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Endocrinology Vol. 138, No. 6 2372-2379
Copyright © 1997 by The Endocrine Society

ARTICLES

Transcriptional Induction of Cyclooxygenase-2 in Osteoblasts Is Involved in Interleukin-6-Induced Osteoclast Formation1

Hitoshi Tai, Chisato Miyaura, Carol C. Pilbeam, Tatsuya Tamura, Yoshiyuki Ohsugi, Yasuo Koishihara, Noboru Kubodera, Hiroshi Kawaguchi, Lawrence G. Raisz and Tatsuo Suda

Department of Biochemistry, School of Dentistry, Showa University (C.M., T.T., T.S.), 1–5-8 Hatanodai, Shinagawa-ku, Tokyo 142; and Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd. (H.T., T.T., Y.O., Y.K., N.K.), Shizuoka 412, Japan; and the Division of Endocrinology and Metabolism, Department of Medicine, University of Connecticut Health Center (C.C.P., H.K., L.G.R.), Farmington, Connecticut 06030

Address all correspondence and requests for reprints to: Dr. Tatsuo Suda, Department of Biochemistry, School of Dentistry, Showa University, 1–5-8 Hatanodai, Shinagawa-ku, Tokyo 142, Japan.

Interleukin-6 (IL-6) induces osteoclast-like cell (osteoclast) formation in a dose-dependent fashion in cocultures of mouse bone marrow cells and osteoblastic cells when soluble IL-6 receptor (sIL-6R) is present. Simultaneous treatment with submaximal doses of IL-1{alpha} and IL-6 with sIL-6R caused marked induction of osteoclast formation and PGE2 synthesis. These effects were suppressed by adding neutralizing antibodies against IL-1{alpha} or IL-6R and were totally abolished by adding nonsteroidal antiinflammatory drugs, such as indomethacin and a selective cyclooxygenase-2 (COX-2) inhibitor (NS398). In mouse osteoblastic cells, both IL-1{alpha} and IL-6 with sIL-6R markedly induced messenger RNA expression of COX-2, but not COX-1, as determined by Northern blot analysis, and luciferase activity in cells stably transfected with a COX-2 promoter-luciferase fusion construct. IL-6 and sIL-6R, when added separately, did not stimulate COX-2 messenger RNA expression. Simultaneous addition of IL-1{alpha} and IL-6 with sIL-6R to osteoblast cultures cooperatively induced transcription of COX-2, which was associated with a marked increase in COX activity measured by the conversion of arachidonic acid into PGE2. The increased PGE2 synthesis by osteoblasts may play an important role in osteoclastogenesis induced by submaximal doses of IL-1 and IL-6.




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