Latent transforming growth factor-β is produced by chondrocytes and activated by extracellular matrix vesicles upon exposure to 1,25-(OH)₂D₃

Resting zone and growth zone (GC) costochondral chondrocytes constitutively release latent, but not active, transforming growth factor-β (TGF-β) into the culture medium. When exogenous TGF-β is added to the culture medium, no autocrine effect is observed. However, when 1,25-(OH)₂D₃ is added, a dose-dependent inhibition of latent TGF-β release is found. Messenger RNA levels for TGF-β1 are unchanged by treatment with either 1,25- (OH)₂D₃ or TGF-β1. Since active growth factor was not observed in the conditioned medium, we tested the hypothesis that latent TGF-β could be activated in the matrix. GC matrix vesicles, extracellular organelles associated with matrix calcification, were able to activate latent TGF-β1 and TGF-β2 when preincubated with 1,25-(OH)₂D₃. In contrast, GC plasma membranes activated latent TGF-β, and addition of 1,25-(OH)₂D₃ inhibited this activation. The 1,25-(OH)₂D₃-dependent decrease in latent TGF-β in the medium, with no detectable change in mRNA level, and the inhibition of plasma membrane activation of latent TGF-β by 1,25-(OH)₂D₃ suggest that 1,25-(OH)₂D₃ may act through post-transcriptional and/or nongenomic mechanisms. The results also suggest that latent TGF-β is activated in the matrix and that 1,25-(OH)₂D₃ regulates this activation by a direct, nongenomic action on the matrix vesicle membrane.