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Antifibrogenic Activities of CYP11A1-derived Vitamin D3-hydroxyderivatives Are Dependent on RORγ

Zorica Janjetovic1, Arnold Postlethwaite2, Hong Soon Kang3

  • 1Department of Dermatology, University of Alabama at Birmingham, Birmingham, Alabama.

Endocrinology
|October 27, 2020
PubMed

Insights

Vitamin D metabolites show antifibrotic effects dependent on retinoic acid-related orphan receptor gamma (RORγ). Loss of RORγ reverses these effects, revealing its crucial role in vitamin D

Area of Science:

  • Endocrinology and Metabolism
  • Dermatology
  • Molecular Biology

Background:

  • Noncalcemic 20(OH)D3, a CYP11A1 product, exhibits antifibrotic properties in skin models.
  • Retinoic acid-related orphan receptor gamma (RORγ) is expressed in the skin and may mediate vitamin D metabolite actions.

Purpose of the Study:

  • To investigate the role of RORγ in mediating the antifibrotic and antiproliferative effects of CYP11A1-derived secosteroids.
  • To compare the activity of vitamin D analogs in fibroblasts with varying RORγ expression levels.

Main Methods:

  • Utilized murine fibroblasts from wild-type (RORγ+/+), heterozygous (RORγ+/-), and knockout (RORγ-/-) mice.
  • Assessed the effects of CYP11A1-derived vitamin D metabolites (20(OH)D3, 20,23(OH)2D3, 1,20(OH)2D3, 1,20,23(OH)3D3) on fibroblast proliferation and collagen synthesis.
  • Analyzed gene expression and transcriptomic changes following treatment.

Main Results:

  • CYP11A1-derived vitamin D analogs inhibited proliferation and TGF-β1-induced collagen synthesis in RORγ+/+ fibroblasts.
  • These inhibitory effects were reversed to stimulatory effects in RORγ-/- fibroblasts, indicating RORγ dependence.
  • Transcriptomic analysis revealed significant differences between RORγ-/- and wild-type fibroblasts, explaining the observed phenotypic variations.

Conclusions:

  • The antiproliferative and antifibrotic activities of vitamin D hydroxy derivatives are critically dependent on a functional RORγ.
  • RORγ plays a key role in mediating the cellular responses to these vitamin D metabolites in skin fibroblasts.
  • These findings provide a molecular basis for understanding the RORγ-mediated mechanisms of vitamin D metabolite action in fibrotic processes.
Keywords:
RORγfibroblastshydroxyderivativesvitamin D3

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