Giant cell tumours (GCT) of bone are locally aggressive and highly bone lytic. Tumours are composed of multinucleated giant cells interspersed with mononuclear tumour and stromal cells, the former cell type exhibiting phenotypic similarity to authentic osteoclasts. Mineralised bone resorption by GCTs has been attributed to the multinucleated, osteoclast-like giant cell component, although the persistence of lytic bone lesions may also involve impaired mineralised bone deposition involving other cellular elements (Dahlin et al., 1970;Roodman, 1996).Bone is composed largely of type I collagen (Gehron Robey, 1989), and type I collagenolytic enzymes have, therefore, been implicated in its degradation. Physiological osteoclast-mediated bone resorption is currently considered to result from the combined action of acidic collagenolytic cystein proteases (cathepsins) and neutral metalloproteinases (MMP) (Baron, 1989;Delaisse and Vaes, 1993;Hill et al., 1995;Roodman, 1996). Within the neutral MMP family, classical type I collagenase, MMP-1, and gelatinases which include MMP-2 and MMP-9 have been implicated in osteoclast-dependent bone resorption (Hill et al., 1995). These enzymes are expressed by GCT cells in vitro and by intraosseous GC tumours in vivo (Wucherpfennig et al., 1994;Rao et al., 1995), suggesting potential roles in GCT pathology.MMPs are secreted in latent form and require N-terminal sequence removal for activity (Cottam and Rees., 1993). Therefore, the physiological mechanisms that control MMP activation are central to the subsequent involvement of MMPs in biological processes. Many MMPs, such as MMP-1 and MMP-9, are activated by proteases such as plasmin, cathepsin G and trypsin-like enzymes. MMP-2, however, is resistant to activation by many of these enzymes (Mackay et al., 1990;Okada et al., 1990;Cottam and Rees, 1993). Activation of MMP-2 has been attributed to autocatalysis or to the action of other MMPs including MMP-1, MMP-7 and MT-MMP or to the serine proteases urokinase and thrombin (Atkinson et al., 1995; Crabbe et al., 1994a,b;Reith and Rucklidge., 1992;Zucker et al., 1995). Recently, a membraneassociated, MMP-dependent, MMP-2 activation mechanism has been described (Brown et al., 1993;Strongin et al., 1995;Ward et al., 1994) that possibly involves members of a novel membrane type MMP (MT-MMP) family (Sato et al., 1994).Bone matrix influences physiological and pathological bone cell behaviour. GCT cells and osteoclasts exhibit ␣V3 integrin and RGD sequence-dependent adherence to bone matrix components such as osteopontin (OPN) and bone sialoprotein (BSP) (Butler, 1989;Gehron Robey, 1989;Denhardt and Xiaojia, 1993;Horton et al., 1985Horton et al., , 1991Horton et al., , 1993Helfrich et al., 1992; Grano et al., 1994a,b;Roodman, 1996), and a close relationship has been reported between bone adherence and mineralised bone resorption (Horton et al., 1993;Grano et al., 1994a). Soluble RGD peptides inhibit RGD-dependent adherence to and resorption of mineralised bone in vitro (Horton et al., 1991(Hort...
