Abstract
Systemic sclerosis (SSc) is an autoimmune disease marked by excessive extracellular matrix deposition in the skin and internal organs. Although the etiology of SSc remains unknown, three major abnormalities are considered to play important roles in the pathophysiology of SSc: autoimmunity, vasculopathy and fibrosis. Mouse models are critical tools for further understanding of the pathophysiology underlying this disease. The bleomycin-induced scleroderma model and TSK/+ mice are the primary SSc models; however, emerging models of SSc, such as Fra-2 Tg mice and the hypochlorous acid (HOCl)-induced scleroderma model, have provided novel insights into the pathophysiology of SSc. Importantly, a growing number of studies suggests a role for B cells, including regulatory B cells, in the pathogenesis of SSc. Thus, for the development of therapies, targeting of profibrogenic cytokines, such as transforming growth factor-β is still a very active area of investigation and B cell-targeted therapies also represent potential treatment options. Furthermore, approaches to antagonize IL-6 or IL-17A signaling or to inhibit signaling pathways that utilize peroxisome proliferator-activated receptor-γ, Wnt or hedgehog are also being explored for the treatment of SSc. Here, we review murine models of SSc as well as recent updates regarding the development of therapeutic approaches using murine models of SSc.
Financial & competing interests disclosure
This work was supported by grants-in-aid from the Ministry of Education, Science and Culture of Japan, and Ministry of Health, Labor and Welfare of Japan. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Key issues
• The bleomycin-induced scleroderma model and TSK/+ mice are well-characterized models of systemic sclerosis (SSc).
• Repetitive hypochlorous acid injections induce extensive skin and lung fibrosis as well as kidney damage. In this novel model, disease is easy to induce and is characterized by fibrosis as well as by vasculopathy, inflammation and autoimmunity.
• The Fra-2-transgenic mouse is a good model for investigating pulmonary arterial hypertension observed in SSc.
• B cell-targeted therapies and antagonizing IL-6 or IL-17A signaling are effective in murine models of SSc. Thus, these treatments may also be effective in SSc patients.