The interaction between retinoic acid and the transforming growth factors-beta in calf articular cartilage organ cultures.
In calf articular cartilage organ cultures, retinoic acid depressed proteoglycan anabolism to levels approximately 10% of control values and increased their catabolism approximately 14-fold at concentrations of 1 x 10(-8) and 1 x 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-beta (TGF-beta s) 1, 2, and 3, leading to preservation of matrix components. At a concentration of 1 x 10(-8) M retinoic acid, the TGF-beta s restored anabolism to control levels and lowered catabolic rates greater than 3-fold. While the TGF-beta s 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-beta and restored control levels of synthesis at 1 x 10(-7) M. Analysis of proteins, labeled using [3H]serine and [35S]sulfate as precursors, by SDS-PAGE revealed that large molecular weight proteins (greater than 100 kDa) were not detectable in retinoic-acid-treated cultures, but treatment with the TGF-beta s 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-beta 2 synthesis, but not TGF-beta 1. While the role of the newly synthesized TGF-beta 2 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-beta in articular cartilage. We propose that the retinoids and TGF-beta s are integral parts of a regulatory network that controls homeostasis, resorption, or growth, depending on their relative contributions.
Morales
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TI
Bone Research Branch, National Institute of Dental Research, National Institutes of Health, Bethesda, Maryland 20892.
Roberts
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D000818:Animals; D002358:Cartilage, Articular / Q000187:drug effects*; D002417:Cattle; D005109:Extracellular Matrix / Q000378:metabolism; D066298:In Vitro Techniques; D011506:Proteins / Q000378:metabolism; D011509:Proteoglycans / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000494:pharmacology*; D014212:Tretinoin / Q000494:pharmacology*
D011506:Proteins; D011509:Proteoglycans; D016212:Transforming Growth Factor beta; D014212:Tretinoin