Peroxisome proliferator activated receptor-γ (PPARγ) represses thyroid hormone signaling in growth plate chondrocytes

Peroxisome proliferator activated receptors (PPARs) are DNA-binding nuclear hormone receptors that are upregulated in response to high fat diets. PPARs are structurally related to the type II nuclear receptors, including the thyroid hormone receptors (TRs). To investigate if PPARs modulate TR-mediated terminal differentiation of growth plate chondrocytes, primary cultures of epiphyseal chondrocytes transiently transfected with TR alpha and PPAR gamma expression vectors were treated with the PPAR ligands ciglitazone or troglitazone. Forced overexpression of PPAR gamma decreased TR alpha 1-mediated transcriptional activity and suppressed T3-induced increases in alkaline phosphatase activity and type X collagen expression. Similar effects were observed when the cells were treated with the PPAR gamma activator ciglitazone or troglitazone. Overexpression of retinoid X receptor-alpha (RXR alpha) partially restored not only the inhibition of transcriptional activation by PPAR gamma but also T3-induced hypertrophic differentiation. These data demonstrate that activation of PPAR gamma signaling by either addition of PPAR gamma ligands or overexpression of PPAR gamma in growth plate chondrocytes inhibits TR-mediated gene transcription and inhibits the biological effects of thyroid hormone on terminal differentiation. The molecular mechanism involved in this inhibition appears to be competition between PPAR gamma and TR alpha for limiting amounts of the heterodimeric partner RXR. (c) 2005 Elsevier Inc. All rights reserved.