Inflammatory-sensitive CHI3L1 protects nucleus pulposus via AKT3 signaling during intervertebral disc degeneration
Inflammatory-sensitive CHI3L1 protects nucleus pulposus via AKT3 signaling during intervertebral disc degeneration
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炎症敏感的 CHI3L1 在椎间盘退变过程中通过 AKT3 信号传导保护髓核
DOI：
10.1096/fj.201902096r
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发表时间：
2020
期刊：
影响因子：
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通讯作者：
Yuan Wen
中科院分区：
文献类型：
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作者：
Wang Ruizhe;Xu Chen;Zhong Huajian;Hu Bo;Wei Leixin;Liu Ning;Zhang Yizhi;Shi Qianghui;Wang Chen;Qi Min;Gu Yifei;Shen Xiaolong;Tian Ye;Liu Yang;Cao Peng;Chen Huajiang;Yuan Wen
椎间盘退变（IDD）是引起下腰痛的主要原因，其发病机制尚未完全阐明。虽然炎症介导的髓核细胞外基质代谢失调是髓核退变的主要原因，但对髓核细胞外基质的保护性因素知之甚少。使用高通量无标记蛋白质组学，我们发现炎症相关自分泌因子几丁质酶-3-样蛋白1（CHI 3L 1或YKL-40）在变性过程中在NP细胞中高度表达。免疫组化结果显示，CHI 3L 1的表达具有NP组织特异性，并在退变过程中显著增加。CHI 3L 1过表达可显著降低细胞外基质的粘附率，增加细胞外基质的粘附率。用siRNA敲除CHI 3L 1则显示相反的结果，这暗示CHI 3L 1在IDD中的保护作用。使用高通量RNA测序和功能分析，我们发现AKT 3表达及其磷酸化主要受CHI 3L 1调节。最后，还利用人和小鼠的退化NP组织验证了其机制。总之，我们的研究结果表明，炎症相关自分泌因子CHI 3L 1是NP特异性的，它通过促进AKT 3信号传导来保护IDD，这可能是椎间盘退变的潜在治疗靶点。
Intervertebral disc degeneration (IDD) is the main cause of low back pain and the mechanism of which is far from fully revealed. Although inflammation directed nucleus pulposus (NP) extracellular matrix metabolism dysregulation is known to be the main cause of the degeneration process, few is known about the protective factors. Using high‐throughput label‐free proteomics, we found that inflammation‐related autocrine factor Chitinase‐3‐like protein 1 (CHI3L1, or YKL‐40) is highly expressed in the NP cells during degeneration. Immunohistochemical analysis show that the expression of CHI3L1 is NP tissue specific, and increase significantly during degeneration. Overexpression of CHI3L1 significantly decrease the catabolism, and increase the anabolism of extracellular matrix. Knockdown of CHI3L1 using siRNAs show the opposite results, which imply that the protective role of CHI3L1 in IDD. Using high‐throughput RNA sequencing and functional analyses, we find that AKT3 expression and its phosphorylation is mainly regulated by CHI3L1. And lastly, the mechanism of which is also validated using human and mouse degenerated NP tissues. In summary, our findings show that the inflammation‐related autocrine factor CHI3L1 is NP specific, and it protects IDD by promoting the AKT3 signaling, which may serve as a potential therapeutic target in intervertebral disc degeneration.