Transforming growth factor-beta and insulin-like growth factor-1 restore proteoglycan metabolism of bovine articular cartilage after depletion by retinoic acid.

Previous studies showed that retinoic acid is a powerful resorbing agent for articular cartilage at physiological doses (10(-8) to 10(-10) M); the possible role of individual cytokines in the reversal of this effect is now explored in bovine articular cartilage organ cultures. Seven days of treatment with the retinoid under serum-free conditions, at 1 x 10(-8) M, led to a suppression of proteoglycan synthesis of 90 +/- 5% (n = 6; n = cultures from different animals; mean +/- SD) and to a net loss of 64 +/- 14% (n = 6). Removal of the retinoid from the feeding medium did not significantly increase proteoglycan synthesis nor diminish the further loss of proteoglycans. Thus, transforming growth factor-beta (TGF-beta) and insulin-like growth factor-1 (IGF-1), cytokines which independently maintain proteoglycan homeostasis (Morales and Roberts, 1988, J. Biol. Chem. 263, 828; and Luyten et al., 1988, Arch. Biochem. Biophys. 267, 416), were tested. TGF-beta (10 ng/ml) or IGF-1 (10 ng/ml) added for 7 days to serum-free medium following retinoic acid treatment led to recoveries of proteoglycan synthesis of 74 +/- 24% (n = 12) and 69 +/- 18% (n = 12), respectively, as compared to controls switched from serum-free conditions to corresponding cytokine treatments. TGF-beta + IGF-1 restored activity to 95 +/- 17% (n = 12) of controls. TGF-beta s 1-3 exhibited identical responses in control and experimental cultures. IGF-2 replaced IGF-1, but a fourfold higher concentration was required; insulin also had IGF-1-like effects, but even at 500 ng/ml it was 25% less effective than IGF-1. In contrast to the cultures switched from retinoic acid treatment to serum-free conditions, the cultures switched to IGF-1, TGF-beta, or IGF-1 + TGF-beta were stabilized from further proteoglycan loss by the treatment; after 1 week, tissue levels were 97 +/- 19, 96 +/- 22, and 114 +/- 15% (n = 6), respectively, compared to the content before switching. Measurements of catabolism were in agreement with these observations. It is proposed that retinoic acid, TGF-beta, and IGF-1 are parts of an endogenous system involved in the reversible modulation of proteoglycan homeostasis in articular cartilage.(ABSTRACT TRUNCATED AT 400 WORDS)