LATENT TRANSFORMING GROWTH-FACTOR-BETA IS PRODUCED BY CHONDROCYTES AND ACTIVATED BY EXTRACELLULAR-MATRIX VESICLES UPON EXPOSURE TO 1,25-(OH)(2)D-3

Resting zone and growth zone (GC) costochondral chondrocytes constitut ively release latent, but not active, transforming growth factor-beta (TGF-beta) into the culture medium. When exogenous TGF-beta is added t o the culture medium, no autocrine effect is observed. However, when 1 ,25-(OH)(2)D-3 is added, a dose-dependent inhibition of latent TGF-bet a release is found. Messenger RNA levels for TGF-beta 1 are unchanged by treatment with either 1,25-(OH)(2)D-3 or TGF-beta 1. Since active g rowth factor was not observed in the conditioned medium, we tested the hypothesis that latent TGF-beta could be activated in the matrix. GC matrix vesicles, extracellular organelles associated with matrix calci fication, were able to activate latent TGF-beta 1 and TGF-beta 2 when preincubated with 1,25-(OH)(2)D-3. In contrast, GC plasma membranes ac tivated latent TGF-beta, and addition of 1,25-(OH)(2)D-3 inhibited thi s activation. The 1,25-(OH)(2)D-3-dependent decrease in latent TGF-bet a in the medium, with no detectable change in mRNA level, and the inhi bition of plasma membrane activation of latent TGF-beta by 1,25-(OH)(2 )D-3 suggest that 1,25-(OH)(2)D-3 may act through post-transcriptional and/or nongenomic mechanisms. The results also suggest that latent TG F-beta is activated in the matrix and that 1,25-(OH)(2)D-3 regulates t his activation by a direct, non-genomic action on the matrix vesicle m embrane.