Session Information
Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud’s – Pathogenesis, Animal Models and Genetics
Session Type: Abstract Submissions (ACR)
Background/Purpose: Fibrosis in scleroderma is associated with transforming growth factor-β (TGF-β) signaling activation, collagen deposition and myofibroblast accumulation. Peroxisome proliferator activated receptor gamma (PPAR-γ) inhibits profibrotic responses, while regulates adiponectin production. Our recent studies demonstrated that adiponectin levels were reduced in patients with diffuse cutaneous scleroderma, and inversely correlated with disease activity, severity and duration. However, the function and molecular signaling of adiponectin during fibrogenesis are still unknown.
Methods: Collagen and α-smooth muscle actin (α-SMA) gene expression and TGF-ß signaling by recombinant adiponectin, AICAR and metformin were examined by real-time qPCR, Western blot, immunofluorescence microscopy and transient transfection assays. AdipoR1 expression on skin fibroblasts was determined by real-time qPCR. Gene expression changes were examined using microarrays.
Results: In skin fibroblasts, recombinant adiponectin inhibited the basal and TGF-β-stimulated collagen and alpha-smooth muscle actin mRNA and protein expression at dose-depend manner, while RNAi knockdown of adiponectin sensitized TGF-β-stimulated fibrotic responses. Similarly, metformin and AICAR, two agonists of 5′ adenosine monophosphate (AMP)-activated protein kinase, inhibited fibrotic responses. AMPK antagonist compound C impaired the anti-fibrotic effects of adiponectin. In adiponectin-null fibroblasts, PPAR-γ ligand PGJ2 failed to inhibit TGF-β-stimulated fibrotic responses. In addition, adiponectin completely abrogated the profibrotic effects of lipopolysaccharide (LPS, a potent ligand of Toll-like receptor 4 (TLR4) with profibrotic effects). Furthermore, the adiponectin receptor 1 showed reduced expression in scleroderma skin biopsies, suggesting the defective adiponectin signaling in scleroderma.
Conclusion: Our results indicate adiponectin plays an important homeostatic role in negative regulation of collagen deposition and myofibroblast accumulation. The anti-fibrotic effects associated with pharmacological PPAR-γ ligands are at least in part due to the activation of the adiponectin signaling pathway. Restoring the adiponectin signaling axis in fibroblasts might represent a novel pharmacological approach to controlling fibrosis.
Disclosure:
F. Fang,
None;
L. Liu,
None;
Y. Yang,
None;
J. Wei,
None;
S. Bhattacharyya,
None;
R. Summer,
None;
B. Ye,
None;
J. Varga,
None.
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