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Effects of Retinol on Activation of Latent Transforming Growth Factor-ß by Isolated Osteoclasts¹

Department of Medicine, Division of Endocrinology, University of Texas Health Science Center (L.F.B., R.O.C.O., C.H.L., S.P.-S., G.R.M.), and Audie L. Murphy Memorial Veteran’s Hospital (L.F.B.), San Antonio, Texas 78284; and Bristol-Myers Squibb Pharmaceutical Research Institute (D.T.), Seattle, Washington 98121

Address all correspondence and requests for reprints to: Dr. L. F. Bonewald, Department of Medicine, Division of Endocrinology, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, Texas 78284-7877.

The multifunctional cytokine, transforming growth factor-ß (TGFß), is found in many tissues in a latent or inactive form. The nature and composition of the latent complex can vary depending on tissue type. The release of active TGFß from its latent complex is a potentially important mechanism for regulation of TGFß activity. We have shown previously that osteoclasts activate latent TGFß produced by bone and that bone cells produce a 100-kDa latent complex that lacks the latent TGFß-binding protein. Here we investigated the effects of retinol on osteoclast activation of various forms of latent TGFß. Two sources of osteoclasts were used that provide either mature avian osteoclasts or avian osteoclast precursors. Whereas both cell populations activate latent TGFß, only mature osteoclasts respond to retinol with an increase in activation of latent TGFß over basal levels. Activation could not be ascribed to pH changes in conditioned medium. Nonacid-dissociable 100-kDa latent complex, which is also produced by bone cells, was added to mature osteoclasts and to osteoclast precursors, but no activation was observed. Platelet latent TGFß, which contains the 130-kDa latent TGFß-binding protein, was activated by both osteoclast populations. Conditioned medium from the precursor population activated latent complex, whereas conditioned medium from mature cells did not. Activation of latent TGFß by retinol-treated mature cells was not blocked by inhibitors of plasmin, nor was activation by conditioned medium from precursor cells. These data suggest that retinol-induced activation of latent TGFß by osteoclasts is dependent on the stage of differentiation of these cells and the presence of other cell types, and that unlike other cell systems, the plasmin-plasminogen activator mechanism is not involved.

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