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- Title
Antifibrogenic Activities of CYP11A1-derived Vitamin D3-hydroxyderivatives Are Dependent on RORγ.
- Authors
Janjetovic, Zorica; Postlethwaite, Arnold; Kang, Hong Soon; Kim, Tae-Kang; Tuckey, Robert C; Crossman, David K; Qayyum, Shariq; Jetten, Anton M; Slominski, Andrzej T
- Abstract
Previous studies showed that noncalcemic 20(OH)D3, a product of CYP11A1 action on vitamin D3, has antifibrotic activity in human dermal fibroblasts and in a bleomycin mouse model of scleroderma. In this study, we tested the role of retinoic acid-related orphan receptor γ (RORγ), which is expressed in skin, in the action of CYP11A1-derived secosteroids using murine fibroblasts isolated from the skin of wild-type (RORγ +/+), knockout (RORγ -/-), and heterozygote (RORγ +/-) mice. CYP11A1-derived 20(OH)D3, 20,23(OH)2D3, 1,20(OH)2D3, and 1,20,23(OH)3D3 inhibited proliferation of RORγ +/+ fibroblasts in a dose-dependent manner with a similar potency to 1,25(OH)2D3. Surprisingly, this effect was reversed in RORγ +/- and RORγ -/- fibroblasts, with the most pronounced stimulatory effect seen in RORγ -/- fibroblasts. All analogs tested inhibited TGF-β1-induced collagen synthesis in RORγ +/+ fibroblasts and the expression of other fibrosis-related genes. This effect was curtailed or reversed in RORγ -/- fibroblasts. These results show that the antiproliferative and antifibrotic activities of the vitamin D hydroxy derivatives are dependent on a functional RORγ. The dramatic changes in the transcriptomes of fibroblasts of RORγ -/- versus wild-type mice following treatment with 20(OH)D3 or 1,20(OH)2D3 provide a molecular basis to explain, at least in part, the observed phenotypic differences.
- Subjects
TRETINOIN; VITAMINS; VITAMIN D; FIBROBLASTS; BLEOMYCIN; CHOLECALCIFEROL
- Publication
Endocrinology, 2021, Vol 162, Issue 1, p1
- ISSN
0013-7227
- Publication type
Article
- DOI
10.1210/endocr/bqaa198