Constitutive Smad signaling and Smad-dependent collagen gene expression in mouse embryonic fibroblasts lacking peroxisome proliferator-activated receptor-gamma

Asish K Ghosh, Jun Wei, Minghua Wu, John Varga
Biochemical and Biophysical Research Communications 2008 September 19, 374 (2): 231-6
Transforming growth factor-beta (TGF-beta), a potent inducer of collagen synthesis, is implicated in pathological fibrosis. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a nuclear hormone receptor that regulates adipogenesis and numerous other biological processes. Here, we demonstrate that collagen gene expression was markedly elevated in mouse embryonic fibroblasts (MEFs) lacking PPAR-gamma compared to heterozygous control MEFs. Treatment with the PPAR-gamma ligand 15d-PGJ(2) failed to down-regulate collagen gene expression in PPAR-gamma null MEFs, whereas reconstitution of these cells with ectopic PPAR-gamma resulted in their normalization. Compared to control MEFs, PPAR-gamma null MEFs displayed elevated levels of the Type I TGF-beta receptor (TbetaRI), and secreted more TGF-beta1 into the media. Furthermore, PPAR-gamma null MEFs showed constitutive phosphorylation of cellular Smad2 and Smad3, even in the absence of exogenous TGF-beta, which was abrogated by the ALK5 inhibitor SB431542. Constitutive Smad2/3 phosphorylation in PPAR-gamma null MEFs was associated with Smad3 binding to its cognate DNA recognition sequences, and interaction with coactivator p300 previously implicated in TGF-beta responses. Taken together, these results indicate that loss of PPAR-gamma in MEFs is associated with upregulation of collagen synthesis, and activation of intracellular Smad signal transduction, due, at least in part, to autocrine TGF-beta stimulation.

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