Tumor necrosis factor α regulates αvβ5 integrin expression by osteoclast precursors in vitro and in vivo

Early osteoclast precursors, in the form of murine bone marrow macrophages (BMMs), while expressing no detectable alpha(v) integrin, contain abundant alpha(v)beta(5) and attach to matrix in an alpha(v)beta(5) integrin-dependent manner. Furthermore, alpha(v)beta(5) expression by osteoclast precursors progressively falls as they assume the resorptive phenotype. We find the osteoclastogenic agent, tumor necrosis factor-a, (TNF) down-regulates alpha(v)beta(5) expression by BMMS via attenuation of beta(5) messenger RNA (mRNA) t1/2. Using BMMs from TNF receptor knockout mice we establish the p55 receptor transmits the beta(5) suppressive effect. The functional implications of TNF-mediated alpha(v)beta(5) down-regulation are underscored by the capacity of an alpha(v) inhibitory peptide mimetic to prevent spreading by BMMs expressing abundant alpha(v)beta(5), while failing to impact those in which the integrin has been diminished by TNF. Finally, beta(5) mRNA in BMMs of wild-type mice administered lipopolysaccharide (LPS) progressively falls with time of in vivo treatment. Alternatively, beta(5) mRNA does not decline in BMMs of LPS-treated mice lacking both TNF receptors, documenting down-regulation of the beta(5) integrin subunit, in vivo, is mediated by TNF. Thus, matrix attachment of osteoclast precursors and mature osteoclasts are governed by distinct cr,integrins which are differentially regulated by specific cytokines.