Division of Rheumatology, Northwestern University Feinberg School of Medicine, , Chicago, Illinois, USA.
Ann Rheum Dis. 2014 Feb;73(2):446-54. doi: 10.1136/annrheumdis-2012-202716. Epub 2013 Mar 20.
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.
To examine the modulation of fibrogenesis by CDDO in explanted fibroblasts, skin organ cultures and murine models of scleroderma.
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.
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.
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.
转化生长因子-β（TGF-β）引发的持续成纤维细胞激活是系统性硬化症发病机制中的一个基本事件，其药理学抑制代表了一种潜在的治疗策略。核受体过氧化物酶体增殖物激活受体 γ（PPAR-γ）发挥着强大的纤维化作用。合成的齐墩果烷三萜 2-氰基-3,12-二氧代-齐墩果酸-1,9-二烯-28-酸（CDDO）是一种 PPAR-γ 激动剂，对 TGF-β 信号转导和皮肤纤维化具有潜在作用。
研究 CDDO 对原代成纤维细胞、皮肤器官培养物和硬皮病小鼠模型中纤维化的调节作用。
评估 CDDO 对博来霉素注射或过表达组成型激活型 I 型 TGF-β 受体（TgfbR1ca）诱导的实验性纤维化的影响。在人皮肤器官培养物中检测纤维化基因表达的调节。为了阐明 CDDO 抗纤维化作用的机制，在二维单层或三维全厚人皮肤等效物中培养原代皮肤成纤维细胞进行研究。
CDDO 显著改善了两种互补的硬皮病小鼠模型以及人皮肤器官培养物和三维人皮肤等效物中的皮肤纤维化。在原代正常成纤维细胞的二维单层培养物中，CDDO 阻断了 TGF-β诱导的成纤维反应。这些 CDDO 作用是通过破坏 Smad 依赖性转录发生的，与 Akt 激活的抑制有关。在硬皮病成纤维细胞中，CDDO 降低了胶原的合成。值得注意的是，CDDO 的体外抗纤维化作用与 PPAR-γ 无关。
PPAR-γ 激动剂三萜 CDDO 通过拮抗经典的 TGF-β/Smad 和 Akt 信号转导，以 PPAR-γ 非依赖性方式减弱纤维化。这些发现表明这种合成三萜类化合物是控制纤维化的一种潜在新疗法。
