The interaction between retinoic acid and the transforming growth factors-β in calf articular cartilage organ cultures

Abstract

In calf articular cartilage organ cultures, retinoic acid depressed proteoglycan anabolism to levels ∼10% of control values and increased their catabolism ∼14-fold at concentrations of 1 × 10 −8 and 1 × 10 −6 m, respectively, leading to a severe depletion of this component from the extracellular matrix (95% loss in 3 weeks). These effects were powerfully antagonized by maximal levels of transforming growth factors-β (TGF-βs) 1, 2, and 3, leading to preservation of matrix components. At a concentration of 1 × 10 −8 m retinoic acid, the TGF-βs restored anabolism to control levels and lowered catabolic rates >3-fold. While the TGF-βs increased protein synthesis 2- to 3-fold over controls, retinoic acid alone did not change protein synthesis, as determined by incorporation of [ 3H]serine. Nevertheless, retinoic acid effectively antagonized the stimulation of protein synthesis by TGF-β and restored control levels of synthesis at 1 × 10 −7 m. Analysis of proteins, labeled using [ 3H]serine and [ 35S]sulfate as precursors, by SDS-PAGE revealed that large molecular weight proteins (>100 kDa) were not detectable in retinoic-acid-treated cultures, but treatment with the TGF-βs restored these components in coincubation cultures, again supporting the antagonistic role of the polypeptide effectors on retinoid action. Treatment of the cultures with retinoic acid elevated levels of TGF-β2 synthesis, but not TGF-β1. While the role of the newly synthesized TGF-β2 in the set of events elicited by retinoic acid in articular cartilage is unclear, the results establish an intrinsic metabolic link between the isoprenoid and TGF-β in articular cartilage. We propose that the retinoids and TGF-βs are integral parts of a regulatory network that controls homeostasis, resorption, or growth, depending on their relative contributions.