| First Author | Janjetovic Z | Year | 2021 |
| Journal | Endocrinology | Volume | 162 |
| Issue | 1 | PubMed ID | 33107570 |
| Mgi Jnum | J:298846 | Mgi Id | MGI:6488343 |
| Doi | 10.1210/endocr/bqaa198 | Citation | Janjetovic Z, et al. (2021) Antifibrogenic Activities of CYP11A1-derived Vitamin D3-hydroxyderivatives Are Dependent on RORgamma. Endocrinology 162(1) |
| abstractText | 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 gamma (RORgamma), which is expressed in skin, in the action of CYP11A1-derived secosteroids using murine fibroblasts isolated from the skin of wild-type (RORgamma +/+), knockout (RORgamma -/-), and heterozygote (RORgamma +/-) mice. CYP11A1-derived 20(OH)D3, 20,23(OH)2D3, 1,20(OH)2D3, and 1,20,23(OH)3D3 inhibited proliferation of RORgamma +/+ fibroblasts in a dose-dependent manner with a similar potency to 1,25(OH)2D3. Surprisingly, this effect was reversed in RORgamma +/- and RORgamma -/- fibroblasts, with the most pronounced stimulatory effect seen in RORgamma -/- fibroblasts. All analogs tested inhibited TGF-beta1-induced collagen synthesis in RORgamma +/+ fibroblasts and the expression of other fibrosis-related genes. This effect was curtailed or reversed in RORgamma -/- fibroblasts. These results show that the antiproliferative and antifibrotic activities of the vitamin D hydroxy derivatives are dependent on a functional RORgamma. The dramatic changes in the transcriptomes of fibroblasts of RORgamma -/- 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. |
