The long term objective of this program is to elucidate the intrinsic regulatory mechanisms that control the structure and function of the resilient layer of articular cartilage that covers and protects the ends of bone. We showed that TGF-beta has the ability to prevent the spontaneous proteoglycan loss that occurs in basal cartilage organ cultures by increasing biosynthetic rates and decreasing degradation. We have now explored the interactions between the response elements for TGF-beta and vitamin A (retinoic acid) in articular cartilage organ cultures. At physiological concentrations, vitamin A acts as a potent degradative signal for articular cartilage. However, this signal is dampened by the simultaneous addition of TGF-beta to the cultures. Furthermore, if the tissue is first treated with vitamin A alone so that 80% of the matrix proteoglycans are released and then treatment is discontinued, the intrinsic ability of the tissue for repair is low, but is powerfully enhanced by addition of TGF-beta. Thus, in the presence of TGF-beta, the rates of proteoglycan synthesis rise more than 20 fold and there is a slow re-accumulation of matrix proteoglycans. The ability of other effectors to interact with TGF-beta and amplify the repair response is presently being explored. The present findings extend our knowledge of the regulatory mechanisms that maintain cartilage matrix structure and function. Further, the repair model in vitro that we have set up and will continue to study should yield important insights concerning the regulation of repair processes in cartilage, an area that is critical for the understanding and eventual management of joint diseases.
