The role of calcium release activated calcium channels in osteoclast differentiation.
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 Ca(2+). 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 Ca(2+) 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.
Zhou
Yandong
Y
Department of Biochemistry, Temple University School of Medicine, Philadelphia, PA 19140.
Lewis
Tricia L
TL
Department of Microbiology, Immunology & Cell Biology, West Virginia University School of Medicine, Morgantown, WV 26506.
Robinson
Lisa J
LJ
Departments of Pathology and Physiology & Cell Biology, University of Pittsburgh School of Medicine, and Veteran's Affairs Medical Center, Pittsburgh, PA 15216.
Brundage
Kathy M
KM
Department of Microbiology, Immunology & Cell Biology, West Virginia University School of Medicine, Morgantown, WV 26506.|Mary Babb Randolph Cancer Center, West Virginia University School of Medicine, Morgantown, WV 26506.
Schafer
Rosana
R
Department of Microbiology, Immunology & Cell Biology, West Virginia University School of Medicine, Morgantown, WV 26506.
Martin
Karen H
KH
Department of Microbiology, Immunology & Cell Biology, West Virginia University School of Medicine, Morgantown, WV 26506.|Mary Babb Randolph Cancer Center, West Virginia University School of Medicine, Morgantown, WV 26506.
Blair
Harry C
HC
Departments of Pathology and Physiology & Cell Biology, University of Pittsburgh School of Medicine, and Veteran's Affairs Medical Center, Pittsburgh, PA 15216.
Soboloff
Jonathan
J
Department of Biochemistry, Temple University School of Medicine, Philadelphia, PA 19140.
Barnett
John B
JB
Department of Microbiology, Immunology & Cell Biology, West Virginia University School of Medicine, Morgantown, WV 26506.|Mary Babb Randolph Cancer Center, West Virginia University School of Medicine, Morgantown, WV 26506.
D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D015640:Ion Channel Gating; D008565:Membrane Proteins / Q000378:metabolism; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000378:metabolism; D000071740:ORAI1 Protein; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D010795:Phthalic Acids / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D000071737:Stromal Interaction Molecule 1
D015220:Calcium Channels; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; D010795:Phthalic Acids; D034741:RNA, Small Interfering; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; C007220:dimethyl 2,3,5,6-tetrachloroterephthalate; D002118:Calcium