Abstract
IntroductionProgressive fibrosis in systemic sclerosis (SSc) is linked to aberrant transforming growth factor beta (TGF-beta) signaling. Peroxisome proliferator-activated receptor gamma (PPAR-gamma) blocks fibrogenic TGF-beta responses in vitro and in vivo. Reduced expression and function of PPAR-gamma in patients with SSc may contribute to progression of fibrosis. Here we evaluated the levels of adiponectin, a sensitive and specific index of PPAR-gamma activity, as a potential fibrogenic biomarker in SSc.MethodsAdiponectin levels were determined in the sera of 129 patients with SSc and 86 healthy controls, and serial determinations were performed in 27 patients. Levels of adiponectin mRNA in skin biopsies from SSc patients were assessed in an expression profiling microarray dataset. Regulation of adiponectin gene expression in explanted human subcutaneous preadipocytes and fibroblasts was examined by real-time quantitative PCR.ResultsPatients with diffuse cutaneous SSc had reduced serum adiponectin levels. A significant inverse correlation between adiponectin levels and the modified Rodnan skin score was observed. In longitudinal studies changes in serum adiponectin levels were inversely correlated with changes in skin fibrosis. Skin biopsies from a subset of SSc patients showed reduced adiponectin mRNA expression which was inversely correlated with the skin score. An agonist ligand of PPAR-gamma potently induced adiponectin expression in explanted mesenchymal cells in vitro.ConclusionsLevels of adiponectin, reflecting PPAR-gamma activity, are correlated with skin fibrosis and might have potential utility as a biomarker in SSc.
Highlights
Progressive fibrosis in systemic sclerosis (SSc) is linked to aberrant transforming growth factor beta (TGF-beta) signaling
In longitudinal studies changes in serum adiponectin levels were inversely correlated with changes in skin fibrosis
Clinical and laboratory information obtained at the time of serum sampling included age, gender, ethnicity, smoking history, body mass index (BMI), disease duration, modified Rodnan skin score (MRSS) (0 to 51), forced vital capacity (FVC), and carbon monoxide diffusion capacity (DlCO) as a percentage of predicted highresolution computerized tomography of the chest (Table 1 and Additional file 1)
Summary
Progressive fibrosis in systemic sclerosis (SSc) is linked to aberrant transforming growth factor beta (TGF-beta) signaling. Peroxisome proliferator-activated receptor gamma (PPAR-gamma) blocks fibrogenic TGF-beta responses in vitro and in vivo. Reduced expression and function of PPAR-gamma in patients with SSc may contribute to progression of fibrosis. We evaluated the levels of adiponectin, a sensitive and specific index of PPAR-gamma activity, as a potential fibrogenic biomarker in SSc. Systemic sclerosis (SSc) is a multisystem disorder with protean clinical manifestations and substantial patientto-patient heterogeneity [1]. Transforming growth factor-beta (TGF-b) plays a key role in initiating and sustaining fibroblast activation and myofibroblast differentiation in SSc [2]. One important endogenous anti-fibrotic defense mechanism involves the peroxisome proliferator-activated receptor-gamma (PPAR-g) pathway, which blocks TGF-b responses [4]
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