Abstract
Systemic sclerosis (SSc; scleroderma) is a chronic fibrotic disease involving TGF-β1. Low serum vitamin D (vit D) correlates with the degree of fibrosis and expression of TGF-β1. This study was designed to determine whether the noncalcemic vit D analog, 17,20S(OH)2pD, suppresses fibrosis and mediators of the TGF-β1 pathway in the bleomycin (BLM) model of fibrosis. Fibrosis was induced into the skin of female C57BL/6 mice by repeated injections of BLM (50 μg/100 μL) subcutaneously. Mice received daily oral gavage with either vehicle (propylene glycol) or 17,20S(OH)2pD using 5, 15, or 30 μg/kg for 21 days. The injected skin was biopsied; analyzed histologically; examined for total collagen by Sircol; and examined for mRNA expression of MMP-13, BMP-7, MCP-1, Gli1, and Gli2 by TR-PCR. Spleen was analyzed for lymphocytes using flow cytometry. Serum was analyzed for cytokines using a multiplexed ELISA. Results showed that all three doses of 17,20S(OH)2pD suppressed net total collagen production, dermal thickness, and total collagen content in the BLM fibrosis model. 17,20S(OH)2pD also increased MMP-13 expression, decreased MCP-1 and Gli-2 expression in vivo, and suppressed serum levels of IL-13, TNF-α, IL-6, IL-10, IL-17, and IL-12p70. In summary, 17,20S(OH)2pD modulates the mediators of fibrosis in vivo and suppresses total collagen production and dermal thickness. This antifibrotic property of 17,20S(OH)2pD offers new therapeutic approaches for fibrotic disorders.
Highlights
Systemic sclerosis (SSc; scleroderma) is a chronic disease characterized by extensive fibrosis of the skin and internal organs
We demonstrate 17,20S(OH)2 pD administered by oral gavage decreases the development of dermal fibrosis and loss of subcutaneous adipose tissue, and affects the expression of key players in the TGF-β1 pathway in the BLM-induced scleroderma model of fibrosis
We examined whether treatment of mice with 17,20S(OH)2pD would increase matrix metalloproteinases (MMP)-13 mRNA expression at the site of BLM injection in the skin
Summary
Systemic sclerosis (SSc; scleroderma) is a chronic disease characterized by extensive fibrosis of the skin and internal organs. Pathogenesis of this disease was reviewed by Pattanaik et al [1] and includes autoimmunity, fibroblast activation, increased deposition of collagen type I (CI) and III (CIII), and decreased collagen degradation by matrix metalloproteinases (MMP). Using the C57BL/6 murine model, cutaneous fibrosis can be induced by injecting bleomycin (BLM) subcutaneously into the same skin site on alternate days [12]. This model mimics early inflammatory changes in SSc with fibrosis limited to the area of injection [13]
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