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Thrombopoietin Inhibits in Vitro Osteoclastogenesis from Murine Bone Marrow Cells

Departments of Biochemistry (T.W., S.O.) and Clinical Hematology (M.H., N.T.) and Second Department of Internal Medicine (A.S., M.I., Y.N., H.M.), Osaka City University Medical School, Osaka 545, Japan

Address all correspondence and requests for reprints to: Atsushi Shioi, M.D., Second Department of Internal Medicine, Osaka City University Medical School, 1–5-7 Asahi-machi, Abeno-ku Osaka 545, Japan. E-mail: as{at}msic.med.osaka-cu.ac.jp

To determine whether thrombopoietin (TPO) can modulate the osteoclastic differentiation from hematopoietic stem cells, we investigated the effect of TPO on in vitro osteoclastogenesis by using the coculture of murine bone marrow cells with the stromal cell line (ST2) in the presence of 1,25-dihydroxyvitamin D₃ and dexamethasone. Recombinant human TPO inhibited the formation of tartrate-resistant acid phosphatase-positive multinucleated cells in a dose-dependent manner (0.02–200 ng/ml). The effect of TPO on differentiation of bone-resorbing capacity was investigated by pit assay. TPO dose dependently decreased the areas of toluidine blue-stained resorption pits (2.0–200 ng/ml). To identify the cellular target of TPO, we used a variety of bone marrow/stromal cell coculture methods. Initially, we found that TPO mainly exerted its effect on the early stage of osteoclastic differentiation in delayed addition experiments. Consequently, the majority of TPO’s inhibition of osteoclastic cell formation was due to its effect on bone marrow cells. Finally, we examined whether transforming growth factor-ß (TGFß) and platelet-derived growth factor (PDGF), major cytokines produced by megakaryocytes, mediate the inhibitory effect of TPO. The addition of either anti-TGFß or anti-PDGF antibody to bone marrow cell culture completely antagonized the effect of TPO on osteoclastogenesis. Furthermore, treatment of bone marrow cells with TGFß or PDGF mimicked the inhibitory effect of TPO. These data suggest that TPO inhibits osteoclastogenesis through stimulating thrombopoiesis and that TGFß and PDGF mediate the effect of TPO by impacting on macrophage-lineage cells as osteoclast precursors.

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