The adipokine adiponectin has potent anti-fibrotic effects mediated via adenosine monophosphate-activated protein kinase: novel target for fibrosis therapy

Abstract

IntroductionFibrosis in scleroderma is associated with collagen deposition and myofibroblast accumulation. Peroxisome proliferator activated receptor gamma (PPAR-γ), a master regulator of adipogenesis, inhibits profibrotic responses induced by transforming growth factor-ß (TGF-β), and its expression is impaired in scleroderma. The roles of adiponectin, a PPAR-γ regulated pleiotropic adipokine, in regulating the response of fibroblasts and in mediating the effects of PPAR-γ are unknown.MethodsRegulation of fibrotic gene expression and TGF-ß signaling by adiponectin and adenosine monophosphate protein-activated (AMP) kinase agonists were examined in normal fibroblasts in monolayer cultures and in three-dimensional skin equivalents. AdipoR1/2 expression on skin fibroblasts was determined by real-time quantitative PCR.ResultsAdiponectin, an adipokine directly regulated by PPAR-γ, acts as a potent anti-fibrotic signal in normal and scleroderma fibroblasts that abrogates the stimulatory effects of diverse fibrotic stimuli and reduces elevated collagen gene expression in scleroderma fibroblasts. Adiponectin responses are mediated via AMP kinase, a fuel-sensing cellular enzyme that is necessary and sufficient for down-regulation of fibrotic genes by blocking canonical Smad signaling. Moreover, we demonstrate that endogenous adiponectin accounts, at least in part, for the anti-fibrotic effects exerted by ligands of PPAR-γ.ConclusionsThese findings reveal a novel link between cellular energy metabolism and extracellular matrix homeostasis converging on AMP kinase. Since the levels of adiponectin as well as its receptor are impaired in scleroderma patients with progressive fibrosis, the present results suggest a potential role for defective adiponectin expression or function in progressive fibrogenesis in scleroderma and other chronic fibrosing conditions. Restoring the adiponectin signaling axis in fibroblasts might, therefore, represent a novel pharmacological approach to controlling fibrosis.

Platelet Rich Plasma (PRP) Produces an Atherofibrotic Histophenotype During Craniofacial Bone Repair Due to Changes of Immunohistochemical Expression of Erk1/2, p38α/β, Adiponectin and Elevated Presence of Cells Exhibiting B-scavenger Receptor (CD36+)

“…On the other hand, the negative correlation between adiponectin expression and fibrogenesis was demonstrated in the scleroderma, suggesting a potential role for adiponectin in the pathogenesis of fibrosis. This hypothesis is supported by results that demonstrated that both RNA-i mediated adiponectin knockdown in normal fibroblast and genetic depletion of adiponectin in mouse fibroblast revealed increase of smooth-actin muscle intracellular filaments as well as increase of collagen deposition (14).…”

“…Since adiponectin has a collagen-like N-terminal, this adipokine acts as an antithrombotic factor, minimizes fibrosis (14) and also contributes to the increase of bone mass and protection against dyslipidemia and foam cell formation, thus contributing to tissue homeostasis (15).…”

Autologous Fat Grafting in the Treatment of Fibrotic Perioral Changes in Patients with Systemic Sclerosis

“…The anti-inflammatory effects may also be due to possible downregulation of different degrading enzymes like collagenase and gelatinase, which are overexpressed in inflammatory responses (41,42). Moreover, the antifibrotic effects of adiponectin as a counterregulator of fibrotic gene expression and transforming growth factor-b (TGF-b) signaling have been recently underlined (11). Finally, the fact that ATDMSCs are able to differentiate into endothelial cells and release angiogenetic factors supports their potential utility in promoting angiogenesis in surrounding tissues (38).…”

Toll-Like Receptor-4 Signaling Drives Persistent Fibroblast Activation and Prevents Fibrosis Resolution in Scleroderma

“…Treatment of fibroblasts with adiponectin, an adipocyte-derived peptide that is reduced in patients with SSc, blocked TLR-dependent fibrotic responses. 58,59 Remarkably, adiponectin induces sustained upregulation of A20 in fibroblasts. Pharmacologic agents that induce A20 expression, such as vitamin E (c-tocotrienol) and adiponectin, hold promise as antifibrotic therapies by restoring endogenous A20 expression, particularly when targeted in a tissue-restricted manner, such as by topical application.…”