Osteoclasts are actively motile on bone surfaces and undergo alternating cycles of migration and resorption. Osteoclast interaction with the extracellular matrix plays a key role in the osteoclast resorptive process and a substantial body of evidence suggests that
integrin receptors are important in osteoclast function. These
integrin receptors bind to the
Arg-Gly-Asp (RGD) sequence found in a variety of
extracellular matrix proteins and it is well established that the interaction of osteoclast alpha v
beta 3 integrin with the RGD motif within bone matrix
proteins is important in osteoclast-mediated
bone resorption. In this study, we characterized the effects of two synthetic
peptidomimetic antagonists of alpha v beta 3,
SC-56631 and
SC-65811, on rabbit osteoclast adhesion to purified matrix
proteins and bone, and on
bone resorption in vitro.
SC-56631 and
SC-65811 are potent inhibitors of
vitronectin binding to purified alpha v beta 3. Both
SC-56631 and
SC-65811 inhibited osteoclast adhesion to
osteopontin- and
vitronectin-coated surfaces and time-lapse video microscopy showed that osteoclasts rapidly retract from
osteopontin-coated surfaces when exposed to
SC-56631 and
SC-65811.
SC-56631 and
SC-65811 blocked osteoclast-mediated
bone resorption in a dose-responsive manner. Further analysis showed that
SC-65811 and
SC-56631 reduced the number of resorption pits produced per osteoclast and the average pit size.
SC-65811 was a more potent inhibitor of
bone resorption and the combination of reduced pit number and size led to a 90% inhibition of
bone resorption. Surprisingly, however, osteoclasts treated with
SC-65811,
SC-56631 or the
disintegrin echistatin, at concentrations that inhibit
bone resorption did not inhibit osteoclast adhesion to bone. These results suggest that alphavbeta3 antagonists inhibited
bone resorption by decreasing osteoclast bone resorptive activity or efficiency but not by inhibiting osteoclast adhesion to bone per se.