Involvement of calpain in osteoclastic bone resorption.
There is increasing evidence that calpain contributes to the reorganization of the cytoskeleton in the integrin-mediated signaling pathway. Osteoclastic bone resorption requires cell-matrix contact, an event mediated by integrin alphavbeta3, and subsequent cytoskeletal reorganization to form characteristic membrane domains such as the sealing zone and ruffled border. In this study, therefore, we investigated whether calpain is involved in osteoclastic bone resorption. Membrane-permeable calpain inhibitors suppress the resorption activity of human osteoclasts, but an impermeable inhibitor does not. Upon the attachment of osteoclasts to bone, micro-calpain is translocated from the cytosolic to the cytoskeletal fraction and is autolytically activated. Both the activation of micro-calpain and the formation of actin-rings, the cytoskeletal structures essential for bone resorption, are inhibited by membrane-permeable calpain inhibitors. The activated micro-calpain in osteoclasts selectively cleaves talin, which links the matrix-recognizing integrin to the actin cytoskeleton. These findings suggest that calpain is a regulator of the bone resorption activity of osteoclasts through reorganization of the cytoskeleton related to actin-ring formation.
Hayashi
Masami
M
Biomembrane Research Group, and Bone Research Group, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015.
Koshihara
Yasuko
Y
Ishibashi
Hideaki
H
Yamamoto
Seizo
S
Tsubuki
Satoshi
S
Saido
Takaomi C
TC
Kawashima
Seiichi
S
Inomata
Mitsushi
M
D000199:Actins / Q000378:metabolism; D000368:Aged; D001862:Bone Resorption / Q000503:physiopathology*; D001842:Bone and Bones / Q000502:physiology; D002154:Calpain / Q000037:antagonists & inhibitors / Q000502:physiology*; D002478:Cells, Cultured; D004151:Dipeptides / Q000494:pharmacology; D006801:Humans; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D010010:Osteoclasts / Q000201:enzymology* / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D016608:Talin / Q000378:metabolism
D000199:Actins; D004151:Dipeptides; D011993:Recombinant Fusion Proteins; D016608:Talin; C503097:calpastat; C071482:calpeptin; C032425:N-(N-(3-carboxyoxirane-2-carbonyl)leucyl)isoamylamine; D002154:Calpain; D007930:Leucine