Transforming growth factor beta inhibits plasminogen activator (PA) activity and stimulates production of urokinase‐type PA, PA inhibitor‐1 mRNA, and protein in rat osteoblast‐like cells

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Abstract
Transforming growth factor(β)(TGFβ) treatment of rat osteoblast‐rich calvarial cells or of the clonal osteogenic sarcoma cells, UMR 106‐01, resulted in dosedependent inhibition of plasminogen activator (PA) activity, and increased production of 3.2 kb mRNA and protein for PA inhibitor‐1 (PAI‐1). Although tissue‐type PA(tPA) protein was not measured, TGF(β)did not influence production of mRNA for tPA. Production of 2.3 kb mRNA for urokinase‐type PA (uPA) was also increased by TGF(β)in a dose‐dependent manner. The effects of TGFβ on synthesis of mRNA for PAI‐1 and uPA were maintained when protein synthesis was inhibited, and were abolished by inhibition of RNA synthesis. Although uPA had not been detected previously as a product of rat osteoblasts, treatment of lysates of osteoblast‐like cells with plasmin yielded a band of PA activity on reverse fibrin autography, corresponding to a low Mr form of uPA. Untreated conditioned media from normal osteoblasts or UMR 106‐01 cells contained no significant TGFβ activity, but activity could be detected in acidified medium. Treatment of conditioned media with plasmin resulted in activation of approximately 50% of the TGFβ detectable in acidified media. The results identify several effects of TGFβ on the PA‐PA inhibitor system in osteoblasts. Net regulation of tPA activity through the stimulatory actions of several calciotropic hormones and the promotion of PAI‐1 formation by TGFβ could determine the amount of osteoblast‐derived TGFβ activated locally in bone. Stimulation of osteoblast production of mRNA for uPA could reflect effects on the synthesis of sc‐uPA, a precursor for the active form of the enzyme.