Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Advances in osteoclast biology: old findings and new insights from mouse models

Nature Reviews Rheumatology volume 7, pages 235–243 (2011)Cite this article

Subjects

Abstract

The maintenance of adequate bone mass is dependent upon the controlled and timely removal of old, damaged bone. This complex process is performed by the highly specialized, multinucleated osteoclast. Over the past 15 years, a detailed picture has emerged describing the origins, differentiation pathways and activation stages that contribute to normal osteoclast function. This information has primarily been obtained by the development and skeletal analysis of genetically modified mouse models. Mice harboring mutations in specific genetic loci exhibit bone defects as a direct result of aberrations in normal osteoclast recruitment, formation or function. These findings include the identification of the RANK–RANKL–OPG system as a primary mediator of osteoclastogenesis, the characterization of ion transport and cellular attachment mechanisms and the recognition that matrix-degrading enzymes are essential components of resorptive activity. This Review focuses on the principal observations in osteoclast biology derived from genetic mouse models, and highlights emerging concepts that describe how the osteoclast is thought to contribute to the maintenance of adequate bone mass and integrity throughout life.

Key Points

  • RANK–RANKL–OPG signaling is an important mediator of osteoclast differentiation

  • Transcriptional regulation of osteoclast formation involves NFκB and NFATc1

  • Osteoclast attachment to the bone surface is necessary for resorption to proceed

  • Osteoclast activity is dependent upon effective ion transport across the cell membrane

  • Matrix-degrading enzymes are essential for effective breakdown of organic bone

  • Osteoclast-targeted therapies are the first-line treatment for excessive bone loss

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Osteoclast differentiation and function.
Figure 2: Principal signaling pathways governing osteoclast formation and activation.
Figure 3: Osteoclastic resorption.

Similar content being viewed by others

References

  1. Krane, S. M. & Inada, M. Matrix metalloproteinases and bone. Bone 43, 7–18 (2008).

    Article  CAS  PubMed  Google Scholar 

  2. Hertwig, P. Sechs neue mutationen bei der hausmaus in ihrer bedeutung für allgemeine vererbungsfragen. Z. Menschl. Vererb. Konstitutionsl. 26, 1–21 (1942).

    Google Scholar 

  3. Grüneberg, H. A new sub-lethal colour mutation in the house mouse. Proc. R. Soc. Lond. B 118, 321–342 (1935).

    Article  Google Scholar 

  4. Dickie, M. Private communication. Mouse News Letter 36, 39 (1967).

    Google Scholar 

  5. Walker, D. G. Spleen cells transmit osteopetrosis in mice. Science 190, 785–787 (1975).

    Article  CAS  PubMed  Google Scholar 

  6. Walker, D. G. Bone resorption restored in osteopetrotic mice by transplants of normal bone marrow and spleen cells. Science 190, 784–785 (1975).

    Article  CAS  PubMed  Google Scholar 

  7. Walker, D. G. Control of bone resorption by hematopoietic tissue. The induction and reversal of congenital osteopetrosis in mice through use of bone marrow and splenic transplants. J. Exp. Med. 142, 651–663 (1975).

    Article  CAS  PubMed  Google Scholar 

  8. Yoshida, H. et al. The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene. Nature 345, 442–444 (1990).

    Article  CAS  PubMed  Google Scholar 

  9. Marks, S. C. Jr & Lane, P. W. Osteopetrosis, a new recessive skeletal mutation on chromosome 12 of the mouse. J. Hered. 67, 11–18 (1976).

    Article  PubMed  Google Scholar 

  10. Wiktor-Jedrzejczak, W. W., Ahmed, A., Szczylik, C. & Skelly, R. R. Hematological characterization of congenital osteopetrosis in op/op mouse. Possible mechanism for abnormal macrophage differentiation. J. Exp. Med. 156, 1516–1527 (1982).

    Article  CAS  PubMed  Google Scholar 

  11. Arai, F. 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. J. Exp. Med. 190, 1741–1754 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Zhang, D. E., Hetherington, C. J., Chen, H. M. & Tenen, D. G. The macrophage transcription factor PU.1 directs tissue-specific expression of the macrophage colony-stimulating factor receptor. Mol. Cell Biol. 14, 373–381 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Pahl, H. L. et al. The proto-oncogene PU.1 regulates expression of the myeloid-specific CD11b promoter. J. Biol. Chem. 268, 5014–5020 (1993).

    CAS  PubMed  Google Scholar 

  14. Tondravi, M. M. et al. Osteopetrosis in mice lacking haematopoietic transcription factor PU.1. Nature 386, 81–84 (1997).

    Article  CAS  PubMed  Google Scholar 

  15. Hodgkinson, C. A. et al. Mutations at the mouse microphthalmia locus are associated with defects in a gene encoding a novel basic-helix-loop-helix-zipper protein. Cell 74, 395–404 (1993).

    Article  CAS  PubMed  Google Scholar 

  16. Luchin, A. et al. The microphthalmia transcription factor regulates expression of the tartrate-resistant acid phosphatase gene during terminal differentiation of osteoclasts. J. Bone Miner. Res. 15, 451–460 (2000).

    Article  CAS  PubMed  Google Scholar 

  17. Luchin, A. et al. Genetic and physical interactions between microphthalmia transcription factor and PU.1 are necessary for osteoclast gene expression and differentiation. J. Biol. Chem. 276, 36703–36710 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. Rehli, M., Lichanska, A., Cassady, A. I., Ostrowski, M. C. & Hume, D. A. TFEC is a macrophage-restricted member of the microphthalmia-TFE subfamily of basic helix-loop-helix leucine zipper transcription factors. J. Immunol. 162, 1559–1565 (1999).

    CAS  PubMed  Google Scholar 

  19. Grigoriadis, A. E. et al. c-Fos: a key regulator of osteoclast-macrophage lineage determination and bone remodeling. Science 266, 443–448 (1994).

    Article  CAS  PubMed  Google Scholar 

  20. Matsumoto, M., Sudo, T., Marumaya, M., Osada, H. & Tsujimoto, M. Activation of p38 mitogen-activated protein kinase is crucial in osteoclastogenesis induced by tumor necrosis factor. FEBS Lett. 486, 23–28 (2000).

    Article  CAS  PubMed  Google Scholar 

  21. Simonet, W. S. et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89, 309–319 (1997).

    Article  CAS  PubMed  Google Scholar 

  22. Yasuda, H. et al. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc. Natl Acad. Sci. USA 95, 3597–3602 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lacey, D. L. et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93, 165–176 (1998).

    Article  CAS  PubMed  Google Scholar 

  24. Wong, B. R. et al. TRANCE is a novel ligand of the tumor necrosis factor receptor family that activates c-Jun N-terminal kinase in T cells. J. Biol. Chem. 272, 25190–25194 (1997).

    Article  CAS  PubMed  Google Scholar 

  25. Anderson, D. M. et al. A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature 390, 175–179 (1997).

    Article  CAS  PubMed  Google Scholar 

  26. Hsu, H. et al. Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. Proc. Natl Acad. Sci. USA 96, 3540–3545 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Bucay, N. et al. Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev. 12, 1260–1268 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Li, J. et al. RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism. Proc. Natl Acad. Sci. USA 97, 1566–1571 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kong, Y. Y. et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397, 315–323 (1999).

    Article  CAS  PubMed  Google Scholar 

  30. Rothe, M., Sarma, V., Dixit, V. M. & Goeddel, D. V. TRAF2-mediated activation of NF-κ B by TNF receptor 2 and CD40. Science 269, 1424–1427 (1995).

    Article  CAS  PubMed  Google Scholar 

  31. Song, H. Y., Régnier, C. H., Kirschning, C. J., Goeddel, D. V. & Rothe, M. Tumor necrosis factor (TNF)-mediated kinase cascades: bifurcation of nuclear factor-κB and c-jun N-terminal kinase (JNK/SAPK) pathways at TNF receptor-associated factor 2. Proc. Natl Acad. Sci. USA 94, 9792–9796 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Nakano, H. et al. TRAF5, an activator of NF-κB and putative signal transducer for the lymphotoxin-β receptor. J. Biol. Chem. 271, 14661–14664 (1996).

    Article  CAS  PubMed  Google Scholar 

  33. Ishida, T. et al. Identification of TRAF6, a novel tumor necrosis factor receptor-associated factor protein that mediates signaling from an amino-terminal domain of the CD40 cytoplasmic region. J. Biol. Chem. 271, 28745–28748 (1996).

    Article  CAS  PubMed  Google Scholar 

  34. Yeh, W. C. et al. Early lethality, functional NF-κB activation, and increased sensitivity to TNF-induced cell death in TRAF2-deficient mice. Immunity 7, 715–725 (1997).

    Article  CAS  PubMed  Google Scholar 

  35. Naito, A. et al. Severe osteopetrosis, defective interleukin-1 signalling and lymph node organogenesis in TRAF6-deficient mice. Genes Cells 4, 353–362 (1999).

    Article  CAS  PubMed  Google Scholar 

  36. Lomaga, M. A. et al. TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. Genes Dev. 13, 1015–1024 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Armstrong, A. P. et al. A RANK/TRAF6-dependent signal transduction pathway is essential for osteoclast cytoskeletal organization and resorptive function. J. Biol. Chem. 277, 44347–44356 (2002).

    Article  CAS  PubMed  Google Scholar 

  38. Bai, S. et al. FHL2 inhibits the activated osteoclast in a TRAF6-dependent manner. J. Clin. Invest. 115, 2742–2751 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Gerondakis, S. et al. Unravelling the complexities of the NF-κB signalling pathway using mouse knockout and transgenic models. Oncogene 25, 6781–6799 (2006).

    Article  CAS  PubMed  Google Scholar 

  40. Iotsova, V. et al. Osteopetrosis in mice lacking NF-κB1 and NF-κB2. Nat. Med. 3, 1285–1289 (1997).

    Article  CAS  PubMed  Google Scholar 

  41. Franzoso, G. et al. Requirement for NF-κB in osteoclast and B-cell development. Genes Dev. 11, 3482–3496 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Xing, L. et al. NF-κB p50 and p52 expression is not required for RANK-expressing osteoclast progenitor formation but is essential for RANK- and cytokine-mediated osteoclastogenesis. J. Bone Miner. Res. 17, 1200–1210 (2002).

    Article  CAS  PubMed  Google Scholar 

  43. Li, Q. et al. IKK1-deficient mice exhibit abnormal development of skin and skeleton. Genes Dev. 13, 1322–1328 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Takeda, K. et al. Limb and skin abnormalities in mice lacking IKKα. Science 284, 313–316 (1999).

    Article  CAS  PubMed  Google Scholar 

  45. Sil, A. K., Maeda, S., Sano, Y., Roop, D. R. & Karin, M. IκB kinase-α acts in the epidermis to control skeletal and craniofacial morphogenesis. Nature 428, 660–664 (2004).

    Article  CAS  PubMed  Google Scholar 

  46. Ruocco, M. G. et al. I{κ}B kinase (IKK){β}, but not IKK{α}, is a critical mediator of osteoclast survival and is required for inflammation-induced bone loss. J. Exp. Med. 201, 1677–1687 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Edwards, J. R. et al. IκBα-deficient mice display increased osteoclast formation and activity and bone loss in vivo [abstract 1147]. J. Bone Miner. Res. 22 (Suppl. 1), S42 (2007).

    Google Scholar 

  48. Takayanagi, H. et al. Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev. Cell 3, 889–901 (2002).

    Article  CAS  PubMed  Google Scholar 

  49. Ranger, A. M. et al. The transcription factor NF-ATc is essential for cardiac valve formation. Nature 392, 186–190 (1998).

    Article  CAS  PubMed  Google Scholar 

  50. de la Pompa, J. L. et al. Role of the NF-ATc transcription factor in morphogenesis of cardiac valves and septum. Nature 392, 182–186 (1998).

    Article  CAS  PubMed  Google Scholar 

  51. Winslow, M. M. et al. Calcineurin/NFAT signaling in osteoblasts regulates bone mass. Dev. Cell 10, 771–782 (2006).

    Article  CAS  PubMed  Google Scholar 

  52. Negishi-Koga, T. & Takayanagi, H. Ca2+-NFATc1 signaling is an essential axis of osteoclast differentiation. Immunol. Rev. 231, 241–256 (2009).

    Article  CAS  PubMed  Google Scholar 

  53. Koga, T. et al. Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis. Nature 428, 758–763 (2004).

    Article  CAS  PubMed  Google Scholar 

  54. Shinohara, M. et al. Tyrosine kinases Btk and Tec regulate osteoclast differentiation by linking RANK and ITAM signals. Cell 132, 794–806 (2008).

    Article  CAS  PubMed  Google Scholar 

  55. Li, Y. et al. B cells and T cells are critical for the preservation of bone homeostasis and attainment of peak bone mass in vivo. Blood 109, 3839–3848 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Kong, Y. Y. et al. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 402, 304–309 (1999).

    Article  CAS  PubMed  Google Scholar 

  57. Roggia, C. et al. Up-regulation of TNF-producing T cells in the bone marrow: a key mechanism by which estrogen deficiency induces bone loss in vivo. Proc. Natl Acad. Sci. USA 98, 13960–13965 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Aubin, J. E. Osteoclast adhesion and resorption: the role of podosomes. J. Bone Miner. Res. 7, 365–368 (1992).

    Article  CAS  PubMed  Google Scholar 

  59. McHugh, K. P. et al. Mice lacking β3 integrins are osteosclerotic because of dysfunctional osteoclasts. J. Clin. Invest. 105, 433–440 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Soriano, P., Montgomery, C., Geske, R. & Bradley, A. Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice. Cell 64, 693–702 (1991).

    Article  CAS  PubMed  Google Scholar 

  61. Blair, H. C. How the osteoclast degrades bone. Bioessays 20, 837–846 (1998).

    Article  CAS  PubMed  Google Scholar 

  62. Supanchart, C. & Kornak, U. Ion channels and transporters in osteoclasts. Arch. Biochem. Biophys. 473, 161–165 (2008).

    Article  CAS  PubMed  Google Scholar 

  63. Li, Y. P., Chen, W., Liang, Y., Li, E. & Stashenko, P. Atp6i-deficient mice exhibit severe osteopetrosis due to loss of osteoclast-mediated extracellular acidification. Nat. Genet. 23, 447–451 (1999).

    Article  CAS  PubMed  Google Scholar 

  64. Scimeca, J. C. 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. Bone 26, 207–213 (2000).

    Article  CAS  PubMed  Google Scholar 

  65. Kornak, U. et al. Mutations in the a3 subunit of the vacuolar H(+)-ATPase cause infantile malignant osteopetrosis. Hum. Mol. Genet. 9, 2059–2063 (2000).

    Article  CAS  PubMed  Google Scholar 

  66. Michigami, T. et al. Novel mutations in the a3 subunit of vacuolar H(+)-adenosine triphosphatase in a Japanese patient with infantile malignant osteopetrosis. Bone 30, 436–439 (2002).

    Article  CAS  PubMed  Google Scholar 

  67. Lee, S. H. et al. v-ATPase V0 subunit d2-deficient mice exhibit impaired osteoclast fusion and increased bone formation. Nat. Med. 12, 1403–1409 (2006).

    Article  CAS  PubMed  Google Scholar 

  68. Boyce, B. F., Yoneda, T., Lowe, C., Soriano, P. & Mundy, G. R. Requirement of pp60c-src expression for osteoclasts to form ruffled borders and resorb bone in mice. J. Clin. Invest. 90, 1622–1627 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Teitelbaum, S. L. & Ross, F. P. Genetic regulation of osteoclast development and function. Nat. Rev. Genet. 4, 638–649 (2003).

    Article  CAS  PubMed  Google Scholar 

  70. Sly, W. S. & Hu, P. Y. Human carbonic anhydrases and carbonic anhydrase deficiencies. Annu. Rev. Biochem. 64, 375–401 (1995).

    Article  CAS  PubMed  Google Scholar 

  71. Margolis, D. S., Szivek, J. A., Lai, L. W. & Lien, Y. H. Phenotypic characteristics of bone in carbonic anhydrase II-deficient mice. Calcif. Tissue Int. 82, 66–76 (2008).

    Article  CAS  PubMed  Google Scholar 

  72. Schlesinger, P. H., Blair, H. C., Teitelbaum, S. L. & Edwards, J. C. Characterization of the osteoclast ruffled border chloride channel and its role in bone resorption. J. Biol. Chem. 272, 18636–18643 (1997).

    Article  CAS  PubMed  Google Scholar 

  73. Kornak, U. et al. Loss of the ClC-7 chloride channel leads to osteopetrosis in mice and man. Cell 104, 205–215 (2001).

    Article  CAS  PubMed  Google Scholar 

  74. Gelb, B. D., Shi, G. P., Chapman, H. A. & Desnick, R. J. Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Science 273, 1236–1238 (1996).

    Article  CAS  PubMed  Google Scholar 

  75. Saftig, P. et al. Impaired osteoclastic bone resorption leads to osteopetrosis in cathepsin-K-deficient mice. Proc. Natl Acad. Sci. USA 95, 13453–13458 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Gowen, M. et al. Cathepsin K knockout mice develop osteopetrosis due to a deficit in matrix degradation but not demineralization. J. Bone Miner. Res. 14, 1654–1663 (1999).

    Article  CAS  PubMed  Google Scholar 

  77. Li, C. Y. et al. Mice lacking cathepsin K maintain bone remodeling but develop bone fragility despite high bone mass. J. Bone Miner. Res. 21, 865–875 (2006).

    Article  CAS  PubMed  Google Scholar 

  78. Delaissé, J. M. et al. Matrix metalloproteinases (MMP) and cathepsin K contribute differently to osteoclastic activities. Microsc. Res. Tech. 61, 504–513 (2003).

    Article  PubMed  CAS  Google Scholar 

  79. Vu, T. H. et al. MMP-9/gelatinase B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes. Cell 93, 411–422 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Inada, M. et al. Critical roles for collagenase-3 (MMP13) in development of growth plate cartilage and in endochondral ossification. Proc. Natl Acad. Sci. USA 101, 17192–17197 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Stickens, D. et al. Altered endochondral bone development in matrix metalloproteinase 13-deficient mice. Development 131, 5883–5895 (2004).

    Article  CAS  PubMed  Google Scholar 

  82. Kosaki, N. et al. Impaired bone fracture healing in matrix metalloproteinase-13 deficient mice. Biochem. Biophys. Res. Commun. 354, 846–851 (2007).

    Article  CAS  PubMed  Google Scholar 

  83. Hollberg, K., Hultenby, K., Hayman, A., Cox, T. & Andersson, G. Osteoclasts from mice deficient in tartrate-resistant acid phosphatase have altered ruffled borders and disturbed intracellular vesicular transport. Exp. Cell Res. 279, 227–238 (2002).

    Article  CAS  PubMed  Google Scholar 

  84. Watts, N. B. & Diab, D. L. Long-term use of bisphosphonates in osteoporosis. J. Clin. Endocrinol. Metab. 95, 1555–1565 (2010).

    Article  CAS  PubMed  Google Scholar 

  85. Bekker, P. J. et al. A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women. J. Bone Miner. Res. 19, 1059–1066 (2004).

    Article  CAS  PubMed  Google Scholar 

  86. McClung, M. R. et al. Denosumab in postmenopausal women with low bone mineral density. N. Engl. J. Med. 354, 821–831 (2006).

    Article  CAS  PubMed  Google Scholar 

  87. Bone, H. G. et al. Odanacatib, a cathepsin-K inhibitor for osteoporosis: a two-year study in postmenopausal women with low bone density. J. Bone Miner. Res. 25, 937–947 (2010).

    PubMed  Google Scholar 

  88. Stoch, S. A. et al. Effect of the cathepsin K inhibitor odanacatib on bone resorption biomarkers in healthy postmenopausal women: two double-blind, randomized, placebo-controlled phase I studies. Clin. Pharmacol. Ther. 86, 175–182 (2009).

    Article  CAS  PubMed  Google Scholar 

  89. Ohno, H. et al. A c-Fms tyrosine kinase inhibitor, Ki20227, suppresses osteoclast differentiation and osteolytic bone destruction in a bone metastasis model. Mol. Cancer Ther. 5, 2634–2643 (2006).

    Article  CAS  PubMed  Google Scholar 

  90. Lark, M. W. et al. Antagonism of the osteoclast vitronectin receptor with an orally active nonpeptide inhibitor prevents cancellous bone loss in the ovariectomized rat. J. Bone Miner. Res. 16, 319–327 (2001).

    Article  CAS  PubMed  Google Scholar 

  91. Murphy, M. G. et al. Effect of L-000845704, an αVβ3 integrin antagonist, on markers of bone turnover and bone mineral density in postmenopausal osteoporotic women. J. Clin. Endocrinol. Metab. 90, 2022–2028 (2005).

    Article  CAS  PubMed  Google Scholar 

  92. Lu, X. et al. A new osteopetrosis mutant mouse strain (ntl) with odontoma-like proliferations and lack of tooth roots. Eur. J. Oral Sci. 117, 625–635 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Tang, Y. et al. TGF-β1-induced migration of bone mesenchymal stem cells couples bone resorption with formation. Nat. Med. 15, 757–765 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Kara, F. M. et al. Adenosine A1 receptors regulate bone resorption in mice: adenosine A1 receptor blockade or deletion increases bone density and prevents ovariectomy-induced bone loss in adenosine A1 receptor-knockout mice. Arthritis Rheum. 62, 534–541 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Whyte, L. S. et al. The putative cannabinoid receptor GPR55 affects osteoclast function in vitro and bone mass in vivo. Proc. Natl Acad. Sci. USA 106, 16511–16516 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Iwasawa, M. et al. The antiapoptotic protein Bcl-xL negatively regulates the bone-resorbing activity of osteoclasts in mice. J. Clin. Invest. 119, 3149–3159 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Martin-Millan, M. et al. The estrogen receptor-α in osteoclasts mediates the protective effects of estrogens on cancellous but not cortical bone. Mol. Endocrinol. 24, 323–334 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Imai, Y. et al. Estrogens maintain bone mass by regulating expression of genes controlling function and life span in mature osteoclasts. Ann. NY Acad. Sci. 1173 (Suppl. 1), E31–E39 (2009).

    Article  CAS  PubMed  Google Scholar 

  99. Chan, A. S. et al. Id1 represses osteoclast-dependent transcription and affects bone formation and hematopoiesis. PLoS ONE 4, e7955 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Edwards, J. R. et al. The aging associated gene SIRT-1 regulates osteoclast formation and bone mass in vivo [abstract 1097]. J. Bone Miner. Res. 22 (Suppl. 1), S29 (2007).

    Google Scholar 

  101. Mizoguchi, F. et al. Osteoclast-specific Dicer gene deficiency suppresses osteoclastic bone resorption. J. Cell Biochem. 109, 866–875 (2010).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Gregory R. Mundy, deceased 25 February 2010. We acknowledge the funding support provided by the American Federation for Aging Research (AFAR) and NIH National Cancer Institute (5P01-CA40035-21) during the preparation of this manuscript, and thank Prof. T. J. Martin of St Vincent's Institute, Melbourne, Australia, for useful comments.

Author information

Authors and Affiliations

  1. Institute of Musculoskeletal Sciences, University of Oxford, Nuffield Orthopedic Center, Windmill Road, OX3 7LD, Oxford, UK

    James R. Edwards

  2. Vanderbilt Center for Bone Biology, 1235 Medical Research Building IV, Vanderbilt University Medical Center, Nashville, 37232-0575, TN, USA

    Gregory R. Mundy

Authors
  1. James R. Edwards
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gregory R. Mundy
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J. R. Edwards and G. R. Mundy discussed article content. J. R. Edwards researched data, wrote the article and revised/edited the manuscript during submission.

Corresponding author

Correspondence to James R. Edwards.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Edwards, J., Mundy, G. Advances in osteoclast biology: old findings and new insights from mouse models. Nat Rev Rheumatol 7, 235–243 (2011). https://doi.org/10.1038/nrrheum.2011.23

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrrheum.2011.23

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing