Molecular regulation of osteoclast activity

Osteoclasts are multinucleated cells derived from hematopoietic precursors that are primarily responsible for the degradation of mineralized bone during bone development, homeostasis and repair. In various skeletal disorders such as osteoporosis, hypercalcemia of malignancy, tumor metastases and Paget’s disease, bone resorption by osteoclasts exceeds bone formation by osteoblasts leading to decreased bone mass, skeletal fragility and bone fracture. The overall rate of osteoclastic bone resorption is regulated either at the level of differentiation of osteoclasts from their monocytic/macrophage precursor pool or through the regulation of key functional proteins whose specific activities in the mature osteoclast control its attachment, migration and resorption. Thus, reducing osteoclast numbers and/or decreasing the bone resorbing activity of osteoclasts are two common therapeutic approaches for the treatment of hyper-resorptive skeletal diseases. In this review, several of the key functional players involved in the regulation of osteoclast activity will be discussed.

[1]  R. Kelly,et al.  Molecular Links between Endocytosis and the Actin Cytoskeleton , 2000, The Journal of cell biology.

[2]  C. Leu,et al.  The integrin ligand echistatin prevents bone loss in ovariectomized mice and rats. , 1998, Endocrinology.

[3]  H. Vogel,et al.  Combined deficiencies of Src, Fyn, and Yes tyrosine kinases in mutant mice. , 1994, Genes & development.

[4]  M. McNiven,et al.  Differential distribution of dynamin isoforms in mammalian cells. , 1998, Molecular biology of the cell.

[5]  G. E. Jones,et al.  Rho family proteins and cell migration. , 1999, Biochemical Society symposium.

[6]  D. Hewett‐Emmett,et al.  Carbonic anhydrase II deficiency identified as the primary defect in the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[7]  M. Weinreb,et al.  Rat osteoclast precursors in vivo express a vitronectin receptor and a chloride-bicarbonate exchanger. , 1998, Connective tissue research.

[8]  W. Dougall,et al.  The Involvement of Multiple Tumor Necrosis Factor Receptor (TNFR)-associated Factors in the Signaling Mechanisms of Receptor Activator of NF-κB, a Member of the TNFR Superfamily* , 1998, The Journal of Biological Chemistry.

[9]  Matthew J. Silva,et al.  Gelsolin Deficiency Blocks Podosome Assembly and Produces Increased Bone Mass and Strength , 2000, The Journal of cell biology.

[10]  c-Fms and the αvβ3 integrin collaborate during osteoclast differentiation , 2003 .

[11]  D. Ory,et al.  A Glanzmann's mutation in beta 3 integrin specifically impairs osteoclast function. , 2001, The Journal of clinical investigation.

[12]  S. Reddy Regulatory mechanisms operative in osteoclasts. , 2004, Critical reviews in eukaryotic gene expression.

[13]  R. Baron,et al.  Role of c‐Src in cellular events associated with colony‐stimulating factor‐1‐induced spreading in osteoclasts , 1997, Molecular reproduction and development.

[14]  S. Razzouk,et al.  Rac-GTPase, osteoclast cytoskeleton and bone resorption. , 1999, European journal of cell biology.

[15]  H. Varmus,et al.  Deficiency of the Hck and Src tyrosine kinases results in extreme levels of extramedullary hematopoiesis. , 1996, Blood.

[16]  Takeshi Nakamura,et al.  Activation of Pyk2/RAFTK induces tyrosine phosphorylation of alpha-synuclein via Src-family kinases. , 2002, FEBS letters.

[17]  T. Suda Modulation of osteoclast differentiation [published erratum appears in Endocr Rev 1992 May;13(2):191] , 1992 .

[18]  T. Yoneda,et al.  Requirement of pp60c-src expression for osteoclasts to form ruffled borders and resorb bone in mice. , 1992, The Journal of clinical investigation.

[19]  Sakae Tanaka,et al.  c-Cbl is downstream of c-Src in a signalling pathway necessary for bone resorption , 1996, Nature.

[20]  G. Rodan,et al.  Comparison of the distribution of 3H-alendronate and 3H-etidronate in rat and mouse bones. , 1996, Bone.

[21]  P. Janmey,et al.  Deconstructing gelsolin: identifying sites that mimic or alter binding to actin and phosphoinositides. , 1998, Chemistry & biology.

[22]  D. Galson,et al.  Phospholipase D- and protein kinase C isoenzyme-dependent signal transduction pathways activated by the calcitonin receptor. , 1998, Endocrinology.

[23]  R. Vallee,et al.  Microtubules and Src homology 3 domains stimulate the dynamin GTPase via its C-terminal domain. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[24]  L. Addadi,et al.  The molecular dynamics of osteoclast adhesions. , 2006, European journal of cell biology.

[25]  K. Siminovitch,et al.  Negative regulation of myeloid cell proliferation and function by the SH2 domain-containing tyrosine phosphatase-1. , 1999, Journal of immunology.

[26]  R. Baron,et al.  The Calcitonin Receptor Stimulates Shc Tyrosine Phosphorylation and Erk1/2 Activation , 1998, The Journal of Biological Chemistry.

[27]  R. Pardi,et al.  A tyrosine‐based sorting signal in the β2 integrin cytoplasmic domain mediates its recycling to the plasma membrane and is required for ligand‐supported migration , 1999, The EMBO journal.

[28]  T. Chambers Osteoblasts release osteoclasts from calcitonin-induced quiescence. , 1982, Journal of cell science.

[29]  T. Stossel,et al.  From signal to pseudopod. How cells control cytoplasmic actin assembly. , 1989, The Journal of biological chemistry.

[30]  K. Lau,et al.  Molecular cloning and expression of a unique rabbit osteoclastic phosphotyrosyl phosphatase. , 1996, The Biochemical journal.

[31]  V. Garsky,et al.  Echistatin is a potent inhibitor of bone resorption in culture , 1990, The Journal of cell biology.

[32]  L. Notarangelo,et al.  Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis , 2000, Nature Genetics.

[33]  A. Thrasher,et al.  WASp deficiency in mice results in failure to form osteoclast sealing zones and defects in bone resorption. , 2004, Blood.

[34]  F. Saltel,et al.  Podosomes display actin turnover and dynamic self-organization in osteoclasts expressing actin-green fluorescent protein. , 2003, Molecular biology of the cell.

[35]  G. Rodan,et al.  Abnormal localisation and hyperclustering of (alpha)(V)(beta)(3) integrins and associated proteins in Src-deficient or tyrphostin A9-treated osteoclasts. , 2001, Journal of cell science.

[36]  H. Lodish,et al.  A recombinant calcitonin receptor independently stimulates 3',5'-cyclic adenosine monophosphate and Ca2+/inositol phosphate signaling pathways. , 1992, Molecular endocrinology.

[37]  Shi Wei,et al.  Tumor Necrosis Factor α Regulatesα vβ5 Integrin Expression by Osteoclast Precursors in Vitro and in Vivo1. , 2000, Endocrinology.

[38]  C. Bosman,et al.  Mechanisms of Osteoclast Dysfunction in Human Osteopetrosis: Abnormal Osteoclastogenesis and Lack of Osteoclast‐Specific Adhesion Structures , 1999, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[39]  S. Schmid,et al.  Dynamin:Gtp Controls the Formation of Constricted Coated Pits, the Rate Limiting Step in Clathrin-Mediated Endocytosis , 2000, The Journal of cell biology.

[40]  M. Horton,et al.  Vitronectin receptor has a role in bone resorption but does not mediate tight sealing zone attachment of osteoclasts to the bone surface , 1991, The Journal of cell biology.

[41]  T. Boggon,et al.  Structure and regulation of Src family kinases , 2004, Oncogene.

[42]  R. Baron,et al.  Integrin Engagement, the Actin Cytoskeleton, and c-Src Are Required for the Calcitonin-induced Tyrosine Phosphorylation of Paxillin and HEF1, but Not for Calcitonin-induced Erk1/2 Phosphorylation* , 2000, The Journal of Biological Chemistry.

[43]  S. Morony,et al.  TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. , 1999, Genes & development.

[44]  G. Rodan,et al.  Tyrosine Phosphorylation of p130Cas Is Involved in Actin Organization in Osteoclasts* , 1998, The Journal of Biological Chemistry.

[45]  R. Kapur,et al.  p85α subunit of class IA PI-3 kinase is crucial for macrophage growth and migration , 2005 .

[46]  S. Schmid,et al.  Induction of mutant dynamin specifically blocks endocytic coated vesicle formation , 1994, The Journal of cell biology.

[47]  J. Parsons,et al.  Src family kinases, key regulators of signal transduction , 2004, Oncogene.

[48]  C. Minkin,et al.  Ultrastructural effects of calcitonin on osteoclasts in tissue culture. , 1972, Journal of ultrastructure research.

[49]  L. Naldini,et al.  Cell-substratum interaction of cultured avian osteoclasts is mediated by specific adhesion structures , 1984, The Journal of cell biology.

[50]  Giorgio F. Gilestro,et al.  The endophilin–CIN85–Cbl complex mediates ligand-dependent downregulation of c-Met , 2002, Nature.

[51]  K. Vuori,et al.  CAS/Crk Coupling Serves as a “Molecular Switch” for Induction of Cell Migration , 1998, The Journal of cell biology.

[52]  P. Camilli,et al.  Accessory factors in clathrin-dependent synaptic vesicle endocytosis , 2000, Nature Reviews Neuroscience.

[53]  R. Birge,et al.  The Adapter Type Protein CMS/CD2AP Binds to the Proto-oncogenic Protein c-Cbl through a Tyrosine Phosphorylation-regulated Src Homology 3 Domain Interaction* , 2001, The Journal of Biological Chemistry.

[54]  A. Ridley,et al.  Rac1-deficient macrophages exhibit defects in cell spreading and membrane ruffling but not migration , 2004, Journal of Cell Science.

[55]  R. Chiusaroli,et al.  Tyrosine phosphatase epsilon is a positive regulator of osteoclast function in vitro and in vivo. , 2003, Molecular biology of the cell.

[56]  Bryan R. G. Williams,et al.  Protein-tyrosine Phosphatase Shp-1 Is a Negative Regulator of IL-4- and IL-13-dependent Signal Transduction* , 1998, Journal of Biological Chemistry.

[57]  O. Destaing,et al.  SH3P2 in complex with Cbl and Src , 2004, FEBS letters.

[58]  A. Zallone,et al.  c-Fms and the alphavbeta3 integrin collaborate during osteoclast differentiation. , 2003, The Journal of clinical investigation.

[59]  M. Horton,et al.  Spatial organization of microfilaments and vitronectin receptor, alpha v beta 3, in osteoclasts. A study using confocal laser scanning microscopy. , 1993, Journal of cell science.

[60]  N. Athanasou,et al.  Effect of parathyroid hormone and calcitonin on the cytoplasmic spreading of isolated osteoclasts. , 1984, The Journal of endocrinology.

[61]  Yuqiong Liang,et al.  Atp6i-deficient mice exhibit severe osteopetrosis due to loss of osteoclast-mediated extracellular acidification , 1999, Nature Genetics.

[62]  C. Leu,et al.  Histomorphometric evidence for echistatin inhibition of bone resorption in mice with secondary hyperparathyroidism. , 1998, Endocrinology.

[63]  S. Blystone,et al.  Tyrosine Phosphorylation of β3 Integrin Provides a Binding Site for Pyk2* , 2005, Journal of Biological Chemistry.

[64]  K. Lau,et al.  Antisense Oligodeoxynucleotide Evidence That a Unique Osteoclastic Protein‐Tyrosine Phosphatase Is Essential for Osteoclastic Resorption , 2001, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[65]  R. Lefkowitz,et al.  β-Arrestin1 Interacts with the Catalytic Domain of the Tyrosine Kinase c-SRC , 2000, The Journal of Biological Chemistry.

[66]  Allan Bradley,et al.  Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice , 1991, Cell.

[67]  Richard O. Hynes,et al.  Integrin-mediated Signals Regulated by Members of the Rho Family of GTPases , 1998, The Journal of cell biology.

[68]  T. Jones,et al.  The effects of rhGM-CSF on macrophage function. , 1993, European journal of cancer.

[69]  E. Wyroba,et al.  Dynamin: characteristics, mechanism of action and function. , 2002, Cellular & molecular biology letters.

[70]  F. Saltel,et al.  Apatite-mediated actin dynamics in resorbing osteoclasts. , 2004, Molecular biology of the cell.

[71]  C. Lowell,et al.  A β1 integrin signaling pathway involving Src‐family kinases, Cbl and PI‐3 kinase is required for macrophage spreading and migration , 1998, The EMBO journal.

[72]  M. Naramura,et al.  A Positive Regulatory Role for Cbl Family Proteins in Tumor Necrosis Factor-related Activation-induced Cytokine (TRANCE) and CD40L-mediated Akt Activation* , 2001, The Journal of Biological Chemistry.

[73]  R. Baron,et al.  Cell-mediated extracellular acidification and bone resorption: evidence for a low pH in resorbing lacunae and localization of a 100-kD lysosomal membrane protein at the osteoclast ruffled border , 1985, The Journal of cell biology.

[74]  A Ciechanover,et al.  Ubiquitin ligase activity and tyrosine phosphorylation underlie suppression of growth factor signaling by c-Cbl/Sli-1. , 1999, Molecular cell.

[75]  M. Tsujimoto,et al.  Involvement of p38 Mitogen-activated Protein Kinase Signaling Pathway in Osteoclastogenesis Mediated by Receptor Activator of NF-κB Ligand (RANKL)* , 2000, The Journal of Biological Chemistry.

[76]  I. Mills,et al.  GTPase activity of dynamin and resulting conformation change are essential for endocytosis , 2001, Nature.

[77]  S. Shimamura,et al.  Association of Cbl with Fms and p85 in response to macrophage colony‐stimulating factor , 2000, FEBS letters.

[78]  S. Teitelbaum,et al.  Osteoclastic bone resorption by a polarized vacuolar proton pump. , 1989, Science.

[79]  F. Maxfield,et al.  Ca2+- and calcineurin-dependent recycling of an integrin to the front of migrating neutrophils , 1995, Nature.

[80]  R. Baron,et al.  Colony-stimulating factor-1 induces cytoskeletal reorganization and c-src-dependent tyrosine phosphorylation of selected cellular proteins in rodent osteoclasts. , 1997, The Journal of clinical investigation.

[81]  I. Nakamura,et al.  Osteoclast integrin alphaVbeta3 is present in the clear zone and contributes to cellular polarization. , 1996, Cell and tissue research.

[82]  A. Hall,et al.  Rho GTPases and their effector proteins. , 2000, The Biochemical journal.

[83]  E. Stanley,et al.  Colony-stimulating Factor-1 Stimulates the Formation of Multimeric Cytosolic Complexes of Signaling Proteins and Cytoskeletal Components in Macrophages* , 1998, The Journal of Biological Chemistry.

[84]  S. M. Sims,et al.  Role of alpha(v)beta(3) integrin in osteoclast migration and formation of the sealing zone. , 1999, Journal of cell science.

[85]  N. Hoffman,et al.  A Novel, Multifunctional c-Cbl Binding Protein in Insulin Receptor Signaling in 3T3-L1 Adipocytes , 1998, Molecular and Cellular Biology.

[86]  M. Sheetz,et al.  Pyk2 regulates multiple signaling events crucial for macrophage morphology and migration , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[87]  R. Baron,et al.  Ligand-induced Ubiquitination of the Epidermal Growth Factor Receptor Involves the Interaction of the c-Cbl RING Finger and UbcH7* , 1999, The Journal of Biological Chemistry.

[88]  R. Felix,et al.  The role of phosphoinositide 3-kinase in spreading osteoclasts induced by colony-stimulating factor-1. , 2001, European journal of endocrinology.

[89]  R. Lefkowitz,et al.  Ras-dependent Mitogen-activated Protein Kinase Activation by G Protein-coupled Receptors , 1997, The Journal of Biological Chemistry.

[90]  R. Chiusaroli,et al.  Deletion of the gene encoding c-Cbl alters the ability of osteoclasts to migrate, delaying resorption and ossification of cartilage during the development of long bones. , 2003, Developmental biology.

[91]  E Ruoslahti,et al.  Integrin signaling. , 1999, Science.

[92]  S. Teitelbaum,et al.  Tumor necrosis factor alpha regulates alpha(v)beta5 integrin expression by osteoclast precursors in vitro and in vivo. , 2000, Endocrinology.

[93]  G. Rodan,et al.  PYK2 Autophosphorylation, but Not Kinase Activity, Is Necessary for Adhesion-induced Association with c-Src, Osteoclast Spreading, and Bone Resorption* , 2003, The Journal of Biological Chemistry.

[94]  S. Shoelson,et al.  The SH3 Domain-binding T Cell Tyrosyl Phosphoprotein p120 , 1995, The Journal of Biological Chemistry.

[95]  P. Jurdic,et al.  Podosomes in osteoclast-like cells: structural analysis and cooperative roles of paxillin, proline-rich tyrosine kinase 2 (Pyk2) and integrin alphaVbeta3. , 2001, Journal of cell science.

[96]  R. Baron,et al.  The tyrosine phosphatase SHP-1 is a negative regulator of osteoclastogenesis and osteoclast resorbing activity: increased resorption and osteopenia in me(v)/me(v) mutant mice. , 1999, Bone.

[97]  A. Teti,et al.  Rous sarcoma virus-transformed fibroblasts and cells of monocytic origin display a peculiar dot-like organization of cytoskeletal proteins involved in microfilament-membrane interactions. , 1987, Experimental cell research.

[98]  G. Bokoch,et al.  Requirements for Both Rac1 and Cdc42 in Membrane Ruffling and Phagocytosis in Leukocytes , 1997, The Journal of experimental medicine.

[99]  D. Schafer Regulating Actin Dynamics at Membranes: A Focus on Dynamin , 2004, Traffic.

[100]  A. Schulz,et al.  Loss of the ClC-7 Chloride Channel Leads to Osteopetrosis in Mice and Man , 2001, Cell.

[101]  N. Heisterkamp,et al.  Crkl Is Complexed with Tyrosine-phosphorylated Cbl in Ph-positive Leukemia (*) , 1995, The Journal of Biological Chemistry.

[102]  T. Chambers,et al.  Optimal bone resorption by isolated rat osteoclasts requires chloride bicarbonate exchange , 1989, Calcified Tissue International.

[103]  Hong-Hee Kim,et al.  TAK1-dependent activation of AP-1 and c-Jun N-terminal kinase by receptor activator of NF-kappaB. , 2002, Journal of biochemistry and molecular biology.

[104]  M. Schena,et al.  Vinculin, talin, and integrins are localized at specific adhesion sites of malignant B lymphocytes , 1988 .

[105]  W. Dougall,et al.  A RANK/TRAF6-dependent Signal Transduction Pathway Is Essential for Osteoclast Cytoskeletal Organization and Resorptive Function* , 2002, The Journal of Biological Chemistry.

[106]  H. Väänänen,et al.  The cell biology of osteoclast function. , 2000, Journal of cell science.

[107]  F. Saltel,et al.  A novel Rho-mDia2-HDAC6 pathway controls podosome patterning through microtubule acetylation in osteoclasts , 2005, Journal of Cell Science.

[108]  M. Horton,et al.  Antibody to beta3 integrin inhibits osteoclast-mediated bone resorption in the thyroparathyroidectomized rat. , 1996, Endocrinology.

[109]  R. Lefkowitz,et al.  beta-arrestin1 interacts with the catalytic domain of the tyrosine kinase c-SRC. Role of beta-arrestin1-dependent targeting of c-SRC in receptor endocytosis. , 2000, The Journal of biological chemistry.

[110]  P. Fort,et al.  Rho and Rac exert antagonistic functions on spreading of macrophage-derived multinucleated cells and are not required for actin fiber formation. , 2000, Journal of cell science.

[111]  R. Baron,et al.  Polarized secretion of lysosomal enzymes: co-distribution of cation- independent mannose-6-phosphate receptors and lysosomal enzymes along the osteoclast exocytic pathway , 1988, The Journal of cell biology.

[112]  T. Ouchi,et al.  The kinase-deficient Src acts as a suppressor of the Abl kinase for Cbl phosphorylation. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[113]  M. Horton,et al.  A study using confocal laser scanning microscopy , 1993 .

[114]  G. Wesolowski,et al.  Phosphatidylinositol 3-kinase association with the osteoclast cytoskeleton, and its involvement in osteoclast attachment and spreading. , 1997, Experimental cell research.

[115]  R. Baron,et al.  Cytoskeleton-dependent tyrosine phosphorylation of the p130(Cas) family member HEF1 downstream of the G protein-coupled calcitonin receptor. Calcitonin induces the association of HEF1, paxillin, and focal adhesion kinase. , 1999, The Journal of biological chemistry.

[116]  S. Hanks,et al.  Identification of p130Cas as a Mediator of Focal Adhesion Kinase–promoted Cell Migration , 1998, The Journal of cell biology.

[117]  S. Ogawa,et al.  A novel signaling molecule, p130, forms stable complexes in vivo with v‐Crk and v‐Src in a tyrosine phosphorylation‐dependent manner. , 1994, The EMBO journal.

[118]  R. Baron,et al.  The Deletion of 14 Amino Acids in the Seventh Transmembrane Domain of a Naturally Occurring Calcitonin Receptor Isoform Alters Ligand Binding and Selectively Abolishes Coupling to Phospholipase C* , 1996, The Journal of Biological Chemistry.

[119]  N. Udagawa,et al.  Possible involvement of focal adhesion kinase, p125FAK, in osteoclastic bone resorption , 1995, Journal of cellular biochemistry.

[120]  Alexander Varshavsky,et al.  The ubiquitin system. , 1998, Annual review of biochemistry.

[121]  P. Jurdic,et al.  Podosomes in osteoclast-like cells: structural analysis and cooperative roles of paxillin, proline-rich tyrosine kinase 2 (Pyk2) and integrin αVβ3 , 2001 .

[122]  D. Bowtell,et al.  Cbl Associates with Pyk2 and Src to Regulate Src Kinase Activity, αvβ3 Integrin-Mediated Signaling, Cell Adhesion, and Osteoclast Motility , 2001, The Journal of cell biology.

[123]  S. K. Shore,et al.  Tyrosine phosphorylation of C-Cbl facilitates adhesion and spreading while suppressing anchorage-independent growth of V-Abl-transformed NIH3T3 fibroblasts , 1999, Oncogene.

[124]  S. Teitelbaum Osteoclasts, integrins, and osteoporosis , 2000, Journal of Bone and Mineral Metabolism.

[125]  J. Parsons,et al.  Stable Association of PYK2 and p130Cas in Osteoclasts and Their Co-localization in the Sealing Zone* , 1999, The Journal of Biological Chemistry.

[126]  A. Teti,et al.  Beta 3 subunit of vitronectin receptor is present in osteoclast adhesion structures and not in other monocyte-macrophage derived cells. , 1989, Connective tissue research.

[127]  P. Janmey,et al.  Gelsolin-polyphosphoinositide interaction. Full expression of gelsolin-inhibiting function by polyphosphoinositides in vesicular form and inactivation by dilution, aggregation, or masking of the inositol head group. , 1989, The Journal of biological chemistry.

[128]  V. Quaranta,et al.  Activation of the integrin alpha v beta 3 involves a discrete cation-binding site that regulates conformation. , 1996, The Journal of biological chemistry.

[129]  L. Mei,et al.  Regulation of the formation of osteoclastic actin rings by proline-rich tyrosine kinase 2 interacting with gelsolin , 2003, The Journal of cell biology.

[130]  Kozo Nakamura,et al.  Signal transduction pathways regulating osteoclast differentiation and function , 2003, Journal of Bone and Mineral Metabolism.

[131]  M. C. Ovejero,et al.  Identification of the membrane-type matrix metalloproteinase MT1-MMP in osteoclasts. , 1997, Journal of cell science.

[132]  W. Langdon,et al.  Fyn, Yes, and Syk Phosphorylation Sites in c-Cbl Map to the Same Tyrosine Residues That Become Phosphorylated in Activated T Cells* , 1998, The Journal of Biological Chemistry.

[133]  I. Mcniece,et al.  Deletion of the Src Homology 3 Domain and C-terminal Proline-rich Sequences in Bcr-Abl Prevents Abl Interactor 2 Degradation and Spontaneous Cell Migration and Impairs Leukemogenesis* , 2001, The Journal of Biological Chemistry.

[134]  L. Cantley,et al.  p120 Is a Cytosolic Adapter Protein That Associates with Phosphoinositide 3-Kinase in Response to Epidermal Growth Factor in PC12 and Other Cells (*) , 1996, The Journal of Biological Chemistry.

[135]  Michael P. Sheetz,et al.  Selective regulation of integrin–cytoskeleton interactions by the tyrosine kinase Src , 1999, Nature Cell Biology.

[136]  R. Pitti,et al.  Effects of kistrin on bone resorption in vitro and serum calcium in vivo , 1994, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[137]  J. Schlessinger New Roles for Src Kinases in Control of Cell Survival and Angiogenesis , 2000, Cell.

[138]  D. Ory,et al.  A Glanzmann’s mutation in β3 integrin specifically impairs osteoclast function , 2001 .

[139]  Marnie L. Havert,et al.  Organization of functional domains in the docking protein p130Cas. , 2004, Biochemical and biophysical research communications.

[140]  T. Martin,et al.  Modulation of osteoclast differentiation. , 1992, Endocrine reviews.

[141]  S. Lev,et al.  A role for Pyk2 and Src in linking G-protein-coupled receptors with MAP kinase activation , 1996, Nature.

[142]  M. Horton,et al.  Modulation of vitronectin receptor‐mediated osteoclast adhesion by Arg‐Gly‐Asp peptide analogs: A structure‐function analysis , 1993, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[143]  Ivan Dikic,et al.  Negative receptor signalling. , 2003, Current opinion in cell biology.

[144]  B. Aggarwal,et al.  Characterization of the intracellular domain of receptor activator of NF-kappaB (RANK). Interaction with tumor necrosis factor receptor-associated factors and activation of NF-kappab and c-Jun N-terminal kinase. , 1998, The Journal of biological chemistry.

[145]  R. Lefkowitz,et al.  Pleiotropic Coupling of G Protein-coupled Receptors to the Mitogen-activated Protein Kinase Cascade , 1999, The Journal of Biological Chemistry.

[146]  M. Aepfelbacher,et al.  Podosomes: adhesion hot-spots of invasive cells. , 2003, Trends in cell biology.

[147]  M. Holtrop,et al.  THE EFFECTS OF PARATHYROID HORMONE, COLCHICINE, AND CALCITONIN ON THE ULTRASTRUCTURE AND THE ACTIVITY OF OSTEOCLASTS IN ORGAN CULTURE , 1974, The Journal of cell biology.

[148]  G. Wesolowski,et al.  Soluble alpha v beta 3-integrin ligands raise [Ca2+]i in rat osteoclasts and mouse-derived osteoclast-like cells. , 1994, The American journal of physiology.

[149]  Ivan Dikic,et al.  CIN85 Participates in Cbl-b-mediated Down-regulation of Receptor Tyrosine Kinases* , 2002, The Journal of Biological Chemistry.

[150]  J. Bonventre,et al.  A cloned porcine renal calcitonin receptor couples to adenylyl cyclase and phospholipase C. , 1992, The American journal of physiology.

[151]  P. De Camilli,et al.  Dynamin forms a Src kinase-sensitive complex with Cbl and regulates podosomes and osteoclast activity. , 2005, Molecular biology of the cell.

[152]  R. Baron,et al.  The Cbl Family: Ubiquitin Ligases Regulating Signaling by Tyrosine Kinases , 2001, Science's STKE.

[153]  R. Baron,et al.  Calcitonin induces dephosphorylation of Pyk2 and phosphorylation of focal adhesion kinase in osteoclasts. , 2002, Bone.

[154]  D. Bowtell,et al.  The Cbl protooncoprotein stimulates CSF‐1 receptor multiubiquitination and endocytosis, and attenuates macrophage proliferation , 1999, The EMBO journal.

[155]  F. Reinholt,et al.  Distribution of integrin subunits on rat metaphyseal osteoclasts and osteoblasts. , 1993, European journal of cell biology.

[156]  Matthew J. Silva,et al.  SHIP-deficient mice are severely osteoporotic due to increased numbers of hyper-resorptive osteoclasts , 2002, Nature Medicine.

[157]  J. Pollard,et al.  Rho, Rac and Cdc42 regulate actin organization and cell adhesion in macrophages. , 1997, Journal of cell science.

[158]  N. Hoffman,et al.  A novel, multifuntional c-Cbl binding protein in insulin receptor signaling in 3T3-L1 adipocytes. , 1998, Molecular and cellular biology.

[159]  G. Rodan,et al.  PYK2 in osteoclasts is an adhesion kinase, localized in the sealing zone, activated by ligation of alpha(v)beta3 integrin, and phosphorylated by src kinase. , 1998, The Journal of clinical investigation.

[160]  B. Zani,et al.  Calcitonin down-regulates immediate cell signals induced in human osteoclast-like cells by the bone sialoprotein-IIA fragment through a postintegrin receptor mechanism. , 1995, Endocrinology.

[161]  K. Burridge,et al.  Focal adhesions, contractility, and signaling. , 1996, Annual review of cell and developmental biology.

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

[163]  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.

[164]  S. Nishikawa,et al.  The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene , 1990, Nature.

[165]  H. Yamada,et al.  Regulatory mechanisms of dynamin-dependent endocytosis. , 2005, Journal of biochemistry.

[166]  L. Holliday,et al.  Actin‐Related Protein 2/3 Complex Is Required for Actin Ring Formation , 2003, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[167]  M A Horton,et al.  A peptidomimetic antagonist of the alpha(v)beta3 integrin inhibits bone resorption in vitro and prevents osteoporosis in vivo. , 1997, The Journal of clinical investigation.

[168]  M. Horton,et al.  Trafficking of matrix collagens through bone-resorbing osteoclasts. , 1997, Science.

[169]  T. Mak,et al.  Proto-oncoprotein Vav interacts with c-Cbl in activated thymocytes and peripheral T cells. , 1997, Journal of immunology.

[170]  R. Baron,et al.  Protein kinase C antagonizes pertussis-toxin-sensitive coupling of the calcitonin receptor to adenylyl cyclase. , 1999, European journal of biochemistry.

[171]  A. Hall,et al.  Rho GTPases in cell biology , 2002, Nature.

[172]  L. Hicke Ubiquitin‐dependent internalization and down‐regulation of plasma membrane proteins , 1997, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[173]  Tetsuya Takahashi,et al.  Activation of Pyk2/RAFTK induces tyrosine phosphorylation of α‐synuclein via Src‐family kinases , 2002 .

[174]  W. Langdon,et al.  The two major sites of cbl tyrosine phosphorylation in abl-transformed cells select the crkL SH2 domain. , 1996, Oncogene.

[175]  S. Teitelbaum,et al.  Genetic regulation of osteoclast development and function , 2003, Nature Reviews Genetics.

[176]  D. Lacey,et al.  Osteoprotegerin Ligand Is a Cytokine that Regulates Osteoclast Differentiation and Activation , 1998, Cell.

[177]  S. Clark,et al.  Macrophage colony-stimulating factor stimulates survival and chemotactic behavior in isolated osteoclasts , 1993, The Journal of experimental medicine.

[178]  W. Langdon,et al.  c-Cbl localizes to actin lamellae and regulates lamellipodia formation and cell morphology. , 2000, Journal of cell science.

[179]  Archana Sanjay,et al.  Src Kinase Activity Is Essential for Osteoclast Function* , 2004, Journal of Biological Chemistry.

[180]  V. Band,et al.  Tyrosine Phosphorylation of Cbl upon Epidermal Growth Factor (EGF) Stimulation and Its Association with EGF Receptor and Downstream Signaling Proteins* , 1996, The Journal of Biological Chemistry.

[181]  H. Datta,et al.  Evidence that the action of calcitonin on rat osteoclasts is mediated by two G proteins acting via separate post-receptor pathways. , 1990, The Journal of endocrinology.

[182]  D. Lt,et al.  Integrin-mediated Signaling in the Regulation of Osteoclast Adhesion and Activation , 1998 .

[183]  J. Guan,et al.  FAK-mediated src phosphorylation of endophilin A2 inhibits endocytosis of MT1-MMP and promotes ECM degradation. , 2005, Developmental cell.

[184]  P. Lehenkari,et al.  Removal of osteoclast bone resorption products by transcytosis. , 1997, Science.

[185]  T. Martin,et al.  Origin of osteoclasts: mature monocytes and macrophages are capable of differentiating into osteoclasts under a suitable microenvironment prepared by bone marrow-derived stromal cells. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[186]  J. Brugge,et al.  Src kinase activation by direct interaction with the integrin β cytoplasmic domain , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[187]  David A. Williams,et al.  Rac and Cdc42 GTPases control hematopoietic stem cell shape, adhesion, migration, and mobilization , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[188]  G. Giannelli,et al.  Localization and possible role of two different alpha v beta 3 integrin conformations in resting and resorbing osteoclasts. , 2002, Journal of cell science.

[189]  O. Jaillon,et al.  The gene encoding the mouse homologue of the human osteoclast-specific 116-kDa V-ATPase subunit bears a deletion in osteosclerotic (oc/oc) mutants. , 2000, Bone.

[190]  W. Swat,et al.  Vav3 regulates osteoclast function and bone mass , 2005, Nature Medicine.

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

[192]  V. Quaranta,et al.  Activation of the Integrin Involves a Discrete Cation-binding Site That Regulates Conformation (*) , 1996, The Journal of Biological Chemistry.

[193]  R. Ganju,et al.  β-Chemokine Receptor CCR5 Signals through SHP1, SHP2, and Syk* , 2000, The Journal of Biological Chemistry.

[194]  David A. Williams,et al.  The Rac2 Guanosine Triphosphatase Regulates B Lymphocyte Antigen Receptor Responses and Chemotaxis and Is Required for Establishment of B-1a and Marginal Zone B Lymphocytes1 , 2002, The Journal of Immunology.

[195]  Sakae Tanaka,et al.  Severe osteopetrosis, defective interleukin‐1 signalling and lymph node organogenesis in TRAF6‐deficient mice , 1999, Genes to cells : devoted to molecular & cellular mechanisms.

[196]  R. Baron,et al.  Osteoclasts express high levels of pp60c-src in association with intracellular membranes , 1992, The Journal of cell biology.

[197]  Sheila M. Thomas,et al.  Cellular functions regulated by Src family kinases. , 1997, Annual review of cell and developmental biology.

[198]  S. Lin,et al.  Differentiation dependent expression of tensin and cortactin in chicken osteoclasts. , 1995, Cell motility and the cytoskeleton.

[199]  K. Hruska,et al.  Rho-A Is Critical for Osteoclast Podosome Organization, Motility, and Bone Resorption* , 2000, The Journal of Biological Chemistry.

[200]  K. Takagi,et al.  Deficiency of SHP-1 protein-tyrosine phosphatase activity results in heightened osteoclast function and decreased bone density. , 1999, The American journal of pathology.

[201]  H. Varmus,et al.  Rescue of osteoclast function by transgenic expression of kinase-deficient Src in src-/- mutant mice. , 1997, Genes & development.

[202]  P. De Camilli,et al.  A Functional Link between Dynamin and the Actin Cytoskeleton at Podosomes , 2000, The Journal of cell biology.

[203]  I. Dikic,et al.  Cbl–CIN85–endophilin complex mediates ligand-induced downregulation of EGF receptors , 2002, Nature.

[204]  C. Begley,et al.  Endophilin-1: a multifunctional protein. , 2002, The international journal of biochemistry & cell biology.

[205]  F. Reinholt,et al.  Osteopontin--a possible anchor of osteoclasts to bone. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[206]  G. Rodan,et al.  Integrin-mediated signaling in the regulation of osteoclast adhesion and activation. , 1998, Frontiers in bioscience : a journal and virtual library.

[207]  G. Rodan,et al.  Inhibition of Osteoclast Function by Adenovirus Expressing Antisense Protein-tyrosine Kinase 2* , 2001, The Journal of Biological Chemistry.

[208]  A. Zallone,et al.  Dynamic changes in the osteoclast cytoskeleton in response to growth factors and cell attachment are controlled by β3 integrin , 2003, The Journal of cell biology.

[209]  D. Ficheux,et al.  Aggregation of mononucleated precursors triggers cell surface expression of alphavbeta3 integrin, essential to formation of osteoclast-like multinucleated cells. , 1998, Journal of cell science.

[210]  S. Morony,et al.  Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[211]  A. Schulz,et al.  Mutations in the a3 subunit of the vacuolar H(+)-ATPase cause infantile malignant osteopetrosis. , 2000, Human molecular genetics.

[212]  R. Kapur,et al.  p85alpha subunit of class IA PI-3 kinase is crucial for macrophage growth and migration. , 2005, Blood.

[213]  A. Saltiel,et al.  The product of the cbl oncogene forms stable complexes in vivo with endogenous Crk in a tyrosine phosphorylation-dependent manner , 1996, Molecular and cellular biology.

[214]  H. Datta,et al.  Immunofluorescent evidence for the abundance of focal adhesion kinase in the human and avian osteoclasts and its down regulation by calcitonin. , 1994, The Journal of endocrinology.

[215]  Russell G. Jones,et al.  Differential Control of CD28-Regulated In Vivo Immunity by the E3 Ligase Cbl-b1 , 2005, The Journal of Immunology.

[216]  Y. Kadono,et al.  Segregation of TRAF6‐mediated signaling pathways clarifies its role in osteoclastogenesis , 2001, The EMBO journal.

[217]  J. Wrana,et al.  Signaling and endocytosis: a team effort for cell migration. , 2005, Developmental cell.

[218]  T. Hunter,et al.  The tyrosine kinase negative regulator c-Cbl as a RING-type, E2-dependent ubiquitin-protein ligase. , 1999, Science.

[219]  M. Horton,et al.  Arg-Gly-Asp (RGD) peptides and the anti-vitronectin receptor antibody 23C6 inhibit dentine resorption and cell spreading by osteoclasts. , 1991, Experimental cell research.

[220]  D. Schlaepfer,et al.  Signaling through focal adhesion kinase. , 1999, Progress in biophysics and molecular biology.

[221]  R. Lefkowitz,et al.  Src-dependent Tyrosine Phosphorylation Regulates Dynamin Self-assembly and Ligand-induced Endocytosis of the Epidermal Growth Factor Receptor* , 2002, The Journal of Biological Chemistry.

[222]  R. Hynes,et al.  Mice lacking beta3 integrins are osteosclerotic because of dysfunctional osteoclasts. , 2000, The Journal of clinical investigation.