The role of calcium release activated calcium channels in osteoclast differentiation

Authors

  • Yandong Zhou,

    1. Department of Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania
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  • Tricia L. Lewis,

    1. Department of Microbiology, Immunology & Cell Biology, West Virginia University School of Medicine, Morgantown, West Virginia
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  • Lisa J. Robinson,

    1. Department of Pathology and Physiology & Cell Biology, Veteran's Affairs Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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  • Kathy M. Brundage,

    1. Department of Microbiology, Immunology & Cell Biology, West Virginia University School of Medicine, Morgantown, West Virginia
    2. Mary Babb Randolph Cancer Center, West Virginia University School of Medicine, Morgantown, West Virginia
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  • Rosana Schafer,

    1. Department of Microbiology, Immunology & Cell Biology, West Virginia University School of Medicine, Morgantown, West Virginia
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  • Karen H. Martin,

    1. Department of Microbiology, Immunology & Cell Biology, West Virginia University School of Medicine, Morgantown, West Virginia
    2. Mary Babb Randolph Cancer Center, West Virginia University School of Medicine, Morgantown, West Virginia
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  • Harry C. Blair,

    1. Department of Pathology and Physiology & Cell Biology, Veteran's Affairs Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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  • Jonathan Soboloff,

    Corresponding author
    1. Department of Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania
    • Department of Biochemistry, Temple University School of Medicine, 3440 N. Broad Street, Philadelphia, PA 19140.
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  • John B. Barnett

    Corresponding author
    1. Department of Microbiology, Immunology & Cell Biology, West Virginia University School of Medicine, Morgantown, West Virginia
    2. Mary Babb Randolph Cancer Center, West Virginia University School of Medicine, Morgantown, West Virginia
    • Department of Microbiology, Immunology, & Cell Biology, West Virginia University School of Medicine, One Medical Center Drive, Morgantown, WV 26506.
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  • Yandong Zhou and Tricia L. Lewis contributed equally to this study.

Abstract

Osteoclasts are specialized macrophage derivatives that secrete acid and proteinases to mobilize bone for mineral homeostasis, growth, and replacement or repair. Osteoclast differentiation generally requires the monocyte growth factor m-CSF and the TNF-family cytokine RANKL, although differentiation is regulated by many other cytokines and by intracellular signals, including Ca2+. Studies of osteoclast differentiation in vitro were performed using human monocytic precursors stimulated with m-CSF and RANKL, revealing significant loss in both the expression and function of the required components of store-operated Ca2+ entry over the course of osteoclast differentiation. However, inhibition of CRAC using either the pharmacological agent 3,4-dichloropropioanilide (DCPA) or by knockdown of Orai1 severely inhibited formation of multinucleated osteoclasts. In contrast, no effect of CRAC channel inhibition was observed on expression of the osteoclast protein tartrate resistant acid phosphatase (TRAP). Our findings suggest that despite the fact that they are down-regulated during osteoclast differentiation, CRAC channels are required for cell fusion, a late event in osteoclast differentiation. Since osteoclasts cannot function properly without multinucleation, selective CRAC inhibitors may have utility in management of hyperresorptive states. J. Cell. Physiol. 226: 1082–1089, 2011. © 2010 Wiley-Liss, Inc.

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