Calpain Is required for normal osteoclast function and Is downregulated by calcitonin

doi:10.1074/jbc.M513516200

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Calpain Is required for normal osteoclast function and Is downregulated by calcitonin

Marilena Marzia, Riccardo Chiusaroli, Lynn Neff, Na-Young Kim, Athar H. Chishti, Roland Baron, and William C. Horne

Department of Orthopaedics, Yale University School of Medicine, New Haven, CT 06520-8044

Corresponding Author: william.horne{at}yale.edu

Osteoclast motility is thought to depend on rapid podosome assembly and disassembly. Both $mu$ -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 $mu$ -calpain^-/- osteoclast-like cells were also reduced, indicating that $mu$ -calpain is required for normal osteoclast activity. Histomorphometric analysis of tibias from $mu$ -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 $mu$ -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.

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