Background/Purpose:  In systemic sclerosis (SSc) patients, skin fibrosis is accompanied by involution of dermal white adipose tissue (dWAT), a prominent source of adiponectin (APN). We hypothesize that impaired APN activity due to loss of dWAT underlies the progression and persistence of skin fibrosis in SSc. To tests our hypothesis, we investigated APN pathway deregulation in SSc and used transgenic mice and APN-mimetic peptides.

Methods: APN pathway activation was evaluated in SSc skin biopsies using expression microarray and immunohistochemistry. Experimental skin and peritoneal fibrosis was investigated in ΔGLY-APN transgenic mice.

Results: Interrogating skin biopsy transcriptome data, we found that a subset of SSc patients showed reduced APN pathway activation (p=0.04), representing a novel molecular subset of SSc. Moreover, SSc skin biopsies (n=20) had significantly reduced levels of phospho-AMP protein kinase in dermal myofibroblasts compared to healthy controls (p=0.01), indicating attenuation of local APN signaling. To assess the effect of systemic APN, fibrosis was induced in ΔGLY-APN transgenic mice. A 2-3-fold increase in levels of circulating APN in these mice was associated with significantly attenuated skin fibrosis induced by bleomycin as well as by constitutively-active TGF-ß. Moreover, transgenic mice showed partial preservation of dWAT during early-stage fibrogenesis, and reduced influx of macrophages. Attenuation of skin fibrosis was accompanied by evidence of defective focal adhesion assembly in dermal cells. Levels of circulating APN in these mice were negatively correlated with dermal thickness (r=-0.747, p<0.001) and collagen content (r=-0.586, p<0.001). Chronic treatment of C57BL6/J mice with short APN mimetic peptides prevented and reversed experimentally-induced dermal fibrosis. ΔGLY-APN mice also showed robust protection from chlorexidine gluconate-induced peritoneal fibrosis (p=0.05) and myofibroblast accumulation (p=0.02). Cell fate-mapping studies showed that >65% of myofibroblasts within fibrotic peritoneal tissue derived from APN-positive progenitor cells resident in the mesothelial sub-lining.

Conclusion: Our results implicate defective APN production and activity in skin fibrosis in a subset of patients with SSc. APN protected mice from experimental skin and peritoneal fibrosis, and circulating levels correlated with dermal thickness. Myofibroblasts within fibrotic tissue largely derive from adipocytic lineage cells resident in the dWAT (skin) or peritoneal mesothelium. These findings suggest that restoring normal APN signaling and normal adipogenesis represent innovative therapeutic approaches to SSc.

« Back to 2016 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/impaired-adiponectin-signaling-in-ssc-contributes-to-myofibroblast-differentiation-and-organ-fibrosis/