Session Information
Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud’s – Pathogenesis, Animal Models and Genetics
Session Type: Abstract Submissions (ACR)
Background/Purpose: Systemic sclerosis (SSc) is characterized by aberrant activation of fibroblasts with increased release of extracellular matrix components. Canonical Wnt signaling has recently emerged as a key mediator of fibroblasts activation and tissue fibrosis in SSc. However, targeting of canonical Wnt signaling has so far been complicated by the lack of pathway components that are amenable to pharmacological inhibition. However, tankyrases have recently demonstrated to regulate Wnt signalling by stimulating the proteasomal degradation of axin. In the present study, we evaluated the tankyrases as a potential novel target for the treatment of fibrosis in SSc.
Methods:
The anti-fibrotic effects of the selective tankyrase inhibitor XAV-939 or of siRNA mediated knockdown of tankyrases were evaluated in the mouse models of bleomycin-induced dermal fibrosis and in experimental fibrosis induced by adenoviral overexpression of a constitutively active TGF-β receptor I (adTBR). Dermal thickness, α-smooth muscle actin (αSMA) and hydroxyproline content were determined by haematoxylin-eosin and trichrome stainings, by immunohistostaining for αSMA and by hydroxyproline assay respectively. Activation of canonical Wnt signaling was assessed by quantification of nuclear β-catenin and analyses of the target gene c-myc.
Results:
Inactivation of tankyrases either by XAV-939 or by siRNA mediated knockdown of tankyrases prevented the activation of canonical Wnt signaling in experimental fibrosis and reduced the nuclear accumulation of β-catenin and the mRNA levels of the target gene c-myc. Pharmacologic inhibition of tankyrases was well tolerated without any clinical signs of toxicity. Treatment with XAV-939 potently reduced bleomycin-induced dermal thickening by 50 % compared to sham-treated mice (p = 0.0007). XAV-939 also significantly reduced the differentiation of resting fibroblasts into myofibroblasts and accumulation of collagen. XAV-939 also exerted potent anti-fibrotic effects in adTBR driven skin fibrosis with reduced dermal thickening, decreased myofibroblast counts and reduced accumulation of collagen compared to sham-treated mice. siRNA mediated knockdown of tankyrases in the skin also exerted potent anti-fibrotic effects confirming that the anti-fibrotic effects of XAV-939 were not due to off-target effects.
Conclusion:
Inactivation of tankyrases abrogated the activation of canonical Wnt signaling and demonstrated potent anti-fibrotic effects in different preclinical models of SSc without evidence of toxicity. Considering the great medical need, the potent anti-fibrotic effects, the good tolerability and first clinical trials with tankyrase inhibitors, tankyrases might be potential candidates for targeted therapies in SSc and other fibrotic diseases.
Disclosure:
A. Distler,
None;
L. Deloch,
None;
J. Huang,
None;
C. Dees,
None;
N. Y. Lin,
None;
C. Beyer,
None;
O. Distler,
Actelion, Pfizer, Boehringer-Ingelheim, Bayer, Roche, Ergonex, BMS, Sanofi-Aventis, United BioSource Corporation, medac, Biovitrium, Novartis and Active Biotec,
2,
Actelion, Pfizer, Boehringer-Ingelheim, Bayer, Roche, Ergonex, BMS, Sanofi-Aventis, United BioSource Corporation, medac, Biovitrium, Novartis and Active Biotec,
5,
Actelion, Pfizer and Ergonex,
8;
G. A. Schett,
None;
J. H. Distler,
None.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/inactivation-of-tankyrases-ameliorates-canonical-wnt-signaling-and-prevents-experimental-fibrosis/