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Abstract：
Chondrocyte apoptosis is recognized as one of the pathological features involved in cartilage degeneration driving the onset and progression of knee osteoarthritis (OA). This study aimed to determine the molecular mechanism underlying the effect of clusterin (CLU), anti-apoptotic molecule, in human knee OA chondrocytes. Primary knee OA chondrocytes were isolated from the cartilage of knee OA patients and divided into five groups: (1) the cells treated with interleukin (IL)-1β, (2) CLU alone, (3) a combination of IL-1β and CLU, (4) LY294002 (PI3K inhibitor) along with IL-1β and CLU, and (5) the untreated cells. Production of apoptotic, inflammatory, anabolic, and catabolic mediators in knee OA chondrocytes was determined after treatment for 24 h. Our in vitro study uncovered that CLU significantly suppressed the production of inflammatory mediators [nitric oxide (NO), IL6, and tumor necrosis factor (TNF)-α] and apoptotic molecule (caspase-3, CASP3). CLU significantly upregulated messenger ribonucleic acid (mRNA) expressions of anabolic factors [SRY-box transcription factor-9 (SOX9) and aggrecan (ACAN)], but significantly downregulated mRNA expressions of IL6, nuclear factor kappa-B (NF-κB), CASP3, and matrix metalloproteinase-13 (MMP13). Anti-apoptotic and anti-inflammatory effects of CLU were mediated through activating PI3K/Akt signaling pathway. The findings suggest that CLU might have beneficial effects on knee OA chondrocytes by exerting anti-apoptotic and anti-inflammatory functions via PI3K/Akt pathway, making CLU a promising target for potential therapeutic interventions in knee OA.
摘要：
软骨细胞凋亡被认为是参与软骨退变驱动膝骨关节炎(OA)发病和进展的病理特征之一。本研究旨在确定聚集素(CLU)效应的分子机制，抗凋亡分子，人膝关节OA软骨细胞。从膝关节OA患者的软骨中分离出原代膝关节OA软骨细胞，分为五组：（1）白细胞介素（IL）-1β处理的细胞，(2)CLU单独，（3）IL-1β和CLU的组合，（4）LY294002（PI3K抑制剂）以及IL-1β和CLU，和(5)未处理的细胞。凋亡的产生，炎症，合成代谢,和分解代谢介质在膝关节OA软骨细胞的测定后24小时。我们的体外研究发现，CLU显着抑制炎症介质的产生[一氧化氮（NO），IL6和肿瘤坏死因子（TNF）-α]和凋亡分子（caspase-3，CASP3）。CLU显著上调合成代谢因子[SRY-box转录因子-9(SOX9)和聚集蛋白聚糖(ACAN)]的信使核糖核酸(mRNA)表达,但显著下调IL6、核因子κB(NF-κB)的mRNA表达,CASP3和基质金属蛋白酶-13(MMP13)。CLU的抗凋亡和抗炎作用是通过激活PI3K/Akt信号通路介导的。研究结果表明，CLU可能通过PI3K/Akt途径发挥抗凋亡和抗炎功能，对膝关节OA软骨细胞产生有益作用。使CLU成为膝关节OA潜在治疗干预的有希望的目标。
