinical Cancer Research.

[16]  Flemming Melsen,et al.  Cancellous Bone Remodeling Occurs in Specialized Compartments Lined by Cells Expressing Osteoblastic Markers , 2001, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[17]  L. Bonewald,et al.  Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism , 2006, Nature Genetics.

[18]  T. Chambers,et al.  Bone cells predispose bone surfaces to resorption by exposure of mineral to osteoclastic contact. , 1985, Journal of cell science.

[19]  C. Ladd,et al.  Determination and expression of platelet-derived growth factor-AA in bone cell cultures. , 1992, Endocrinology.

[20]  P. Sathyanarayana,et al.  Erythropoietin modulation of podocalyxin and a proposed erythroblast niche. , 2007, Blood.

[21]  M. Kneissel,et al.  SOST is a target gene for PTH in bone. , 2005, Bone.

[22]  Michael C. Ostrowski,et al.  The Expression of Clcn7 and Ostm1 in Osteoclasts Is Coregulated by Microphthalmia Transcription Factor* , 2007, Journal of Biological Chemistry.

[23]  A. Robling,et al.  Mechanical stimulation in vivo reduces osteocyte expression of sclerostin. , 2006, Journal of musculoskeletal & neuronal interactions.

[24]  Silvia Bernardini,et al.  Decreased C-Src Expression Enhances Osteoblast Differentiation and Bone Formation , 2000, The Journal of cell biology.

[25]  R. Martin,et al.  Targeted bone remodeling involves BMU steering as well as activation. , 2007, Bone.

[26]  David B. Jones,et al.  The influence of mechanical stimulation on osteocyte apoptosis and bone viability in human trabecular bone. , 2006, Journal of musculoskeletal & neuronal interactions.

[27]  G. Rodan Introduction to bone biology. , 1992, Bone.

[28]  H. Genant,et al.  Osteoblast-derived PTHrP is a potent endogenous bone anabolic agent that modifies the therapeutic efficacy of administered PTH 1-34. , 2005, The Journal of clinical investigation.

[29]  T. Martin,et al.  Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. , 1999, Endocrine reviews.

[30]  W. Wiktor-Jedrzejczak,et al.  Total absence of colony-stimulating factor 1 in the macrophage-deficient osteopetrotic (op/op) mouse. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[31]  P. Lips,et al.  Mean wall thickness of trabecular bone packets in the human iliac crest: Changes with age , 1978, Calcified Tissue Research.

[32]  T. Chambers,et al.  Mammalian collagenase predisposes bone surfaces to osteoclastic resorption , 2004, Cell and Tissue Research.

[33]  D. Fisher,et al.  Linkage of M-CSF signaling to Mitf, TFE3, and the osteoclast defect in Mitf(mi/mi) mice. , 2001, Molecular cell.

[34]  S. Teitelbaum,et al.  Recruitment of osteoclast precursors by purified bone matrix constituents , 1982, The Journal of cell biology.

[35]  E. Froesch,et al.  Triiodothyronine (T3) stimulates insulin-like growth factor (IGF)-1 and IGF binding protein (IGFBP)-2 production by rat osteoblasts in vitro. , 1992, Acta endocrinologica.

[36]  M Dioszegi,et al.  Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). , 2001, Human molecular genetics.

[37]  T. Martin,et al.  Expression of parathyroid hormone‐related protein in cells of osteoblast lineage , 1996, Journal of cellular physiology.

[38]  T. Taniguchi,et al.  Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis , 2004, Nature.

[39]  Yongwon Choi,et al.  v-ATPase V0 subunit d2–deficient mice exhibit impaired osteoclast fusion and increased bone formation , 2006, Nature Medicine.

[40]  M. Klagsbrun,et al.  Growth factors in bone matrix. Isolation of multiple types by affinity chromatography on heparin-Sepharose. , 1986, The Journal of biological chemistry.

[41]  E. Canalis,et al.  Transforming growth factor-beta and remodeling of bone. , 1991, The Journal of bone and joint surgery. American volume.

[42]  H. Hanafusa,et al.  TRANCE, a TNF family member, activates Akt/PKB through a signaling complex involving TRAF6 and c-Src. , 1999, Molecular cell.

[43]  T. Miyata,et al.  Commitment and Differentiation of Osteoclast Precursor Cells by the Sequential Expression of C-Fms and Receptor Activator of Nuclear Factor κb (Rank) Receptors , 1999, The Journal of experimental medicine.

[44]  B. Lanske,et al.  Conditionally immortalized murine bone marrow stromal cells mediate parathyroid hormone-dependent osteoclastogenesis in vitro. , 1998, Endocrinology.

[45]  Minqi Li,et al.  Targeted ablation of osteocytes induces osteoporosis with defective mechanotransduction. , 2007, Cell metabolism.

[46]  S. Marks,et al.  The osteopetrotic mutation toothless (tl) is a loss-of-function frameshift mutation in the rat Csf1 gene: Evidence of a crucial role for CSF-1 in osteoclastogenesis and endochondral ossification , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[47]  M. Tanaka,et al.  Haploinsufficiency of parathyroid hormone-related peptide (PTHrP) results in abnormal postnatal bone development. , 1996, Developmental biology.

[48]  Z. Massy,et al.  The pathophysiology of vascular calcification: are osteoclast-like cells the missing link? , 2008, Diabetes & metabolism.

[49]  A. Mócsai,et al.  The immunomodulatory adapter proteins DAP12 and Fc receptor γ-chain (FcRγ) regulate development of functional osteoclasts through the Syk tyrosine kinase , 2004 .

[50]  R. Baron,et al.  Dissociation between bone resorption and bone formation in osteopenic transgenic mice. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[51]  R. Jilka,et al.  Chronic elevation of parathyroid hormone in mice reduces expression of sclerostin by osteocytes: a novel mechanism for hormonal control of osteoblastogenesis. , 2005, Endocrinology.

[52]  G. Roodman,et al.  Chemokines in multiple myeloma. , 2006, Experimental hematology.

[53]  W. Dougall,et al.  RANK is essential for osteoclast and lymph node development. , 1999, Genes & development.

[54]  P. Saftig,et al.  The Bone Lining Cell: Its Role in Cleaning Howship's Lacunae and Initiating Bone Formation , 2002, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[55]  Nicolas Houde,et al.  Osteoprotegerin decreases human osteoclast apoptosis by inhibiting the TRAIL pathway , 2008, Journal of cellular physiology.

[56]  G Shimamoto,et al.  Osteoprotegerin: A Novel Secreted Protein Involved in the Regulation of Bone Density , 1997, Cell.

[57]  K. Toh,et al.  RANKL-induced DC-STAMP Is Essential for Osteoclastogenesis , 2004, The Journal of experimental medicine.

[58]  R. Turner,et al.  Evidence that intermittent treatment with parathyroid hormone increases bone formation in adult rats by activation of bone lining cells. , 1995, Endocrinology.

[59]  A. Parfitt The Bone Remodeling Compartment: A Circulatory Function for Bone Lining Cells , 2001, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[60]  D B Burr,et al.  Increased intracortical remodeling following fatigue damage. , 1993, Bone.

[61]  S. Khosla,et al.  Remodeling and Vascular Spaces in Bone , 2006, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[62]  C. Wilkinson,et al.  Osteoprogenitor response to defined topographies with nanoscale depths. , 2006, Biomaterials.

[63]  T. Suda,et al.  Bidirectional ephrinB2-EphB4 signaling controls bone homeostasis. , 2006, Cell metabolism.

[64]  E. Lanino,et al.  Clinical, genetic, and cellular analysis of 49 osteopetrotic patients: implications for diagnosis and treatment , 2005, Journal of Medical Genetics.

[65]  B. Sacchetti,et al.  Self-Renewing Osteoprogenitors in Bone Marrow Sinusoids Can Organize a Hematopoietic Microenvironment , 2007, Cell.

[66]  Sheila J. Jones,et al.  Topographically induced bone formation in vitro: implications for bone implants and bone grafts. , 1996, Bone.

[67]  S. Mohan,et al.  Bone growth factors. , 1991, Clinical orthopaedics and related research.

[68]  K. Hruska,et al.  Osteopontin deficiency produces osteoclast dysfunction due to reduced CD44 surface expression. , 2003, Molecular biology of the cell.

[69]  M. Noda,et al.  Parathyroid Hormone-induced Bone Resorption Does Not Occur in the Absence of Osteopontin* , 2001, The Journal of Biological Chemistry.

[70]  T. Martin,et al.  Osteotropic agents regulate the expression of osteoclast differentiation factor and osteoprotegerin in osteoblastic stromal cells. , 1998, Endocrinology.

[71]  N. Sims,et al.  Cardiotrophin‐1 Is an Osteoclast‐Derived Stimulus of Bone Formation Required for Normal Bone Remodeling , 2008, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[72]  M. Akhter,et al.  Osteoclast Deficiency Results in Disorganized Matrix, Reduced Mineralization, and Abnormal Osteoblast Behavior in Developing Bone , 2004, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[73]  S. Teitelbaum,et al.  αvβ3 and macrophage colony‐stimulating factor: partners in osteoclast biology , 2005 .

[74]  R. Kumar,et al.  Aberrant Phex function in osteoblasts and osteocytes alone underlies murine X-linked hypophosphatemia. , 2008, The Journal of clinical investigation.

[75]  D. Ovcharenko,et al.  Genomic deletion of a long-range bone enhancer misregulates sclerostin in Van Buchem disease. , 2005, Genome research.

[76]  T. Martin,et al.  Osteoclast Inhibitory Lectin, an Immune Cell Product That Is Required for Normal Bone Physiology in Vivo* , 2008, Journal of Biological Chemistry.

[77]  A. Parfitt Targeted and nontargeted bone remodeling: relationship to basic multicellular unit origination and progression. , 2002, Bone.

[78]  T. Martin,et al.  Tumor Necrosis Factor (cid:97) Stimulates Osteoclast Differentiation by a Mechanism Independent of the ODF/RANKL–RANK Interaction , 2022 .

[79]  R. Civitelli Cell-cell communication in the osteoblast/osteocyte lineage. , 2008, Archives of biochemistry and biophysics.

[80]  P. Collin‐Osdoby,et al.  Stromal Cell‐Derived Factor‐1 (SDF‐1) Recruits Osteoclast Precursors by Inducing Chemotaxis, Matrix Metalloproteinase‐9 (MMP‐9) Activity, and Collagen Transmigration , 2003, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[81]  Olivier Verborgt,et al.  Spatial Distribution of Bax and Bcl‐2 in Osteocytes After Bone Fatigue: Complementary Roles in Bone Remodeling Regulation? , 2002, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[82]  Josef M. Penninger,et al.  Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand , 1999, Nature.

[83]  Allan Bradley,et al.  Increased bone formation in osteocalcin-deficient mice , 1996, Nature.

[84]  J. Latham,et al.  Sclerostin promotes the apoptosis of human osteoblastic cells: a novel regulation of bone formation. , 2004, Bone.

[85]  R. Baron,et al.  An electron-microscopic study of the bone-remodeling sequence in the rat , 2004, Cell and Tissue Research.

[86]  Peter Pivonka,et al.  Model structure and control of bone remodeling: a theoretical study. , 2008, Bone.

[87]  W. McKinstry,et al.  A Novel Osteoblast-derived C-type Lectin That Inhibits Osteoclast Formation* , 2001, The Journal of Biological Chemistry.

[88]  M. Karsdal,et al.  Osteoclasts secrete non-bone derived signals that induce bone formation. , 2008, Biochemical and biophysical research communications.

[89]  S. Mochizuki,et al.  Isolation of a novel cytokine from human fibroblasts that specifically inhibits osteoclastogenesis. , 1997, Biochemical and biophysical research communications.

[90]  B. Noble,et al.  Apoptotic Bodies Convey Activity Capable of Initiating Osteoclastogenesis and Localized Bone Destruction , 2008, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[91]  F. Melsen,et al.  Structural and histomorphometric studies of iliac crest trabecular and cortical bone in autosomal dominant osteopetrosis: a study of two radiological types. , 1989, Bone.

[92]  S. Orkin,et al.  Rb Regulates Interactions between Hematopoietic Stem Cells and Their Bone Marrow Microenvironment , 2007, Cell.

[93]  A. Parfitt Misconceptions V—Activation of osteoclasts is the first step in the bone remodeling cycle , 2006 .

[94]  Kosaku Kurata,et al.  Bone Marrow Cell Differentiation Induced by Mechanically Damaged Osteocytes in 3D Gel‐Embedded Culture , 2006, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[95]  Florent Elefteriou Regulation of bone remodeling by the central and peripheral nervous system. , 2008, Archives of biochemistry and biophysics.

[96]  John A Latham,et al.  Osteocyte control of bone formation via sclerostin, a novel BMP antagonist , 2003, The EMBO journal.

[97]  U. Lerner,et al.  IL-6, Leukemia Inhibitory Factor, and Oncostatin M Stimulate Bone Resorption and Regulate the Expression of Receptor Activator of NF-κB Ligand, Osteoprotegerin, and Receptor Activator of NF-κB in Mouse Calvariae1 , 2002, The Journal of Immunology.

[98]  T. Martin,et al.  Osteoclast inhibitory lectin (OCIL) inhibits osteoblast differentiation and function in vitro. , 2007, Bone.

[99]  N. Sims,et al.  EphrinB2 Regulation by PTH and PTHrP Revealed by Molecular Profiling in Differentiating Osteoblasts , 2008, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[100]  P. De Camilli,et al.  Defective microtubule-dependent podosome organization in osteoclasts leads to increased bone density in Pyk2−/− mice , 2007, The Journal of cell biology.

[101]  Ruili Li,et al.  Interleukin‐11 Receptor Signaling Is Required for Normal Bone Remodeling , 2005, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[102]  J. Rossant,et al.  Bone sialoprotein plays a functional role in bone formation and osteoclastogenesis , 2008, The Journal of experimental medicine.

[103]  S. Morony,et al.  osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. , 1998, Genes & development.

[104]  L. Lanyon,et al.  Mechanical loading: biphasic osteocyte survival and targeting of osteoclasts for bone destruction in rat cortical bone. , 2003, American journal of physiology. Cell physiology.

[105]  Hen-Li Chen,et al.  Anabolic actions of parathyroid hormone during bone growth are dependent on c-fos. , 2002, Endocrinology.

[106]  K. Lindpaintner,et al.  Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease , 2002, Journal of medical genetics.

[107]  S. Vukicevic,et al.  Localization of osteogenic protein-1 (bone morphogenetic protein-7) during human embryonic development: high affinity binding to basement membranes. , 1994, Biochemical and biophysical research communications.