TR1, A NEW MEMBER OF THE TUMOR-NECROSIS-FACTOR RECEPTOR SUPERFAMILY, INDUCES FIBROBLAST PROLIFERATION AND INHIBITS OSTEOCLASTOGENESIS AND BONE-RESORPTION

A newly identified member of the tumor necrosis factor receptor (TNFR) superfamily shows activities associated with osteoclastogenesis inhib ition and fibroblast proliferation. This new member, called TR1, was i dentified from a search of an expressed sequence tag database, and enc odes 401 amino acids with a 21-residue signal sequence. Unlike other m embers of TNFR, TR1 does not contain a transmembrane domain and is sec reted as a 62 kDa glycoprotein. TR1 gem maps to chromosome 8q23-24.1 a nd its mRNA is abundantly expressed on primary osteoblasts, osteogenic sarcoma cell lines, and primary fibroblasts. The receptors for TR1 we re detected on a monocytic cell line (THP-1) and in human fibroblasts. Scatchard analyses indicated two classes of high and medium-high affi nity receptors with a kD of approximately 45 and 320 pM, respectively. Recombinant TRI induced proliferation of human foreskin fibroblasts a nd potentiated TNF-induced proliferation in these cells. In a cocultur e system of osteoblasts and bone marrow cells, recombinant TR1 complet ely inhibited the differentiation of osteoclast-like multinucleated ce ll formation in the presence of several bone-resorbing factors. TR1 al so strongly inhibited bone-resorbing function on dentine slices by mat ure osteoclasts and decreased Ca-45 release in fetal long-bone organ c ultures. Anti-TR1 monoclonal antibody promoted the formation of osteoc lasts in mouse marrow culture assays. These results indicate that TRI has broad biological activities in fibroblast growth and in osteoclast differentiation and its functions.-Kwon, B. S., Wang, S., Udagawa, N. , Haridas, V., Lee, Z. H., Rim, K. K., Oh, K.-O., Greene, J., Li, Y., Su, J., Gentz., R., Aggarwal, B. B., Ni, J. TR1, a new member of tumor necrosis factor receptor superfamily, induces fibroblast proliferatio n and inhibits osteoclastogenesis and bone resorption.