PPAR-gamma: A Novel Target in Scleroderma Fibrosis

John Varga, MD
Northwestern University

Project Summary:

PPAR-gamma is a nuclear receptor with key roles in insulin sensitivity, energy metabolism and the development of fat tissue. Drugs that activate PPAR-gamma (glitazones) are now used to treat type 2 diabetes. The Varga lab has recently found that PPAR-gamma is expressed in normal fibroblasts (cell found within connective tissue) and its activity is reduced in some patients with scleroderma. Additionally, they have shown that agents that activate PPAR-gamma also attenuate pro-fibrotic responses that lead to scar formation. They hypothesize that PPAR-gamma is a natural suppressor of fibrosis, and its impaired expression or activity contributes to progression of fibrosis in scleroderma; thus, PPAR-gamma is a promising target for anti-fibrotic therapy. The Varga lab is characterizing the expression and mechanism of action of PPAR-gamma in fibrosis, and its role in scleroderma. Additionally, using mouse models of fibrosis, they are exploring whether novel compounds that activate PPAR-gamma can ameliorate fibrosis.

Research Update:

Dr. Varga's lab has observed that both natural and synthetic agonists of PPAR-gamma abrogated the stimulation of collagen synthesis and myofibroblast differentiation induced by TGF-beta in vitro. To characterize the role of PPAR-gamma in the fibrotic process in vivo, the synthetic agonist rosiglitazone (Avandia^®) was used in a mouse model of scleroderma. Rosiglitazone reduced bleomycin-induced skin fibrosis, loss of subcutaneous fat, increased collagen gene expression and numbers of myofibroblasts in the skin. Novel compounds that activate PPAR-gamma, but are more selective or have improved safety profiles, are under investigation as anti-fibrotic agents.

The effects of PPAR-gamma agonists on restoring tissue function and preventing fibrosis might be achieved via action in fibroblasts or macrophages (a type of white blood that ingests foreign material). On-going studies will advance these findings, including the evaluation of novel ligands of PPAR-gamma, as well as the determination of PPAR-gamma activity in patients with scleroderma, and genetic associations of scleroderma with specific PPAR-gamma gene variants.

What this project means for people with scleroderma:

The PPAR-gamma pathway is a potent natural regulator of fibroblast function that represents the nexus between metabolism and fibrosis. Impaired expression and function of PPAR-gamma may underlie the progression of fibrosis in scleroderma. The ongoing studies will provide an understanding of the role of PPAR-gamma in regulating fibrosis and the potential clinical utility of novel therapies targeting PPAR-gamma in patients with scleroderma.

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