PPAR ACTIVATION IN GROWTH PLATE CHONDROCYTES

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Childhood obesity is a rapidly growing concern which now threatens one in four children with long-term health problems. Recent advances in the understanding of adipogenesis and lipid metabolism at the molecular level have revealed the existence of a family of nuclear hormone receptors which link nutritional signals to the control of gene expression, and are induced or activated in response to a high fat diet. These molecules, termed peroxisome proliferator activated receptors (PPARs), are also expressed in bone and cartilage, and interfere with thyroid hormone receptor (TR) mediated gene transcription in cells in which PPARs and TRs are co-expressed. Given that peroxisomal function is required for normal endochondral ossification, and that thyroid hormone lays a central role in regulating skeletal maturation at growth plate, it is reasonable to ask if crosstalk may exist between TR and PPAR mediated transcriptional regulation in growth plate chondrocytes. Crosstalk between the TR and PPAR signaling pathways in growth plate cells may have direct clinical implication regarding the etiology of an obesity-related hip disease in children, slipped capital femoral epiphysis (SCFE). This proposal will test the hypothesis that PPARs are inducible repressors of TR mediated gene transcription i growth plate chondrocytes. The specific aims this work are: 1) to document the expression of PPAR isoforms in the growth plate and to establish if PPARs are co-expressed with TRs in individual growth plate chondrocytes; 2) to determine if exposure of growth plate chondrocytes to PPAR activators results in induction of PPAR expression and activation of PPAR-mediated gene transcription in these cells; 3) to characterize the molecular interactions of PPARs with TRs and RXRs in growth plate chondrocytes and describe the effect of these interactions on TR-mediated gene transcription; and 4) to define the effects of PPAR activation on thyroid hormone-induced growth arrest and terminal differentiation of growth plate cells.