Mechanosignaling activation of TGFβ maintains intervertebral disc homeostasis.
Mechanosignaling activation of TGFβ maintains intervertebral disc homeostasis.
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DOI：
10.1038/boneres.2017.8
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发表时间：
2017
期刊：
影响因子：
12.7
通讯作者：
Cao X
中科院分区：
文献类型：
--
作者：
Bian Q;Ma L;Jain A;Crane JL;Kebaish K;Wan M;Zhang Z;Edward Guo X;Sponseller PD;Séguin CA;Riley LH;Wang Y;Cao X
椎间盘（IVD）退变是导致残疾的主要原因，没有疾病改善治疗。IVD退变与脊柱中不稳定的机械负荷有关，但关于机械应力如何调节脊索核（NC）细胞以维持IVD稳态知之甚少。我们在此报道了机械应力可导致过度整合素αvβ6介导的转化生长因子β（TGFβ）活化，NC细胞空泡减少，基质蛋白多糖产生增加，并导致退行性椎间盘疾病（DDD）。敲除NC细胞中的TGFβ II型受体（TβRII）或整合素αv可抑制出生后NC细胞的功能活性，并导致机械负荷下的DDD。给予RGD肽、TGFβ和αvβ6中和抗体可减弱IVD变性。因此，整合素介导的TGFβ活化在调节IVD细胞功能和稳态的机械信号转导中起关键作用。对这一信号通路的调控可能是改善DDD的潜在治疗靶点。
Intervertebral disc (IVD) degeneration is the leading cause of disability with no disease-modifying treatment. IVD degeneration is associated with instable mechanical loading in the spine, but little is known about how mechanical stress regulates nucleus notochordal (NC) cells to maintain IVD homeostasis. Here we report that mechanical stress can result in excessive integrin αvβ6-mediated activation of transforming growth factor beta (TGFβ), decreased NC cell vacuoles, and increased matrix proteoglycan production, and results in degenerative disc disease (DDD). Knockout of TGFβ type II receptor (TβRII) or integrin αv in the NC cells inhibited functional activity of postnatal NC cells and also resulted in DDD under mechanical loading. Administration of RGD peptide, TGFβ, and αvβ6-neutralizing antibodies attenuated IVD degeneration. Thus, integrin-mediated activation of TGFβ plays a critical role in mechanical signaling transduction to regulate IVD cell function and homeostasis. Manipulation of this signaling pathway may be a potential therapeutic target to modify DDD.