WISP-1 induced by mechanical stress contributes to fibrosis and hypertrophy of the ligamentum flavum through Hedgehog-Gli1 signaling.
WISP-1 induced by mechanical stress contributes to fibrosis and hypertrophy of the ligamentum flavum through Hedgehog-Gli1 signaling.
复制标题
机械应力诱导的 WISP-1 通过 Hedgehog-Gli1 信号传导导致黄韧带纤维化和肥大
DOI：
10.1038/s12276-021-00636-5
复制
发表时间：
2021-06
影响因子：
12.8
通讯作者：
Liu X
中科院分区：
文献类型：
--
作者：
Sun C;Ma Q;Yin J;Zhang H;Liu X
黄韧带(LF)的慢性纤维化和肥大是腰椎管狭窄(LSCS)的重要原因。我们以前的工作表明，WNT1诱导的信号通路蛋白1(WSAP-1)是LF纤维化的关键驱动因素。然而，其潜在的机制还没有被探索。在这里，我们发现Gli1在肥大的LF组织中上调，在成纤维细胞的纤维化形成中是必需的。此外，机械牵张增加了LF成纤维细胞中WISP-1的表达。此外，WISP-1通过Hedgehog-Gli1途径在体外诱导纤维化形成。WISP-1激活LFHedgehog-Gli1通路，环丙胺可减弱WISP-1诱导的纤维化作用，这一事实支持这一结论。WISP-1还通过Hedgehog途径促进成纤维细胞向肌成纤维细胞的转化。重要的是，机械应力诱导的肥厚性LF兔模型也显示出纤维化的病理变化和WISP-1、Gli1和α-SMA的表达增加。在机械应激诱导的兔模型中，治疗性应用环丙胺减少了胶原蛋白的表达、成纤维细胞的增殖和肌成纤维细胞的分化，改善了纤维化。综上所述，我们的研究结果表明，机械应激/WSAP-1/Hedgehog信号是导致LF肥大的新的纤维化轴，并确定Hedgehog信号是预防和治疗LF纤维化的治疗靶点。
Ongoing chronic fibrosis and hypertrophy of the ligamentum flavum (LF) is an important cause of lumbar spinal canal stenosis (LSCS). Our previous work showed that WNT1-inducible signaling pathway protein 1 (WISP-1) is a critical driver of LF fibrosis. However, the potential mechanism has not been explored. Here, we found that Gli1 was upregulated in hypertrophic LF tissues and required for fibrogenesis in fibroblasts. Moreover, mechanical stretching increased the expression of WISP-1 in LF fibroblasts. Furthermore, WISP-1 induced fibrogenesis in vitro through the Hedgehog-Gli1 pathway. This conclusion was supported by the fact that WISP-1 activated the Hedgehog-Gli1 pathway in LF fibroblasts and that cyclopamine attenuated the effect of WISP-1-induced fibrogenesis. WISP-1 also promoted the transition of fibroblasts into myofibroblasts via the Hedgehog pathway. Importantly, a hypertrophic LF rabbit model induced by mechanical stress also showed pathological changes in fibrosis and elevated expression of WISP-1, Gli1, and α-SMA. Therapeutic administration of cyclopamine reduced collagen expression, fibroblast proliferation, and myofibroblast differentiation and ameliorated fibrosis in the mechanical stress-induced rabbit model. Collectively, our findings show mechanical stress/WISP-1/Hedgehog signaling as a new fibrotic axis contributing to LF hypertrophy and identify Hedgehog signaling as a therapeutic target for the prevention and treatment of LF fibrosis.
登录
查看更多内容
DOI：
10.1038/nrneph.2016.54
发表时间：
2016-07
期刊：
Nature reviews. Nephrology
影响因子：
--
作者：
Edeling M;Ragi G;Huang S;Pavenstädt H;Susztak K
通讯作者：
Susztak K
影响因子：
5.7
作者：
Hegde, Ganapati V.;Munger, Corey M.;Joshi, Shantaram S.
通讯作者：
Joshi, Shantaram S.
影响因子：
3
作者：
Sairyo, Koichi;Biyani, Ashok;Mohan, Suneeth E.
通讯作者：
Mohan, Suneeth E.
影响因子：
4.5
作者：
Ammendolia, Carlo;Rampersaud, Y. Raja;Cote, Pierre
通讯作者：
Cote, Pierre
影响因子：
13.5
作者：
Omenetti, Alessia;Bass, Lee M.;Whitington, Peter F.
通讯作者：
Whitington, Peter F.