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 TRα and PPARγ expression vectors were treated with the PPAR ligands ciglitazone or troglitazone. Forced overexpression of PPARγ decreased TRα1-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 PPARγ activator ciglitazone or troglitazone. Overexpression of retinoid X receptor-α (RXRα) partially restored not only the inhibition of transcriptional activation by PPARγ but also T3-induced hypertrophic differentiation. These data demonstrate that activation of PPARγ signaling by either addition of PPARγ ligands or overexpression of PPARγ 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 PPARγ and TRα for limiting amounts of the heterodimeric partner RXR.