The pathogenesis of fibrosis in systemic sclerosis (SSc) is poorly understood and effective treatments are lacking. Recent findings point to a previously unappreciated complex relationship between adipose tissue (AT), adipokines and fibrosis. AT is an important reservoir of both multipotent mesenchymal progenitor cells, and adipocytes secreting adipokines with pro- and anti-fibrotic paracrine activities. Loss of intradermal AT is associated with dermal fibrosis in SSc and precedes dermal fibrosis in mouse models of scleroderma, suggesting that it is a primary event in pathogenesis. In response to the adipogenic master regulator PPAR-gamma, AT secretes copious amounts of adiponectin. Our preliminary results showed reduced levels of adiponectin in the serum and skin in SSc, and an inverse correlation with skin score. Adiponectin has potent anti-fibrotic effects, and mediates the salutary effects of PPAR-gamma in fibroblasts, whereas loss of adiponectin in the mouse results in exacerbated fibrosis. I hypothesize that impaired adiponectin function results in persistent hypoadiponectinemic state in SSc that contributes to unchecked fibroblast activation and progression of skin fibrosis. Further, I hypothesize that adiponectin is a novel fibrosis biomarker and a potential target for therapy. In this proposal I will i) examine how adiponectin gain-of-function modulates experimental fibrosis in transgenic mice; and ii) evaluate the clinical correlates of serum and tissue adiponectin levels in well-characterized SSc patient cohorts. These results will contribute to a better understanding of fibrosis, and indicate if augmenting adiponectin in specific SSc patient subsets may be a potential approach to therapy.
Systemic sclerosis (SSc) is a fibrotic disease with high morbidity and mortality. Remarkably, there are no approved therapies for SSc or other fibrotic conditions. The proposed experiments seek to study a novel mechanism that could be involved in SSc with the goal of better understanding the fibrotic process, identify a fibrosis biomarker and develop novel treatment approach to prevent or reverse the process.
| Korman, Benjamin; Marangoni, Roberta Goncalves; Lord, Gabriel et al. (2018) Adipocyte-specific Repression of PPAR-gamma by NCoR Contributes to Scleroderma Skin Fibrosis. Arthritis Res Ther 20:145 |
| Marangoni, Roberta G; Masui, Yuri; Fang, Feng et al. (2017) Adiponectin is an endogenous anti-fibrotic mediator and therapeutic target. Sci Rep 7:4397 |
| Korman, Benjamin D; Marangoni, Roberta Goncalves; Hinchcliff, Monique et al. (2017) Brief Report: Association of Elevated Adipsin Levels With Pulmonary Arterial Hypertension in Systemic Sclerosis. Arthritis Rheumatol 69:2062-2068 |
