17,20S(OH)2pD Can Prevent the Development of Skin Fibrosis in the Bleomycin-Induced Scleroderma Mouse Model

Systemic sclerosis (SSc; scleroderma) is a chronic fibrotic disease involving TGF-beta 1. Low serum vitamin D (vit D) correlates with the degree of fibrosis and expression of TGF-beta 1. This study was designed to determine whether the noncalcemic vit D analog, 17,20S(OH)(2)pD, suppresses fibrosis and mediators of the TGF-beta 1 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 mu g/100 mu L) subcutaneously. Mice received daily oral gavage with either vehicle (propylene glycol) or 17,20S(OH)(2)pD using 5, 15, or 30 mu g/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)(2)pD suppressed net total collagen production, dermal thickness, and total collagen content in the BLM fibrosis model. 17,20S(OH)(2)pD also increased MMP-13 expression, decreased MCP-1 and Gli-2 expression in vivo, and suppressed serum levels of IL-13, TNF-alpha, IL-6, IL-10, IL-17, and IL-12p70. In summary, 17,20S(OH)(2)pD modulates the mediators of fibrosis in vivo and suppresses total collagen production and dermal thickness. This antifibrotic property of 17,20S(OH)(2)pD offers new therapeutic approaches for fibrotic disorders.

Automated summary

The study shows that the noncalcemic vitamin D analog, 17,20S(OH)(2)pD, can suppress total collagen production, dermal thickness, and total collagen content in a fibrosis model, while also increasing MMP-13 expression and decreasing expression of other related factors, as well as suppressing certain cytokines in the serum. This antifibrotic property offers new therapeutic approaches for fibrotic disorders.