Abstract：
Osteoarthritis (OA) is a chronic joint disease, characterized by degenerative destruction of articular cartilage. Chondrocytes, the unique cell type in cartilage, mediate the metabolism of extracellular matrix (ECM), which is mainly constituted by aggrecan and type II collagen. A disintegrin and metalloproteinase with thrombospondin 5 (ADAMTS5) is an aggrecanase responsible for the degradation of aggrecan in OA cartilage. CCAAT/enhancer binding protein β (C/EBPβ), a transcription factor in the C/EBP family, has been reported to mediate the expression of ADAMTS5. Our previous study showed that 5,7,3\',4\'-tetramethoxyflavone (TMF) could activate the Sirt1/FOXO3a signaling in OA chondrocytes. However, whether TMF protected against ECM degradation by down-regulating C/EBPβ expression was unknown. In this study, we found that aggrecan expression was down-regulated, and ADAMTS5 expression was up-regulated. Knockdown of C/EBPβ could up-regulate aggrecan expression and down-regulate ADAMTS5 expression in IL-1β-treated C28/I2 cells. TMF could compromise the effects of C/EBPβ on OA chondrocytes by activating the Sirt1/FOXO3a signaling. Conclusively, TMF exhibited protective activity against ECM degradation by mediating the Sirt1/FOXO3a/C/EBPβ pathway in OA chondrocytes.
摘要：
骨关节炎(OA)是一种慢性关节疾病,以关节软骨的退行性破坏为特征。软骨细胞,软骨中独特的细胞类型，介导细胞外基质（ECM）的代谢，主要由聚集蛋白聚糖和II型胶原构成。具有血小板反应蛋白5的整合素和金属蛋白酶（ADAMTS5）是负责OA软骨中聚集蛋白聚糖降解的聚集蛋白聚糖酶。CCAAT/增强子结合蛋白β（C/EBPβ），C/EBP家族中的转录因子，已报道介导ADAMTS5的表达。我们之前的研究表明，5,7,3\'，4'-四甲氧基黄酮（TMF）可以激活OA软骨细胞中的Sirt1/FOXO3a信号。然而,TMF是否通过下调C/EBPβ表达来防止ECM降解未知。在这项研究中,我们发现聚集蛋白聚糖表达下调，ADAMTS5表达上调。在IL-1β处理的C28/I2细胞中，敲低C/EBPβ可以上调聚集蛋白聚糖的表达并下调ADAMTS5的表达。TMF可以通过激活Sirt1/FOXO3a信号来损害C/EBPβ对OA软骨细胞的作用。最后，TMF通过介导OA软骨细胞中的Sirt1/FOXO3a/C/EBPβ途径表现出对ECM降解的保护活性。
