BACKGROUND: Persistent fibroblast activation initiated by transforming growth factor β (TGF-β) is a fundamental event in the pathogenesis of systemic sclerosis, and its pharmacological inhibition represents a potential therapeutic strategy. The nuclear receptor, peroxisome proliferator-activated receptor γ (PPAR-γ), exerts potent fibrotic activity. The synthetic oleanane triterpenoid, 2-cyano-3,12-dioxo-olean-1,9-dien-28-oic acid (CDDO), is a PPAR-γ agonist with potential effects on TGF-β signalling and dermal fibrosis. OBJECTIVE: To examine the modulation of fibrogenesis by CDDO in explanted fibroblasts, skin organ cultures and murine models of scleroderma. MATERIAL AND METHODS: The effects of CDDO on experimental fibrosis induced by bleomycin injection or by overexpression of constitutively active type I TGF-β receptor (TgfbR1ca) were evaluated. Modulation of fibrotic gene expression was examined in human skin organ cultures. To delineate the mechanisms underlying the antifibrotic effects of CDDO, explanted skin fibroblasts cultured in two-dimensional monolayers or in three-dimensional full-thickness human skin equivalents were studied. RESULTS: CDDO significantly ameliorated dermal fibrosis in two complementary mouse models of scleroderma, as well as in human skin organ cultures and in three-dimensional human skin equivalents. In two-dimensional monolayer cultures of explanted normal fibroblasts, CDDO abrogated fibrogenic responses induced by TGF-β. These CDDO effects occurred via disruption of Smad-dependent transcription and were associated with inhibition of Akt activation. In scleroderma fibroblasts, CDDO attenuated the elevated synthesis of collagen. Remarkably, the in vitro antifibrotic effects of CDDO were independent of PPAR-γ. CONCLUSIONS: The PPAR-γ agonist triterpenoid CDDO attenuates fibrogenesis by antagonistically targeting canonical TGF-β/Smad and Akt signalling in a PPAR-γ-independent manner. These findings identify this synthetic triterpenoid as a potential new therapy for the control of fibrosis.
BACKGROUND: Persistent fibroblast activation initiated by transforming growth factor β (TGF-β) is a fundamental event in the pathogenesis of systemic sclerosis, and its pharmacological inhibition represents a potential therapeutic strategy. The nuclear receptor, peroxisome proliferator-activated receptor γ (PPAR-γ), exerts potent fibrotic activity. The synthetic oleananetriterpenoid, 2-cyano-3,12-dioxo-olean-1,9-dien-28-oic acid (CDDO), is a PPAR-γ agonist with potential effects on TGF-β signalling and dermal fibrosis. OBJECTIVE: To examine the modulation of fibrogenesis by CDDO in explanted fibroblasts, skin organ cultures and murine models of scleroderma. MATERIAL AND METHODS: The effects of CDDO on experimental fibrosis induced by bleomycin injection or by overexpression of constitutively active type I TGF-β receptor (TgfbR1ca) were evaluated. Modulation of fibrotic gene expression was examined in human skin organ cultures. To delineate the mechanisms underlying the antifibrotic effects of CDDO, explanted skin fibroblasts cultured in two-dimensional monolayers or in three-dimensional full-thickness human skin equivalents were studied. RESULTS:CDDO significantly ameliorated dermal fibrosis in two complementary mouse models of scleroderma, as well as in human skin organ cultures and in three-dimensional human skin equivalents. In two-dimensional monolayer cultures of explanted normal fibroblasts, CDDO abrogated fibrogenic responses induced by TGF-β. These CDDO effects occurred via disruption of Smad-dependent transcription and were associated with inhibition of Akt activation. In scleroderma fibroblasts, CDDO attenuated the elevated synthesis of collagen. Remarkably, the in vitro antifibrotic effects of CDDO were independent of PPAR-γ. CONCLUSIONS: The PPAR-γ agonist triterpenoidCDDO attenuates fibrogenesis by antagonistically targeting canonical TGF-β/Smad and Akt signalling in a PPAR-γ-independent manner. These findings identify this synthetic triterpenoid as a potential new therapy for the control of fibrosis.
Authors: Liu Yang; Che-Chang Chan; Oh-Sang Kwon; Songling Liu; Jason McGhee; Stephen A Stimpson; Lihong Z Chen; W Wallace Harrington; William T Symonds; Don C Rockey Journal: Am J Physiol Gastrointest Liver Physiol Date: 2006-06-22 Impact factor: 4.052
Authors: Pratima Karnik; Zenar Tekeste; Thomas S McCormick; Anita C Gilliam; Vera H Price; Kevin D Cooper; Paradi Mirmirani Journal: J Invest Dermatol Date: 2008-12-04 Impact factor: 8.551
Authors: Mohit Kapoor; Matthew McCann; Shangxi Liu; Kun Huh; Christopher P Denton; David J Abraham; Andrew Leask Journal: Arthritis Rheum Date: 2009-09
Authors: Melinda S Yates; Mi-Kyoung Kwak; Patricia A Egner; John D Groopman; Sridevi Bodreddigari; Thomas R Sutter; Karen J Baumgartner; B D Roebuck; Karen T Liby; Mark M Yore; Tadashi Honda; Gordon W Gribble; Michael B Sporn; Thomas W Kensler Journal: Cancer Res Date: 2006-02-15 Impact factor: 12.701
Authors: Alfiya Akhmetshina; Katrin Palumbo; Clara Dees; Christina Bergmann; Paulius Venalis; Pawel Zerr; Angelika Horn; Trayana Kireva; Christian Beyer; Jochen Zwerina; Holm Schneider; Anika Sadowski; Marc-Oliver Riener; Ormond A MacDougald; Oliver Distler; Georg Schett; Jörg H W Distler Journal: Nat Commun Date: 2012-03-13 Impact factor: 14.919
Authors: Jun Wei; Hongyan Zhu; Gabriel Lord; Mitra Bhattachayya; Brielle M Jones; Graham Allaway; Shyam S Biswal; Benjamin Korman; Roberta G Marangoni; Warren G Tourtellotte; John Varga Journal: Transl Res Date: 2016-12-09 Impact factor: 7.012
Authors: Carmen Del Rio; Irene Cantarero; Belén Palomares; María Gómez-Cañas; Javier Fernández-Ruiz; Carolina Pavicic; Adela García-Martín; Maria Luz Bellido; Rafaela Ortega-Castro; Carlos Pérez-Sánchez; Chary López-Pedrera; Giovanni Appendino; Marco A Calzado; Eduardo Muñoz Journal: Br J Pharmacol Date: 2018-08-23 Impact factor: 8.739