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Tribbles homologue 3 stimulates canonical TGF-β signalling to regulate fibroblast activation and tissue fibrosis
  1. Michal Tomcik1,2,
  2. Katrin Palumbo-Zerr1,
  3. Pawel Zerr1,
  4. Barbora Sumova1,2,
  5. Jerome Avouac3,
  6. Clara Dees1,
  7. Alfiya Distler1,
  8. Radim Becvar2,
  9. Oliver Distler4,
  10. Georg Schett1,
  11. Ladislav Senolt2,
  12. Jörg H W Distler1
  1. 1Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
  2. 2Department of Rheumatology, 1st Faculty of Medicine, Institute of Rheumatology, Charles University, Prague, Czech Republic
  3. 3Rheumatology A Department, Paris Descartes University, Cochin Hospital, Paris, France
  4. 4Center of Experimental Rheumatology and Zurich Center of Integrative Human Physiology, University Hospital, Zurich, Switzerland
  1. Correspondence to Dr Jörg H W Distler, Department of Internal Medicine 3, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen D-91054, Germany; joerg.distler{at}uk-erlangen.de

Abstract

Objectives Tribbles homologue 3 (TRB3) is a pseudokinase that modifies the activation of various intracellular signalling pathways to control fundamental processes extending from mitosis and cell activation to apoptosis and modulation of gene expression. Here, we aimed to analyse the role of TRB3 in fibroblast activation in systemic sclerosis (SSc).

Methods The expression of TRB3 was quantified by quantitative PCR, western blot and immunohistochemistry. The role of TRB3 was analysed in cultured fibroblasts and in experimental fibrosis using small interfering RNA (siRNA)-mediated knockdown and overexpression of TRB3.

Results TRB3 expression was increased in fibroblasts of patients with SSc and in murine models of SSc in a transforming growth factor-β (TGF-β)/Smad-dependent manner. Overexpression of TRB3 stimulated canonical TGF-β signalling and induced an activated phenotype in resting fibroblasts. In contrast, knockdown of TRB3 reduced the profibrotic effects of TGF-β and decreased the collagen synthesis. Moreover, siRNA-mediated knockdown of TRB3 exerted potent antifibrotic effects and ameliorated bleomycin as well as constitutively active TGF-β receptor I-induced fibrosis with reduced dermal thickening, decreased hydroxyproline content and impaired myofibroblast differentiation.

Conclusions The present study characterises TRB3 as a novel profibrotic mediator in SSc. TGF-β induces TRB3, which in turn activates canonical TGF-β/Smad signalling and stimulates the release of collagen, thereby inducing a positive feedback loop that may contribute to aberrant TGF-β signalling in SSc.

  • Fibroblasts
  • Systemic Sclerosis
  • Treatment

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