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Osteoclastic differentiation and function regulated by old and new pathways

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Abstract

The osteoclast is a specialized multinucleated variant of the macrophage family. It degrades mineralized tissue, and is required for modeling and remodeling of bone. The osteoclast has long been known to require vitamin D for its differentiation and to be regulated by parathyroid hormone via circulating Ca2+ levels. Two local signals important in osteoclast survival and differentiation, CSF-1 and RANKL, were characterized by the mid-1990s. A basic framework of specialized cell attachment and resorption molecules was also clear by that time, including the αvβ3 integrin, the key adhesion molecule of the mature osteoclast, the highly expressed vacuolar-type H+-ATPase that drives acid secretion to dissolve mineral, and cathepsin K, the predominant acid proteinase for collagenolysis. Recently, additional detail has been added to this framework, showing that the osteoclast has more complex regulation than was previously believed. These include the findings that one component of the V-H+-ATPase is unique to the osteoclast, that chloride transport and probably Cl−/H+ exchange are also required for mineral degradation, and that additional receptors besides RANK and Fms regulate osteoclast formation and survival. Additional receptors include estrogen receptor-α, TNF-family receptors other than RANK, and, at least in some cases, glycoprotein hormone receptors including the TSH-R and the FSH-R. Challenges in understanding osteoclast biology include how the signalling mechanisms function cooperatively. Recent findings suggest that there is a network of cytoplasmic adapters, including Gab-2 and BCAR1, which are modified by multiple signalling mechanisms and which serve to integrate the signalling pathways.

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Acknowledgments

Supported by the Department of Veterans’ Affairs (HCB and MZ) and by NIH grants AG12951, AR47700 (to HCB), DK70526 and AG23176 (to MZ).

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Authors and Affiliations

  1. Department of Pathology, University of Pittsburgh and Veterans’ Affairs Health System, Pittsburgh, PA, 15261, USA

    Harry C. Blair

  2. Department of Cell Biology and Physiology, University of Pittsburgh and Veterans’ Affairs Health System, Pittsburgh, PA, 15261, USA

    Harry C. Blair

  3. Mount Sinai Bone Program, Mount Sinai School of Medicine, New York, NY, 10029, USA

    Mone Zaidi

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  1. Harry C. Blair
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  2. Mone Zaidi
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Correspondence to Mone Zaidi.

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Blair, H.C., Zaidi, M. Osteoclastic differentiation and function regulated by old and new pathways. Rev Endocr Metab Disord 7, 23–32 (2006). https://doi.org/10.1007/s11154-006-9010-4

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  • DOI: https://doi.org/10.1007/s11154-006-9010-4

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