Date: Monday, November 6, 2017
Session Type: ACR Concurrent Abstract Session
Session Time: 4:30PM-6:00PM
Background/Purpose: The Retinoic-acid related Orphan Receptor-alpha (RORα) is a member of the nuclear receptor superfamily and a ligand-dependent transcription factor implicated in a wide range of physiological and pathological processes. The key objective for this study is to evaluate the role of RORα in tissue repair and to elucidate antifibrotic effects of targeting RORα in preclinical models of fibrosis.
Methods: The expression was analysed by qPCR, Western blot and immunofluorescence staining. The expression of RORα was modulated via genetic abrogation or adenoviral overexpression. RORα was also targeted pharmaceutically using the small molecule inhibitor SR3335. The role of RORα in fibrosis was evaluated in TGF-β receptor I (TBRI) and bleomycin-induced murine models.
Results: The expression of RORα was increased in fibroblasts in both human and murine fibrotic lung and liver. Activation of canonical Wnt/ β-catenin signalling mimicked the upregulation of RORα in fibrosis and potently induced RORα expression. Consistently, reporter-assays showed that canonical Wnt ligands induced the promoter activity of RORα target gene BMla1. Overexpression of RORα in fibroblasts induced fibroblast-to-myofibroblast transition and collagen release. Inactivation of RORα signalling, either by knockout of RORα or by treatment with SR3335 inhibited WNT- and TGF-β-dependent fibroblast activation and blocked extracellular matrix secretion. Inhibition of RORα also demonstrated potent antifibrotic effects in the mouse models of bleomycin- and TBRI-induced fibrosis. Mice treated with SR3335 demonstrated reduced dermal thickening, decreased hydroxyproline content and impaired myofibroblast differentiation as compared to vehicle-treated mice.
Conclusion: Our study identifies RORα as a key checkpoint of TGF-β- and WNT- induced fibroblast activation. RORα is induced in fibrotic diseases in a WNT-dependent manner to promote TGF-β- and WNT-induced fibroblast activation and tissue fibrosis. Targeting of RORα simultaneously interferes with TGF-β- and WNT-signalling as two core profibrotic pathways, which translates into potent antifibrotic effects.
To cite this abstract in AMA style:Kagwiria R, Liang R, Chen CW, Burris T, Schett G, Distler J. The Nuclear Receptor ROR-Alpha As a Key Checkpoint of Tissue Repair [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/the-nuclear-receptor-ror-alpha-as-a-key-checkpoint-of-tissue-repair/. Accessed January 18, 2022.
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