Scleroderma (systemic sclerosis, SSc) is a progressive multisystem, autoimmune disease with a high morbidity and mortality. Despite important advances in our understanding of SSc pathogenesis, there are no reliable diagnostic or prognostic biomarkers or effective disease-modifying treatments for SSc. Current paradigms point to the involvement of autoimmunity and inflammation, vasculopathy, and excessive extracellular matrix (ECM) deposition. Mononuclear cells, including T-cells and macrophages, are recruited to affected tissues triggering fibroblast activation, myofibroblast differentiation, nd ECM deposition. We have recently determined that cadherin-11 (Cad11) is increased in the serum and skin of SSc patients. Additional studies demonstrate that Cad11 deficient mice have reduced tissue fibrosis in models of dermal and pulmonary fibrosis. As expected, Cad11 was expressed on fibroblasts and myofibroblasts. Surprisingly Cad11 expression was also observed in tissue macrophages, a novel finding. Given the expression of Cad11 on multiples cellular populations, fibroblast and macrophages, it is likely that Cad11 contributes to the complex, multistep pathogenesis of tissue fibrosis and SSc through its regulation of these cells, but the current proposal will focus on how Cad11 regulates macrophage cytokine production. Therefore, we hypothesize that Cad11 regulates the development of dermal fibrosis, in part through the regulation of macrophage cytokine production. We also hypothesize that serum cadherin- 11 levels are elevated in SSc patients and that serum and/or dermal cadherin-11 may be a novel biomarker in SSc patients. In the current proposal, the experiments proposed in Aim 1 will further our understanding of how Cad11 contributes to the development of dermal fibrosis in vivo by taking advantage of unique Cad11 specific tools and multiple murine models of dermal fibrosis that each capture different processes and pathways believed to be relevant to SSc pathogenesis. In vitro studies in Aim 2 will demonstrate that Cad11 plays a role in the regulation of macrophage function. Finally, in Aim 3, we will determine the extent to which Cad11 levels are elevated in SSc patients and correlate the levels with clinical features of SSc. These studies will take advantage of unique molecular tools such as neutralizing anti-Cad11 monoclonal antibodies and Cad11 deficient mice as well as unique clinical resources such as large prospective SSc patient cohorts headquartered at our University to efficiently and effectively address these aims.
Systemic Sclerosis (scleroderma) is a potentially devastating disease clinically manifesting as progressive fibrosis of skin and visceral organs. Effective disease-modifying treatments or reliable clinical biomarkers do not exist for this disease that results in the death of up to 55% of patients with the diffuse form of systemic sclerosis within 5 years. Data from our laboratory has identified cadherin-11 as a potential therapeutic target and serum biomarker in systemic sclerosis and the current proposal seeks to advance our understanding of cadherin-11 in systemic sclerosis and translate these findings to patients suffering from systemic sclerosis.
|Pedroza, Mesias; Le, Thuy T; Lewis, Katherine et al. (2016) STAT-3 contributes to pulmonary fibrosis through epithelial injury and fibroblast-myofibroblast differentiation. FASEB J 30:129-40|
|Row, Sindhu; Liu, Yayu; Alimperti, Stella et al. (2016) Cadherin-11 is a novel regulator of extracellular matrix synthesis and tissue mechanics. J Cell Sci 129:2950-61|
|Wu, Minghua; Pedroza, Mesias; Lafyatis, Robert et al. (2014) Identification of cadherin 11 as a mediator of dermal fibrosis and possible role in systemic sclerosis. Arthritis Rheumatol 66:1010-21|
|Wu, Minghua; Schneider, Daniel J; Mayes, Maureen D et al. (2012) Osteopontin in systemic sclerosis and its role in dermal fibrosis. J Invest Dermatol 132:1605-14|