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J. Biol. Chem., Vol. 281, Issue 14, 9745-9754, April 7, 2006

This Article Full Text Full Text (PDF) All Versions of this Article: 281/14/9745    most recent M513516200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Marzia, M. Articles by Horne, W. C. Search for Related Content PubMed PubMed Citation Articles by Marzia, M. Articles by Horne, W. C. Social Bookmarking                      What's this?

Calpain Is Required for Normal Osteoclast Function and Is Down-regulated by Calcitonin^*

Marilena Marzia¹, Riccardo Chiusaroli², Lynn Neff, Na-Young Kim³, Athar H. Chishti^¶, Roland Baron, and William C. Horne⁴

From the Departments of Orthopaedics and Rehabilitation and Cell Biology, Yale University School of Medicine, New Haven, Connecticut 06520-8044, the Department of Medicine, St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02135, and the ^¶Department of Pharmacology/Cancer Center, University of Illinois College of Medicine, Chicago, Illinois 60607

Osteoclast motility is thought to depend on rapid podosome assembly and disassembly. Both µ-calpain and m-calpain, which promote the formation and disassembly of focal adhesions, were observed in the podosome belt of osteoclasts. Calpain inhibitors disrupted the podosome belt, blocked the constitutive cleavage of the calpain substrates filamin A, talin, and Pyk2, which are enriched in the podosome belt, induced osteoclast retraction, and reduced osteoclast motility and bone resorption. The motility and resorbing activity of µ-calpain^-/- osteoclast-like cells were also reduced, indicating that µ-calpain is required for normal osteoclast activity. Histomorphometric analysis of tibias from µ-calpain^-/- mice revealed increased osteoclast numbers and decreased trabecular bone volume that was apparent at 10 weeks but not at 5 weeks of age. In vitro studies suggested that the increased osteoclast number in the µ-calpain^-/- bones resulted from increased osteoclast survival, not increased osteoclast formation. Calcitonin disrupted the podosome ring, induced osteoclast retraction, and reduced osteoclast motility and bone resorption in a manner similar to the effects of calpain inhibitors and had no further effect on these parameters when added to osteoclasts pretreated with calpain inhibitors. Calcitonin inhibited the constitutive cleavage of a fluorogenic calpain substrate and transiently blocked the constitutive cleavage of filamin A, talin, and Pyk2 by a protein kinase C-dependent mechanism, demonstrating that calcitonin induces the inhibition of calpain in osteoclasts. These results indicate that calpain activity is required for normal osteoclast activity and suggest that calcitonin inhibits osteoclast bone resorbing activity in part by down-regulating calpain activity.

Received for publication, December 19, 2005

^* This work was supported by NIAMS, National Institutes of Health (NIH), Public Health Service Grant AR-49879 (to W. C. H.), NIDCR, NIH, Public Health Service Grant DE-04724 (to R. B.), and NHLBI, NIH, Public Health Service Grant HL-51445 (to A. H. C.). Other support included NIH Grant AR-46032 (to the Yale Core Center for Musculoskeletal Diseases). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: Endocrine Unit, Massachusetts General Hospital, Boston, MA 02114.

² Present address: Pharmacology and Toxicology Dept., Rottapharm S.p.A., 20052 Monza, Italy.

³ Present address: Division of Infectious Diseases, Children's Hospital, Boston, MA 02115.

⁴ To whom correspondence should be addressed: Dept. of Orthopaedics and Rehabilitation, Yale University School of Medicine, P.O. Box 208044, New Haven, CT 06520-8044. Tel.: 203-785-5986; Fax: 203-785-2744; E-mail: william.horne{at}yale.edu.

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