The Synergistic Effects of Vitamin D Metabolites and Transforming Growth Factor- on Costochondral Chondrocytes Are Mediated by Increases in Protein Kinase C Activity Involving Two Separate Pathways

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Abstract
Transforming growth factor-b (TGFb), as well as the vitamin D3 metabolites 1,25-dihydroxyvitamin D3 (1,25) and 24,25-dihydroxyvi- tamin D3 (24,25), regulate chondrocyte differentiation and matura- tion during endochondral bone formation. Both the growth factor and secosteroids also affect protein kinase C (PKC) activity, although each has its own unique time course of enzyme activation. Vitamin D3 metabolite effects are detected soon after addition to the media, whereas TGFb effects occur over a longer term. The present study examines the interrelation between the effects of 1,25, 24,25, and TGFb on chondrocyte differentiation, matrix production, and prolif- eration. We also examined whether the effect is hormone-specific and maturation-dependent and whether the effect of combining hormone and growth factor is mediated by PKC. This study used a chondrocyte culture model developed in our laboratory that allows comparison of chondrocytes at two stages of differentiation: the more mature growth zone (GC) cells and the less mature resting zone chondrocyte (RC) cells. Only the addition of 24,25 with TGFb showed synergistic effects on RC alkaline phosphatase- specific activity (ALPase). No similar effect was found when 24,25 plus TGFb was added to GC cells or when 1,25 plus TGFb were added to GC or RC cells. The addition of 1,25 plus TGFb and 24,25 plus TGFb to GC and RC cells, respectively, produced a synergistic increase in (35S)sulfate incorporation and had an additive effect on (3H)thymidine incorporation. To examine the signal transduction pathway involved in producing the synergistic effect of 24,25 and TGFb on RC cells, the level of PKC activity was examined. Addition of 24,25 and TGFb for 12 h produced a synergistic increase in PKC activity. Moreover, a similar effect was found when 24,25 was added for only the last 90 min of a 12-h incubation. However, a synergistic effect could not be found

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