BLOCKADE OF OSTEOCLAST-MEDIATED BONE-RESORPTION THROUGH OCCUPANCY OF THE INTEGRIN RECEPTOR - A POTENTIAL APPROACH TO THE THERAPY OF OSTEOPOROSIS

Bone resorption requires the tight attachment of the bone-resorbing ce lls, the osteoclasts, to the bone mineralized matrix. Integrins, a cla ss of cell surface adhesion glycoproteins, play a key role in the atta chment process. Most integrins bind to their ligands via the arginyl-g lycyl-aspartyl (R-G-D) tripeptide present within the ligand sequence. The interaction between integrins and ligands results in bidirectional transfer of signals across the plasma membrane. Tyrosine phosphorylat ion occurs within cells as a result of integrin binding to ligands and probably plays a role in the formation of the osteoclast clear zone, a specialized region of the osteoclast membrane maintained by cytoskel etal structure and involved in bone resorption. Human osteoclasts expr ess alpha(2) beta(1) and alpha(v) beta(3) integrins on their surface. Such signaling may also lead to ''inside-out'' effects, like increased expression of integrin receptors on the cell surface, or increased af finity of the integrin to its ligand. The alpha(v) beta(3) integrin, a vitronectin receptor, plays an essential role in bone resorption. Ant ibodies to this integrin and short synthetic RGD-containing peptides a re able to block bone resorption in vitro. Echistatin, an RGD-containi ng protein from a snake venom, binds to the alpha(v) beta(3) integrin and blocks bone resorption both in vitro and in vivo. Peptides contain ing the RGD motif are potential competitive ''antagonists'' of the ost eoclast integrins and may have utility in the blockade of bone resorpt ion. Agonists may be identified by stimulation of intracellular signal ing. In theory, tissue specificity can be achieved by 1) introducing s pecific amino acids in positions adjacent to the RGD sequence, 2) iden tifying non-RGD integrin binding domains, or 3) modulating the affinit y of integrins for their endogenous ligands. (C) 1994 Wiley-Liss, Inc.