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 and the development of fat cells. Pharmacological agents that activate PPAR-gamma (glitazones) are now used clinically to treat type 2 diabetes. The Varga lab has found that PPAR-gamma is expressed in normal fibroblasts and that PPAR gamma gene expression and PPAR-gamma protein levels are reduced in some patients with scleroderma. Additionally, they have shown that agents activating PPAR-gamma can reduce pro-fibrotic collagen gene expression induced by transforming growth factor (TGF-beta). They hypothesize that PPAR-gamma is a natural suppressor of fibrosis and impaired PPAR-gamma gene expression or protein activity could be a factor in progressive fibrosis in scleroderma. Thus, PPAR-gamma may be an interesting target for anti-fibrotic therapy.

In this project, the Varga lab will characterize the expression of PPAR-gamma and its role in scleroderma. Additionally they will use a mouse model of fibrosis to examine the effect of activators of PPAR-gamma on fibrosis and determine whether deleting PPAR-gamma expression from fibroblasts enhances fibrosis. They will also define how PPAR-gamma interacts with TGF-beta to regulate 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 attenuated bleomycin-induced skin inflammation and dermal fibrosis as well as subcutaneous lipoatrophy and counteracted the up-regulation of collagen gene expression and myofibroblast accumulation in the lesioned skin.

Since the anti-PPAR-gamma agents are now commercially available (Avandia®, Actos®), future studies will determine if in fact they seem to help sustain the fibrosis process.

Dr. Varga’s work was recently cited in the American Journal of Pathology and is progressing. In the published work on induced fibrosis model in animals, PPAR-gamma agonists did restore function and prevented fibrosis. This might be achieved via action in macrophages (a type of white blood that ingests foreign material). Macrophages are key players in the immune response to foreign invaders such as infectious microorganisms or even in lung and skin fibroblasts, all of which have recently been shown to express PPAR-gamma.

Future studies will advance these findings, including the generation of transgenic mice with a conditional deletion of PPAR-gamma in fibroblasts.

What this project means for people with scleroderma:

PPAR-gamma is a potent negative regulator of fibrosis and may represent a novel target for therapy. These studies will provide an understanding of the role of PPAR-gamma in regulating fibrosis and the potential clinical utility of therapies targeting PPAR-gamma in scleroderma.

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