The Role of PPAR Gamma in Systemic Sclerosis

Abstract

Fibrosis is recognized as an important feature of many chronic diseases, such as systemic sclerosis (SSc), an autoimmune disease of unknown etiology, characterized by immune dysregulation and vascular injury, followed by progressive fibrosis affecting the skin and multiple internal organs. SSc has a poor prognosis because no therapy has been shown to reverse or arrest the progression of fibrosis, representing a major unmet medical need. Recently, antifibrotic effects of PPARγ ligands have been studied in vitro and in vivo and some theories have emerged leading to new insights. Aberrant PPARγ function seems to be implicated in pathological fibrosis in the skin and lungs. This antifibrotic effect is mainly related to the inhibition of TGF-β/Smad signal transduction but other pathways can be involved. This review focused on recent studies that identified PPARγ as an important novel pathway with critical roles in regulating connective tissue homeostasis, with emphasis on skin and lung fibrosis and its role on systemic sclerosis.

Reassessing the Role of the Active TGF-β1 as a Biomarker in Systemic Sclerosis: Association of Serum Levels with Clinical Manifestations

“…Lung fibrosis was observed using high-resolution computed tomography (HRCT); esophagus involvement was determined by scintillography and/or endoscopy; proximal muscle weakness and elevated serum creatine kinase indicated muscle involvement. Pulmonary artery pressure was estimated by Doppler echocardiogram; pressures above 35 mmHg were interpreted as pulmonary hypertension [15, 16]. The modified Rodnan total skin thickness score (mRSS) was used to evaluate skin fibrosis [17].…”

Peroxisome proliferator‐activated receptor γ plays dual roles on experimental periodontitis in rats

“…Peroxisome proliferator‐activated receptor γ (PPARγ) is a ligand‐dependent nuclear receptor that belongs to the nuclear hormone receptor superfamily and regulates many physiologic and disease processes (Dantas et al., ). The role of PPARγ involves regulating adipocyte differentiation and glucose utilization, inhibiting inflammatory signalling and mediating bone metabolism (Croasdell et al., ).…”

The Myofibroblast: TGFβ-1, A Conductor which Plays a Key Role in Fibrosis by Regulating the Balance between PPARγ and the Canonical WNT Pathway

“…Crosstalk between PPARγ, the canonical WNT and TGF-β1 (Figures 1 and 2) The link between TGF-β1, canonical WNT/β-catenin and PPARγ has been established [6,7,107]. TGF-β1 has been shown to activate the canonical WNT signaling, and to inhibit PPARγ.…”

“…Conversely, other molecules increase PPARγ expression. Therse include adiponectin, TZDs, L-carnitine, statins, eplerenone, and irbesartan [107]. Adiponectin increases PPARγ 2 expression and inhibits LPS-induced NF-kappaB activation and IL-6 production in adipocytes [108].…”

“…In human fibrotic diseases, PPARγ expression is diminished such as in lung [176], liver [164], kidney [165] and scarring alopecia [177]. In several human fibrotic diseases, reduced PPARγ expression and/or activity precede fibrosis suggesting a causal role for fibrosis [6,107]. In mice suffering from bleomycin-induced systemic sclerosis (SSc), expression of PPARγ is decreased in cutaneous tissue and the TZD rosiglitazone abrogates bleomycin-induced scleroderma and blocks profibrotic responses through PPARγ [122].…”