EFFECTS OF KISTRIN ON BONE-RESORPTION IN-VITRO AND SERUM-CALCIUM IN-VIVO

In many cell systems, cell-cell and cell-matrix interactions are media ted by integrins, a family of cell surface heterodimeric glycoprotein receptors. Osteoclast integrins may play a role in the process of bone resorption. Osteoclasts express the ct, and p, subunits of the vitron ectin receptor and adhere to a wide range of proteins in vitro, all of which contain the amino acid sequence Arg-Gly-Asp (RGD), an adhesion site recognition sequence common to many protein ligands that bind to integrins. The effect of kistrin, an ROD-containing snake venom protei n, on osteoclast-mediated bone resorption was investigated in vivo and in vitro. When kistrin was infused into normocalcemic and hypercalcem ic mice, serum calcium was significantly lowered at 3 and 6 h after th e start of infusion, indicating an inhibitory effect on osteoclast act ivity in vivo. In vitro, kistrin potently inhibited bone resorption by isolated rat osteoclasts cultured on slices of bovine bone, and kistr in also inhibited the attachment of 293 cells expressing recombinant h uman alpha(v) beta(3) to fibrinogen (IC50 = 1 nM). These results indic ate the potential therapeutic use of ROD-containing molecules for hype rcalcemia of malignancy or for other disorders associated with bone lo ss.