Asporin regulated by miR-26b-5p mediates chondrocyte senescence and exacerbates osteoarthritis progression via TGF-β1/Smad2 pathway
Asporin regulated by miR-26b-5p mediates chondrocyte senescence and exacerbates osteoarthritis progression via TGF-β1/Smad2 pathway
复制标题
miR-26b-5p 调节的阿孢素通过 TGF-β1/Smad2 途径介导软骨细胞衰老并加剧骨关节炎进展。
DOI：
10.1093/rheumatology/keab725
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发表时间：
2021-11-18
期刊：
影响因子：
5.5
通讯作者：
Cai, Daozhang
中科院分区：
文献类型：
--
作者：
Liu, Liangliang;Zhao, Chang;Cai, Daozhang
目的探讨asporin在OA病理过程中对软骨细胞衰老的调控作用及其机制。方法检测人和实验性OA小鼠软骨标本中Asporin和衰老相关标志物的表达。在内侧半月板（DMM）去稳定化手术后，通过关节内注射每周一次向10周龄雄性C57小鼠施用表达重组蛋白（rm-asporin）或asporin-siRNA的慢病毒以诱导OA。使用骨关节炎研究协会国际评分测量腕关节损伤。衰老相关的β-半乳糖苷酶（SA-β-Gal）染色，γ H2 AX，p21和p16（INK 4a）通过免疫荧光染色和蛋白质印迹分析，以评估asporin在软骨细胞衰老中的特定作用。进一步评价TGF-β 1-Smad 2信号通路和miR-26 b-5 p以探讨asporin在OA中的作用机制。结果OA患者和DMM小鼠关节软骨细胞中Asporin表达上调，并伴有衰老细胞的积累。Asporin过度表达加剧了OA的进展，而沉默asporin恢复了软骨细胞的稳态，延缓了软骨细胞的衰老，导致DMM诱导的OA明显减弱。细胞和分子分析显示，asporin可以被miR-26 b-5 p抑制，miR-26 b-5 p在OA软骨中显著下调，导致实验性OA的恶化，部分通过抑制软骨细胞中的TGF-β 1-Smad 2信号传导。结论asporin在软骨细胞衰老和OA发病中起重要作用。通过miR-26 b-5 p上调，asporin抑制TGF-β 1-Smad 2途径，加速软骨细胞衰老并加剧软骨退化。靶向miR-26 b-5 p-asporin-Smad 2轴可作为延迟软骨细胞衰老和OA发展的实用治疗策略。
Objectives This study aimed to investigate the role and mechanism of asporin in modulating chondrocyte senescence in OA pathology. Methods Asporin and senescence-related hallmark expression were examined in human and experimental OA mouse cartilage samples. Twelve-week-old male C57 mice were administered with recombinant protein (rm-asporin)- or asporin-siRNA-expressing lentiviruses via intra-articular injection once a week after destabilization of the medial meniscus (DMM) surgery to induce OA. Cartilage damage was measured using the Osteoarthritis Research Society International score. Senescence-associated beta-galactosidase (SA-beta-Gal) staining, gamma H2AX, p21 and p16(INK4a) were analysed by immunofluorescence staining and western blot to assess the specific role of asporin in chondrocyte senescence. The TGF-beta 1-Smad2 signalling pathway and miR-26b-5p were further evaluated to explore the mechanism of asporin in OA. Results Asporin was upregulated in articular chondrocytes of OA patients and DMM mice and accompanied by accumulation of senescent cells. Asporin overexpression exaggerated OA progression, whereas silencing asporin restored chondrocyte homeostasis and deferred chondrocyte senescence, leading to markedly attenuated DMM-induced OA. Cellular and molecular analyses showed that asporin can be inhibited by miR-26b-5p, which was significantly downregulated in OA cartilage, leading to exacerbation of experimental OA partially through inhibition of TGF-beta 1-Smad2 signalling in chondrocytes. Conclusions Our findings indicate that asporin plays an essential role in chondrocyte senescence and OA pathogenesis. Upregulated by miR-26b-5p, asporin inhibits the TGF-beta 1-Smad2 pathway to accelerate chondrocyte senescence and exacerbate cartilage degeneration. Targeting the miR-26b-5p-asporin-Smad2 axis may serve as a practical therapeutic strategy to delay chondrocyte senescence and OA development.