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Tumor Necrosis Factor Regulates _vß₅ Integrin Expression by Osteoclast Precursors in Vitro and in Vivo¹

Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110

Address all correspondence and requests for reprints to: Steven L. Teitelbaum, M.D., Department of Pathology, Washington University School of Medicine, Barnes-Jewish Hospital North, 216 South Kingshighway, St. Louis, Missouri 63110. E-mail: teitelbs{at}medicine.wustl.edu

Early osteoclast precursors, in the form of murine bone marrow macrophages (BMMs), while expressing no detectable _vß₃ integrin, contain abundant _vß₅ and attach to matrix in an _v integrin-dependent manner. Furthermore, _vß₅ expression by osteoclast precursors progressively falls as they assume the resorptive phenotype. We find the osteoclastogenic agent, tumor necrosis factor-, (TNF) down-regulates _vß₅ expression by BMMS via attenuation of ß₅ messenger RNA (mRNA) t1/2. Using BMMs from TNF receptor knockout mice we establish the p55 receptor transmits the ß₅ suppressive effect. The functional implications of TNF-mediated _vß₅ down-regulation are underscored by the capacity of an _v inhibitory peptide mimetic to prevent spreading by BMMs expressing abundant _vß₅ while failing to impact those in which the integrin has been diminished by TNF. Finally, ß₅ mRNA in BMMs of wild-type mice administered lipopolysaccharide (LPS) progressively falls with time of in vivo treatment. Alternatively, ß₅ mRNA does not decline in BMMs of LPS-treated mice lacking both TNF receptors, documenting down-regulation of the ß₅ integrin subunit, in vivo, is mediated by TNF. Thus, matrix attachment of osteoclast precursors and mature osteoclasts are governed by distinct _v integrins which are differentially regulated by specific cytokines.

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