Integrin function in osteoclasts

Abstract Integrins are a large family of heteromeric cell surface receptors composed of non-covalently bound α and β subunits which interact with extracellular matrix molecules, serum constituents and the adhesion molecules of the immunoglobulin family. The extracellular domains of many integrins recognize the RGD (Arg-Gly-Asp) tripeptide found in several extracellular macromolecules such as fibronectin, vitronectin, fibrinogen and osteopontin. The vitronectin receptor, αvβ3 integrin, is highly expressed in osteoclasts, the bone resorbing cells, and binds many of these RGD containing proteins including osteopontin, which is abundant in bone. Antibodies to αvβ3, RGD peptides and RGD containing proteins such as echistatin, and kistrin were shown to inhibit bone resorption in vitro and in vivo. The identity of the αvβ3 natural ligand and its mode of action in bone are so far not known. In addition to the very high levels of αvβ3, mammalian osteoclasts also express α2β1, a collagen/laminin receptor and αvβ1, another vitronectin receptor. Signaling events that follow substrate recognition by osteoclasts are not well understood. RGD containing peptides and proteins modulate [Ca2+] transients in osteoclasts and phosphatidylinositol 3-kinase and pp60c-src are associated with αvβ3 in these cells. αv and β3 genes were shown to be regulated by the calciotropic hormone 1,25(OH)2D3 and by a number of cytokines known to be modulators of bone metabolism. In summary, elucidation of the interactions of osteoclast integrins with components of bone matrix, may lead to further understanding of the mechanism of bone resorption. Journal of Endocrinology (1997) 154, S47–S56