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

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.

• Authors: Monica L Brown Lobbins, Imara-Safi O Scott, Andrzej T Slominski, Karen A Hasty, Sicheng Zhang, Duane D Miller, Wei Li, Tae-Kang Kim, Zorica Janjetovic, Tejesh S Patel, Linda K Myers, Arnold E Postlethwaite
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 16 (Aug 19 2021) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 34445632 (Publication Type: Journal Article)

Chemical References

• 17,20-dihydroxypregnacalciferol-3,17,20-trihydroxy-9,10-secopregna-5,7,10-triene
• Antibiotics, Antineoplastic
• Cytokines
• Bleomycin
• Cholecalciferol

Topics

• Animals
• Antibiotics, Antineoplastic (toxicity)
• Bleomycin (toxicity)
• Cholecalciferol (analogs & derivatives, pharmacology)
• Cytokines (metabolism)
• Disease Models, Animal
• Female
• Fibrosis (drug therapy, etiology, pathology)
• Mice
• Mice, Inbred C57BL
• Scleroderma, Systemic (chemically induced, complications, pathology)
• Skin Diseases (drug therapy, etiology, pathology)