Biphasic Effects of Transforming Growth Factor-β on the Production of Osteoclast-Like Cells in Mouse Bone Marrow Cultures: The Role of Prostaglandins in the Generation of These Cells

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Abstract
Osteoclast-like multinucleated giant cells are induced in bone marrow cultures by 1,25-dihydroxyvitamin D3 and other agents. These cells resemble osteoclasts in their morphology, their ability to resorb bone, and the possession of calcitonin receptors. We report here a biphasic effect of transforming growth factor-.beta. (TGF.beta.) on the generation of these cells in mouse bone marrow cultures. At low concentrations (10-100 pg/ml) TGF.beta. enhanced 1,25-dihydroxyvitamin D3-dependent production of osteoclast-like cells, while at higher concentrations TGF.beta. was inhibitory. Complete inhibition was seen at 4 ng/ml. Antibodies directed against TGF.beta. significantly reduced the generation of osteoclast-like cells in 1,25-dihydroxyvitamin D3-treated cultures, indicating the contribution of endogenous TGF.beta. activity. TGF.beta. also enhanced the accumulation of prostaglandin E2 (PGE2) in a dose-dependent manner. Moreover, we found that the generation of these cells in response to 1,25-dihydroxyvitamin D3 was also dependent on PG accumulation, since it was inhibited by indomethacin (250 ng/ml), and this inhibition could be reversed by exogenous PGE2. It is, thus, suggested that PG activity, probably PGE2, mediates the enhancing effect of low TGF.beta. concentrations and is required for the generation of osteoclast-like cells in this system.

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