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Tumor Necrosis Factor-α Promotes the Expression of Osteoprotegerin in Rheumatoid Synovial Fibroblasts
AYAKO KUBOTA, KAZUHISA HASEGAWA, TORU SUGURO, and YASUKO KOSHIHARA
ABSTRACT. Objective. To clarify the regulation of osteoprotegerin (OPG) expression in rheumatoid synovial fibroblasts by investigating the effect of tumor necrosis factor-α (TNF-α) and the mechanism of TNF-α-induced OPG expression. Methods. OPG expression was examined by Northern blot hybridization and reverse transcriptase-polymerase chain reaction in synovial fibroblasts from patients with rheumatoid arthritis (RA) and osteoarthritis (OA) and subjects with no inflammatory condition. Amounts of OPG in conditioned medium were determined by ELISA. The effect of OPG on TNF-α-induced osteoclastogenesis was investigated in primary cultures of RA synovial cells. Results. OPG was highly expressed in RA synovial fibroblasts compared to OA and noninflammatory synovial fibroblasts. Different levels of OPG expression were found among patients with RA. TNF-α induced OPG expression in all synovial fibroblasts, even OA and noninflammatory fibroblasts, and expression occurred to a remarkable degree in RA fibroblasts. The OPG expression was upregulated by TNF-α in a time- and dose-dependent manner. TNF-α-induced OPG expression was inhibited by hymenialdisine, a nuclear factor-κB inhibitor, in a dose-dependent manner, and expression was inhibited by soluble TNF receptor/Fc fusion protein I (TNFs-RI/Fc), not by TNFs-RII/Fc. In contrast, TNF-α-induced osteoclastogenesis in primary cultures of RA synovial cells was inhibited by the addition of OPG. Conclusion. These results suggest that OPG is highly expressed and is upregulated by TNF-α in rheumatoid synovial fibroblasts. TNF-α-induced OPG expression is mediated predominately through TNF-RI. Although TNF-α is known to stimulate bone destruction, TNF-α-induced upregulation of OPG may contribute to self-protection from the bone destruction in RA. (J Rheumatol 2004;31:426-35) Key Indexing Terms:
OSTEOPROTEGERIN
From the Faculty of Medicine, Toho University, and the Bone Research Group, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan. A. Kubota, MD; K. Hasegawa, MD, PhD; T. Suguro, MD, PhD, Faculty of Medicine, Toho University; Y. Koshihara, PhD, Tokyo Metropolitan Institute of Gerontology. Address reprint requests to Dr. Y. Koshihara, Bone Research Group, Metropolitan Institute of Gerontology, 35-2 Sakaecho, Itabashi-ku, Tokyo 173-0015, Japan. E-mail: ykoshi@tmig.or.jp Submitted July 12, 2002; revision accepted August 11, 2003. |