IS THE ARTICULAR CHONDROCYTE A TERMINALLY DIFFERENTIATED CELL?

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The articular chondrocyte is often considered a terminally differentiated cell due to its limited tendency to replicate in vivo. In patients with osteoarthritis, however, articular chondrocytes demonstrate the ability to clonally divide, synthesize type, X collagen, and assume an appearance similar to the terminally differentiated hypertrophic growth plate chondrocyte. Moreover, articular chondrocytes harvested from several species of animals and cultured in vitro divide in response to mitogenic signals present in serum, and have also been shown to synthesize type X collagen under certain culture conditions. These observations suggest that the articular chondrocyte may not be a terminally differentiated cell, but rather a cell suspended in an intermediate stage of differentiation which can be induced to differentiate further when placed into a permissive environment, or when exposed to a specific pathologic stimulus. The fact that articular chondrocytes in vivo have only been shown to express this hypertrophic phenotype under osteoarthritic conditions suggests that this phenotype may be involved in the pathogenesis of cartilage injury and attempted repair. Despite several published reports of type X collagen synthesis by articular chondrocytes, little is known about the mechanism by which this phenomenon occurs. One possible factor which may be involved in signalling this response is thyroid hormone. Although there is abundant evidence linking thyroid hormone to terminal differentiation of growth plate chondrocytes, no data currently exist to support or refute a role for thyroid hormone in type X collagen synthesis by articular chondrocytes. We have developed a chemically defined model of rat growth plate chondrncyte differentiation in which cells are cultured as a three dimensional cell pellet under serum free conditions. Addition of thyroid hormone to this system results in the rapid differentiation of cells into hypertrophic chondrocytes which cease dividing, express type x collagen and alkaline phosphatase mRNA, and demonstrate high levels of alkaline phosphatase enzymatic activity. We propose to use this system to test the hypothesis that the articular chondrocyte is a terminally differentiated cell by pursuing the following specific aims. (1) To successfully establish three dimensional cultures of rat articular chondrocytes maintained under chemically defined conditions in vitro; (2) To determine if rat articular chondrocytes express thyroid hormone receptor isoforms in vivo; and (3) To ascertain whether articular chondrocytes cultured in vitro under chemically defined conditions respond to thyroid hormone treatment by expressing markers associated with the hypertrophic chondrocyte phenotype.