Antifibrogenic Activities of CYP11A1-derived Vitamin D3-hydroxyderivatives Are Dependent on RORγ.
Animals
Animals, Newborn
Bleomycin
/ toxicity
Cell Differentiation
/ drug effects
Cell Proliferation
/ drug effects
Cholecalciferol
/ analogs & derivatives
Cholesterol Side-Chain Cleavage Enzyme
/ metabolism
Drug Tapering
Female
Fibroblasts
/ drug effects
Gene Expression Regulation
/ drug effects
Mice
Mice, Inbred C57BL
Mice, Knockout
Nuclear Receptor Subfamily 1, Group F, Member 3
/ genetics
Scleroderma, Limited
RORγ
fibroblasts
hydroxyderivatives
vitamin D3
Journal
Endocrinology
ISSN: 1945-7170
Titre abrégé: Endocrinology
Pays: United States
ID NLM: 0375040
Informations de publication
Date de publication:
01 01 2021
01 01 2021
Historique:
received:
27
07
2020
pubmed:
28
10
2020
medline:
15
5
2021
entrez:
27
10
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33107570
pii: 5940802
doi: 10.1210/endocr/bqaa198
pmc: PMC7717072
pii:
doi:
Substances chimiques
Nuclear Receptor Subfamily 1, Group F, Member 3
0
Bleomycin
11056-06-7
Cholecalciferol
1C6V77QF41
Cholesterol Side-Chain Cleavage Enzyme
EC 1.14.15.6
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIAMS NIH HHS
ID : R01 AR071189
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR073004
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR052190
Pays : United States
Organisme : BLRD VA
ID : I01 BX004293
Pays : United States
Organisme : NIAID NIH HHS
ID : R21 AI149267
Pays : United States
Informations de copyright
© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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