Role of (alpha)v(beta)3 integrin in osteoclasts

Osteoclasts are macrophage-related multinucleated cells that resorb bone. Osteoclastic bone-resorbing activity involves a number of differentiation and activation steps including: (i) proliferation and homing of hemopoietic precursors to bone, (ii) their differentiation into mononuclear osteoclasts, (iii) fusion of these cells to form multinucleated osteoclasts, (iv) formation of a sealing zone (clear zone) surrounding a resorption lacuna, and (v) following resorption, migration to a new site (Suda et al., 1996; Roodman, 1996). Integrins are suggested to play a key role in osteoclast migration and activation (Horton and Rodan, 1995). Integrins are transmembrane heterodimeric glycoproteins that mediate cell-cell and cell-matrix interactions. Ligand binding to integrins activates signal transduction pathways involved in cytoskeletal rearrangements associated with cell adhesion and motility (Hynes, 1992). While osteoclasts also express α2β1 and αvβ1 integrins, their predominant integrin is αvβ3 (Davies et al., 1989; Horton et al., 1991; Helfrich et al., 1992; Nesbitt et al., 1993). The αvβ3 integrin belongs to a class of integrins which recognize the arginine-glycine-aspartic acid (RGD) moiety in extracellular matrix (ECM) proteins (Hynes, 1992). Disintegrins, αvβ3 blocking antibodies and RGD peptide mimetics have been shown to inhibit bone resorption, osteoclast formation, attachment, and spreading in vitro (Chambers et al., 1986; Sato et al., 1990, 1994; Lakkakorpi et al., 1991; Horton et al., 1991; Nakamura et al., 1996, 1998). Anti-β3 antibodies, an RGD peptide mimetic and disintegrins such as echistatin, inhibit bone resorption in vivo (Fisher et al., 1993; King et al., 1994; Crippes et al., 1996; Engleman et al., 1997; Yamamoto et al., 1998; Masarachia et al., 1998). Although the αvβ3 integrin is known to be essential for osteoclast function, its mode of action is not fully understood. Interfering with αvβ3 function in vitro, using blocking antibodies or echistatin, induces osteoclast retraction and detachment (Chambers et al., 1986; Sato et al., 1990; Horton et al., 1991). On the other hand, inhibition of bone resorption in vivo by echistatin was accompanied by no significant reduction in the number of osteoclasts on the bone surface (Masarachia et al., 1998). Consistent with this observation, targeted disruption of β3 integrin in mice induces progressive osteosclerosis without an apparent reduction in the number of osteoclasts on bone (McHugh et al., 1998). The observations outlined above suggest that in vivo, interference with αvβ3 integrin signaling may reduce osteoclastic resorption efficiency without affecting osteoclast differentiation and recruitment to bone. 3985 Journal of Cell Science 112, 3985-3993 (1999) Printed in Great Britain © The Company of Biologists Limited 1999 JCS0569