The ability of osteoclasts to resorb bone relies on a well defined sequence of events starting with their attachment to matrix. This binding is mediated to a significant degree, by the integrin alphavbeta3 and thus, regulation of the heterodimer's expression on the cell surface represents a logical approach to controlling the resorptive process. We find that retinoic acid, a member of the steroid hormone superfamily which enhances bone resorption in vivo and in vitro, increases steady state levels of beta3-integrin mRNA and expression of alphavbeta3 on the surface of avian osteoclast precursors. We hypothesize that: 1) retinoic acid enhances steady state beta3 mRNA levels by retinoic acid receptor-mediated transcriptional activation; 2) retinoic acid enhances alphavbeta3 surface expression on osteoclast precursors by selective synthesis to the beta3 subunit; and 3) retinoic acid-stimulated alphavbeta3 surface expression by their precursors enhances the capacity of the osteoclasts to attach to matrix and ultimately resorb bone. To explore these hypotheses, we propose to: 1) Characterize the regulatory elements responding to retinoic acid in the beta3 gene and their interaction with retinoic acid receptor. 2) Determine the effects of retinoic acid on both synthesis and degradation of alphav and beta3 by osteoclast precursors. 3) Examine the effects of osteoclast precursor treatment with retinoic acid on the ability of mature osteoclasts to attach to matrix and resorb bone.
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