BACKGROUND Osteoarthritis (OA) is one of the most prevalent joint disease, and there are still no effective therapeutic agents or clinical methods for the cure of this disease to date. The degradation of cartilage extracellular matrix (ECM) is a major cause of OA. METHOD IL-1β was used to induce chondrogenic degradation. Q-PCR and Western blotting were used to detect mRNA and protein level, respectively. ELISA was used to detect the secreted TNF-α and IL-6 level. Immunofluorescence was used to detect the protein level of Aggrecan, Collagen II and ki67. TUNEL and flow cytometry were used to examine cell apoptosis of chondrocytes. ChIP and luciferase assay were used to study molecular gene regulation. Osteoarthritic animal model and Safranin-O staining were used to determine the in vivo OA phenotype. RESULTS The expression of ADAM8 was up-regulated in osteoarthritic chondrocytes. Knockdown of ADAM8 suppressed the OA phenotype in the in vitro OA cell model. ADAM8 regulated OA progression through the activation of EGFR/ERK/NF-κB signaling pathway. Inhibition of Notch signaling suppressed OA phenotype in the in vitro OA cell model. Notch signaling regulated the gene expression of ADAM8 directly via Hes1. Notch1-ADAM8 positive feedback loop promoted the progression of OA in vivo. CONCLUSION Notch1-ADAM8 feed-back loop regulates the degradation of chondrogenic extracellular matrix and osteoarthritis progression.

中文翻译：

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Notch1-ADAM8阳性反馈环调节软骨源性细胞外基质的降解和骨关节炎的进展。

背景技术骨关节炎（OA）是最普遍的关节疾病之一，迄今为止，尚无有效的治疗剂或临床方法可治愈该疾病。软骨细胞外基质（ECM）的降解是OA的主要原因。方法采用IL-1β诱导软骨细胞降解。Q-PCR和蛋白质印迹分别用于检测mRNA和蛋白质水平。ELISA用于检测分泌的TNF-α和IL-6水平。免疫荧光法用于检测Aggrecan，胶原II和ki67的蛋白质水平。TUNEL和流式细胞术用于检查软骨细胞的细胞凋亡。使用ChIP和荧光素酶测定法研究分子基因调控。用骨关节炎动物模型和番红O染色来确定体内OA表型。结果在骨关节炎软骨细胞中ADAM8的表达上调。在体外OA细胞模型中，敲除ADAM8可抑制OA表型。ADAM8通过激活EGFR / ERK /NF-κB信号通路来调节OA进程。Notch信号的抑制在体外OA细胞模型中抑制了OA表型。Notch信号直接通过Hes1调节ADAM8的基因表达。Notch1-ADAM8阳性反馈环促进了体内OA的发展。结论Notch1-ADAM8反馈环调节软骨源性细胞外基质的降解和骨关节炎的进展。Notch信号的抑制在体外OA细胞模型中抑制了OA表型。Notch信号直接通过Hes1调节ADAM8的基因表达。Notch1-ADAM8阳性反馈环促进了体内OA的发展。结论Notch1-ADAM8反馈环调节软骨源性细胞外基质的降解和骨关节炎的进展。Notch信号的抑制在体外OA细胞模型中抑制了OA表型。Notch信号直接通过Hes1调节ADAM8的基因表达。Notch1-ADAM8阳性反馈环促进了体内OA的发展。结论Notch1-ADAM8反馈环调节软骨源性细胞外基质的降解和骨关节炎的进展。