Session Information
Date: Monday, November 9, 2015
Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud's - Pathogenesis, Animal Models and Genetics I
Session Type: ACR Concurrent Abstract Session
Session Time: 4:30PM-6:00PM
Background/Purpose: Hedgehog signaling plays a critical role in the pathogenesis of fibrosis in Systemic sclerosis (SSc). Besides canonical hedgehog signaling with Smoothened (Smo)-dependent activation of Gli transcription factors, Gli can be activated independently of classical hedgehog ligands and receptors (so-called non-canonical pathways). The aim of the present study was to evaluate the role of non-canonical hedgehog signaling in SSc and to test the efficacy of direct Gli-inhibitors that target simultaneously canonical and non-canonical hedgehog pathways.
Methods: The Gli-inhibitor GANT-61 was used to inhibit canonical as well as non-canonical hedgehog signaling, while the Smo-inhibitor vismodegib was used to selectively target canonical hedgehog signaling. In addition, Gli2 was selectively depleted in fibroblasts using the Cre LoxP system. The effects of pharmacologic or genetic of Gli2 on TGF-β signaling were analyzed in cultured fibroblasts, in bleomycin-induced pulmonary fibrosis and in mice with overexpression of a constitutively active TGF-b receptor I (TBRI).
Results: The expression of Gli2 was transcriptionally upregulated in fibroblasts and in murine tissues by TGF-β in a Smad-independent manner. Consistent with a novel role of Gli2 as a downstream mediator of TGF-β in fibroblasts, fibroblast-specific knockout of Gli2 reduced the stimulatory effects of TGF-β on fibroblasts and ameliorated TBR-induced skin fibrosis. The Gli2 inhibitor GANT-61 also prevented the stimulatory effects of TGF-β on fibroblasts in vitro and in vivo. Treatment with GANT-61 downregulated the levels of prototypical TGF-b targeted genes, reduced the collagen release and also blocked TGF-b-induced myofibroblast differentiation. In contrast, inhibition of canonical hedgehog signaling by vismodegib did not ameliorate TGF-β-induced fibroblast activation. Furthermore, GANT-61 ameliorated experimental fibrosis of the skin more efficiently than vismodegib. In the model of TBRI-induced fibrosis, mice treated with GANT-61 showed reduced dermal thickening, lower myofibroblast counts and decreased hydroxyproline content, whereas inhibition of canonical hedgehog signaling by vismodegib had no anti-fibrotic effect. GANT-61 also exerted potent anti-fibrotic effects in the model of bleomycin-induced pulmonary fibrosis and induced regression of pre-established fibrosis. In both models, GANT-61 did not only reduce levels of the hedgehog target genes, but also the levels of the TGF-b target genes, thus confirming inhibition of TGF-b signaling upon targeting of Gli2.
Conclusion: We characterize Gli2 as a novel intracellular mediator of the pro-fibrotic effects of TGF-b. Pharmacologic inhibition of Gli2 targets canonical as well as non-canonical hedgehog signaling and ameliorates the pro-fibrotic effects of TGF-b . The potent anti-fibrotic effects of Gli2 inhibitors on cultured fibroblasts, dermal and pulmonary fibrosis and availability of direct Gli2 inhibitors for clinical use encourage additional studies to further explore the potential of Gli2 inhibitors for the treatment of fibrosis.
To cite this abstract in AMA style:
Liang R, Dees C, Palumbo-Zerr K, Zhang Y, Distler O, Schett G, Distler JH. Inhibition of Gli Ameliorates the Pro-Fibrotic Effects of Transforming Growth Factor-β in Systemic Sclerosis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/inhibition-of-gli-ameliorates-the-pro-fibrotic-effects-of-transforming-growth-factor-i%c2%b2-in-systemic-sclerosis/. Accessed .« Back to ACR/ARHP Annual Meeting 2015
ACR Meeting Abstracts - https://acrabstracts.org/abstract/inhibition-of-gli-ameliorates-the-pro-fibrotic-effects-of-transforming-growth-factor-i%c2%b2-in-systemic-sclerosis/