软骨细胞凋亡被认为是导致膝骨关节炎（OA）发生和进展的软骨退变的病理特征之一。本研究旨在确定抗凋亡分子簇蛋白 (CLU) 在人膝骨关节炎软骨细胞中作用的分子机制。从膝骨关节炎患者的软骨中分离出原代膝骨关节炎软骨细胞，并将其分为五组：（1）用白细胞介素（IL）-1β处理的细胞，（2）单独的CLU，（3）IL-1β和CLU的组合、(4) LY294002（PI3K 抑制剂）以及 IL-1β 和 CLU，以及 (5) 未经处理的细胞。治疗 24 小时后测定膝 OA 软骨细胞中凋亡、炎症、合成代谢和分解代谢介质的产生。我们的体外研究发现，CLU 显着抑制炎症介质 [一氧化氮 (NO)、IL6 和肿瘤坏死因子 (TNF)-α] 和凋亡分子（caspase-3、CASP3）的产生。 CLU 显着上调合成代谢因子 [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，但显着下调 IL6、核因子 kappa-B (NF-κB)、 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 通路发挥抗凋亡和抗炎功能，对膝关节 OA 软骨细胞产生有益影响，使 CLU 成为膝关节 OA 潜在治疗干预的有希望的靶标。© 2024 作者。 《临床和转化科学》由 Wiley periodicals LLC 代表美国临床药理学和治疗学会出版。

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.© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.