Cartilage undergoes a multi-phase process of maturation during which chondrocytes proliferate, become hypertrophic, mineralize their matrix, and are replaced by bone. This cartilage maturation process is crucial for normal bone formation, postnatal growth and bone repair. Despite its obvious importance, little is known about the regulation of cartilage maturation. In the previous project, the hypothesis that vitamin A regulates the expression of type X collagen in maturing chondrocytes was examined in detail and, in the course of this work, strong evidence was found to support the idea that physiologic retinoids do not simply induce expression of one gene (collagen type X), but also cause expression of several maturation-related genes, matrix mineralization, and metabolic shifts in energy production. This complex sequence of events is precisely that occurring during the latter part of cartilage maturation in vivo, leading to the current proposal, an examination of the idea that retinoids induce the final phases of the chondrocyte maturation process. Since retinoids exert their biological functions by interactions with nuclear transcription factors, the retinoic acid receptors (RARs) and retinoid receptors (RXRs), and there is preliminary data to suggest that the expression of RARgamma is selectively activated in pre-hypertrophic and hypertrophic chondrocytes in the growth plate, in vivo, while immature resting and proliferating chondrocytes and articular chondrocytes do not express this receptor, this renewal proposes to study the expression and function of RARgamma in chondrocyte maturation. The central hypothesis to be tested is that the induction of the final phases of maturation by retinoids is mediated by RARgamma. Specifically, determination of the RARgamma isoform expressed during chondrocyte maturation, the regulation of RARgamma gene expression, the endogenous retinoids present in chondrocytes, and the function of RARgamma in chondrocytes will be addressed. The results of the proposed work are intended to provide crucial information on how retinoids and their nuclear receptors regulate cartilage maturation, and identify possible candidate mechanisms which may be affected during abnormal endochondral bone formation.
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