Loss of PPARγ expression by fibroblasts enhances dermal wound closure

Mice deleted for PPARγ in skin fibroblasts show an enhanced rate of dermal wound closure, concomitant with elevated phosphorylation of Smad3, Akt and ERK, and increased expression of proliferating cell nuclear antigen (PCNA), collagen, α-smooth muscle actin (α-SMA) and CCN2. Conversely, dermal homeostasis was not appreciably affected by loss of PPARγ expression.PPARγ expression by fibroblasts suppresses cutaneous tissue repair. In the future, direct PPARγ antagonists and agonists might be of clinical benefit in controlling chronic wounds or scarring, respectively.If the dermis is injured, specialized fibroblasts called myofibroblasts repopulate the wound and synthesize and remodel new connective tissue [1]. Wound repair is very complex and dynamic, involving the interactions of multiple cell types and growth factors/cytokines; dysregulation of this process results in chronic wounds or fibrosis [2]. Thus, understanding the molecular mechanisms controlling the normal tissue repair program is likely to be of clinical relevance.Expression of the nuclear receptor peroxisome proliferator-activated receptor (PPAR)-γ is reduced in dermal fibroblasts isolated from fibrotic lesions of patients with the autoimmune connective tissue disease scleroderma (systemic sclerosis, SSc); moreover, the PPARγ agonist rosiglitazone reverses the persistent fibrotic phenotype of this cell type [3]. Normally, PPAR-γ is bound to the retinoid X receptor (RXR) and co-repressors, preventing its binding to DNA; however, upon receptor ligation, the co-repressors are displaced from the PPAR-γ/RXR complex allowing PPAR-γ to bind PPAR-γ response elements in the promoters of target genes [4]. The PPAR/RXR transcriptional complex plays a critical role in maintaining energy balance, which is dysregulated in conditions such as obesity, diabetes, and atherosclerosis [4].An increasing body of evidence also suggests that PPAR-γ plays a key role in connective tissue turnover, a key process involved with tissu