ACR Meeting Abstracts

ACR Meeting Abstracts

  • Home
  • Meetings Archive
    • ACR Convergence 2022
    • ACR Convergence 2021
    • ACR Convergence 2020
    • 2020 ACR/ARP PRSYM
    • 2019 ACR/ARP Annual Meeting
    • 2018 ACR/ARHP Annual Meeting
    • 2017-2009 Meetings
    • Download Abstracts
  • Keyword Index
  • Advanced Search
  • Your Favorites
    • Favorites
    • Login
    • View and print all favorites
    • Clear all your favorites
  • Meeting Resource Center

Abstract Number: 121

Inhibition of Nuclear Receptor Coactivator 3 Attenuates Fibrosis in Murine Models of Systemic Sclerosis

Sebastian Poetter1, Clara Dees1, Christina Bergmann1, Andreas Ramming1, Oliver Distler2, Georg Schett3 and Jörg Distler1, 1Department of Internal Medicine 3 and Institute for Clinical Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Erlangen, Germany, 2Research of Systemic Autoimmune Diseases, Division of Rheumatology, University Hospital Zurich, 8952 Schlieren, Switzerland, 3Friedrich-Alexander-University Erlangen-Nuremberg (FAU), Department of Internal Medicine 3 – Rheumatology and Immunology, University Hospital Erlangen, Erlangen, Germany

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: fibrosis, Nuclear hormone receptor, systemic sclerosis and transcriptional regulation

  • Tweet
  • Email
  • Print
Session Information

Date: Sunday, October 21, 2018

Session Title: Systemic Sclerosis and Related Disorders – Basic Science Poster I

Session Type: ACR Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose: Uncontrolled activation of fibroblasts releasing large amounts of extracellular matrix proteins is a key feature of systemic sclerosis (SSc). The nuclear receptor coactivators (NCOA) are named after their role as coactivators for nuclear hormone receptors, but are indeed modulating a large number of signaling pathways. In this study, we aimed to analyze whether targeting of NCOA3 may ameliorate fibrosis in preclinical models of SSc.

Methods: Fibroblasts were exposed to chronically high levels of TGF-β to mimic the situation in fibrotic diseases. The expression of different transcriptional cofactors in response to TGF-β stimulation was analyzed by quantitative real-time PCR. Protein levels were analyzed by Western Blot. Knockdown of NCOA3 was achieved via transfection with siRNA in vitro. For knockdown of NCOA3 in vivo, siRNA was premixed with atelocollagen for stabilization and injected subcutaneously at the site of bleomycin injections. Additionally, NCOA3 was targeted with the SRC3 inhibitor-2 (SI-2) in different murine models. The interaction of NCOA3 and TGF-β/SMAD signaling was analyzed by SMAD-responsive reporter as well as CoIP assays.

Results:

SiRNA-mediated knockdown of NCOA3 strongly decreased the pro-fibrotic effects of TGF-β, with significant reductions in collagen protein, in the mRNA levels of COL1A1 and ACTA2 as well as significant decreases in the prototypical TGF-β target genes PAI1 and CTGF. Knockdown of NCOA3 also ameliorated fibrosis in the bleomycin-induced dermal fibrosis model of SSc, with reductions of dermal thickening, of myofibroblast counts and of hydroxyproline content. Furthermore, pharmacological targeting of NCOA3 by the inhibitor SI-2 was able to ameliorate fibrosis in bleomycin-induced pulmonary fibrosis and in dermal fibrosis induced by overexpression of constitutively active TGF-β receptor type I (TBRIact). Mechanistically, NCOA3 directly interacts with SMAD3 to promote TGF-β/SMAD3 signaling as shown by reporter studies and CoIP assays.

When we analyzed the expression levels of NCOA3 in SSc and in matched healthy individuals, we observed a modest, but statistically significant downregulation of NCOA3 expression, a phenotype that persisted also in cultured SSc fibroblasts. Stimulation of normal fibroblasts with chronically high levels of TGF-β also decreased the mRNA and protein levels of NCOA3. Given the profibrotic effects of NCOA3, the downregulation of NCOA3 in fibrotic SSc skin may be an endogenous regulatory attempt to counteract the increased activity of TGF-β/SMAD3 signaling.

Conclusion: We demonstrate in our study that inhibition of NCOA3 has profound anti-fibrotic effects and serves as a coactivator for the profibrotic effects of TGF-β/SMAD. Antagonizing NCOA3 augments an endogenous regulatory loop to reduce persistent fibroblast activation and tissue fibrosis in SSc.


Disclosure: S. Poetter, None; C. Dees, None; C. Bergmann, None; A. Ramming, None; O. Distler, None; G. Schett, None; J. Distler, 4DScience, 1, 4,Anamar, Active Biotech, Array Biopharma, aTyr, BMS, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, Novartis, Sanofi-Aventis, RedX, UCB, 2,Actelion, Active Biotech, Anamar, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, JB Therapeutics, Medac, Pfizer, RuiYi and UCB, 8.

To cite this abstract in AMA style:

Poetter S, Dees C, Bergmann C, Ramming A, Distler O, Schett G, Distler J. Inhibition of Nuclear Receptor Coactivator 3 Attenuates Fibrosis in Murine Models of Systemic Sclerosis [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 9). https://acrabstracts.org/abstract/inhibition-of-nuclear-receptor-coactivator-3-attenuates-fibrosis-in-murine-models-of-systemic-sclerosis/. Accessed February 2, 2023.
  • Tweet
  • Email
  • Print

« Back to 2018 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/inhibition-of-nuclear-receptor-coactivator-3-attenuates-fibrosis-in-murine-models-of-systemic-sclerosis/

Advanced Search

Your Favorites

You can save and print a list of your favorite abstracts during your browser session by clicking the “Favorite” button at the bottom of any abstract. View your favorites »

ACR Pediatric Rheumatology Symposium 2020

© COPYRIGHT 2023 AMERICAN COLLEGE OF RHEUMATOLOGY

Wiley

  • Home
  • Meetings Archive
  • Advanced Search
  • Meeting Resource Center
  • Online Journal
  • Privacy Policy
  • Permissions Policies
  • Cookie Preferences