A peptidomimetic antagonist of the αvβ3 integrin inhibits bone resorption in vitro and prevents osteoporosis in vivo

Abstract

Osteoclastic bone degradation requires intimacy between the matrix and the resorptive cell. While the precise role the integrin αvβ3 plays in the process is not yet understood, occupancy of the heterodimer by soluble ligand or by blocking antibody effectively inhibits bone resorption in vitro and in vivo, suggesting that αvβ3 blockade may prevent postmenopausal osteoporosis. Thus, we identified a synthetic chemical peptide mimetic, β- [2-I[5-[(aminoiminomethyl)amino]-1-oxopentyl]amino]-1-oxoethyl]amino-3- pyridinepropanoic acid, bistrifluoroacetate (SC56631) based upon the αvβ3 ligand, Arg-Gly-Asp (RGD), which recognizes the isolated integrin, and its relative, αvβ3 as effectively as does the natural peptide. The mimetic dampens osteoclastic bone resorption in vitro and in vivo. Most importantly, intravenous administration of the mimetic prevents the 55% loss of trabecular bone sustained by rats within 6 wk of oophorectomy. Histological examination of bones taken from SC56631-treated, oophorectomized animals also demonstrates the compound's bone sparing properties and its capacity to decrease osteoclast number. Thus, an RGD mimetic prevents the rapid bone loss that accompanies estrogen withdrawal.