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.

Novel Vitamin D3 Hydroxymetabolites Require Involvement of the Vitamin D Receptor or Retinoic Acid-Related Orphan Receptors for Their Antifibrogenic Activities in Human Fibroblasts

“…We have discovered several CYP11A1-derived vitamin D3 hydroxymetabolites, some of which are naturally found in human serum [72,73], in human organs or cells [13,14] and in bees' honey [74], with metabolites lacking a hydroxyl group on C1α being non-calcemic [24,25]. We previously reported that these vitamin D3 hydroxymetabolites, similarly to 1,25(OH) 2 D3 [52], have the ability to reduce fibrosis in human cells [22,23] or murine skin in vivo [17,53]. In mice, this effect required the expression of the RORγ receptor [55].…”

“…A plethora of studies have demonstrated the inhibitory effect of 1,25(OH) 2 D3 in fibrotic skin diseases [28,44,48,49,51,52]. In addition, several D3 metabolites have been tested on fibroblasts, including 20(OH)D3 and 20,23(OH) 2 D3, the major products of CYP11A1-mediated vitamin D3 metabolism [17,23,53,54]. Both metabolites suppress fibrogenesis and cell proliferation, as tested on murine skin and human skin cells [17,23,55].…”

Vitamin D in Systemic Sclerosis: A Review

“…Consistent with these data, the anti-fibrogenic activity of vitamin D has been reported in murine models of scleroderma. Specifically, in mice with bleomycin-induced skin fibrosis, the treatment with systemic topical vitamin D analogs reduced the amount of fibrosis [ 27 , 28 , 29 , 30 ] by down-regulating TGF-β signalling and by modulating cytokine mediators, such as IL-13, TNF-α, IL-6, IL-17, and IL-12p70 [ 34 ]. These findings suggest that the effect of vitamin D in this context is in part directly related to its activity on crucial pathways of fibrosis development and in part to the modulation of the immune system; indeed, in blood samples collected from SSc patients, vitamin D supplementation increased IL-10 production by T-reg lymphocytes providing a “suppressive” cytokine milieu able to modulate immune response [ 31 ].…”

Promising Functions of Novel Vitamin D Derivatives as Cosmetics: A New Fountain of Youth in Skin Aging and Skin Protection

“…CYP11A1-derived secosteroids can inhibit proliferation of human keratinocytes and melanocytes [61][62][63][64], stimulate cell differentiation [259,260], decrease inflammation [249,250,260] and prevent pathological skin fibrosis [261,262] similarly to 1,25(OH) 2 D3 (Figure 2). However, they can act through different receptors.…”