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Jun N-terminal kinase as a potential molecular target for prevention and treatment of dermal fibrosis

Nicole Reich1, Michal Tomcik, Pawel Zerr

  • 1Department for Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.

Annals of the Rheumatic Diseases
|January 20, 2012
PubMed
Abstract

Insights

The selective c-Jun N-terminal kinase (JNK) inhibitor CC-930 demonstrated potent antifibrotic effects in preclinical models of systemic sclerosis (SSc). CC-930 prevented and reversed fibrosis by inhibiting JNK signaling, highlighting JNK as a therapeutic target for SSc.

Area of Science:

  • Fibrosis research
  • Dermatology
  • Pharmacology

Background:

  • Systemic sclerosis (SSc) is characterized by excessive extracellular matrix deposition driven by activated fibroblasts.
  • Transforming growth factor beta (TGFβ) and platelet-derived growth factor (PDGF) are key pro-fibrotic cytokines implicated in SSc.
  • c-Jun N-terminal kinase (JNK) signaling is activated by TGFβ and PDGF, mediating pro-fibrotic responses in fibroblasts.

Purpose of the Study:

  • To analyze the antifibrotic effects of CC-930, a selective JNK inhibitor, in preclinical models of systemic sclerosis (SSc).
  • To investigate the role of JNK as a downstream mediator of TGFβ and PDGF in SSc fibroblasts.
  • To evaluate CC-930's potential for both preventing and inducing regression of experimental fibrosis.

Main Methods:

  • Western blot and immunohistochemistry were used to detect phosphorylated c-Jun.
  • Experimental fibrosis was induced using bleomycin and the tight skin 1 (TSK1) mouse models.
  • CC-930's efficacy was assessed in preventing fibrosis development and promoting regression of established fibrosis.

Main Results:

  • CC-930 inhibited JNK phosphorylation and reduced collagen release stimulated by TGFβ and PDGF in vitro.
  • Inhibition of JNK by CC-930 dose-dependently prevented dermal thickening, myofibroblast differentiation, and collagen accumulation in mouse models.
  • CC-930 demonstrated efficacy in inducing regression of established experimental fibrosis at pharmacologically relevant doses.

Conclusions:

  • JNK is identified as a critical downstream mediator of pro-fibrotic signaling by TGFβ and PDGF in SSc fibroblasts.
  • Selective JNK inhibition with CC-930 exhibits significant antifibrotic activity both in vitro and in vivo.
  • JNK represents a promising molecular target for developing novel antifibrotic therapies for systemic sclerosis.

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