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Thiazolidinediones Inhibit Osteoclast-Like Cell Formation and Bone Resorption in Vitro¹

Third Department of Medicine, Teikyo University School of Medicine (R.O., M.T., K.T.), Ichihara, Chiba 299-0111; the Division of Endocrinology, Department of Internal Medicine, University of Tokyo School of Medicine (S.F., T.F., Y.T.), Bunkyo-ku, Tokyo 112-8688; and Sankyo Co., Ltd., Pharmacology and Molecular Biology Research Laboratories (M.M.), Shinagawa-ku, Tokyo 140-8710, Japan

Address all correspondence and requests for reprints to: Ryo Okazaki, M.D., Third Department of Medicine, Teikyo University School of Medicine, 3426–3 Anesaki, Ichihara, 299-0111 Japan. E-mail: rokazaki{at}med.teikyo-u.ac.jp

Osteoblasts and adipocytes are derived from common bone marrow stromal cells that play crucial roles in the generation of osteoclasts. Activation of peroxisome proliferator-activated receptor- (PPAR) induces adipogenic differentiation of stromal cells; however, whether this would affect osteoblast/osteoclast differentiation is unknown. Thus, we examined the effects of the thiazolidinedione (TZD) class of antidiabetic agents that activate PPAR on osteoblast/osteoclast differentiation using mouse whole bone marrow cell culture. As reported, all TZDs we tested (troglitazone, pioglitazone, and BRL 49653) markedly increased the number of Oil Red O-positive adipocytes and the expression of adipsin and PPAR 2. 1,25-Dihydroxyvitamin D₃ [1,25-(OH)₂D₃] did not affect adipogenic differentiation induced by TZDs. TZDs did not affect alkaline phosphatase activity, an early marker of osteoblastic differentiation, despite their marked adipogenic effects. TZDs decreased the number of tartrate-resistant acid phosphatase-positive multinucleated osteoclast-like cells induced by 1,25-(OH)₂D₃ or PTH. Troglitazone dose dependently inhibited basal and 1,25-(OH)₂D₃- and PTH-induced bone resorption as assessed by pit formation assay. Interleukin-11 blocked the induction by troglitazone of adipogenesis, but had no effect on the inhibition of osteoclast-like cell formation. These results indicate that TZDs are potent inhibitors of bone resorption in vitro. Inhibitory effects of TZDs on osteoclastic bone resorption was not osteotropic factor specific and did not appear to be related to their adipogenic effects. Thus, TZDs may suppress bone resorption in diabetic patients and prevent bone loss.

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