Pharmacological blockade of PCAF ameliorates osteoarthritis development via dual inhibition of TNF-α-driven inflammation and ER stress
Pharmacological blockade of PCAF ameliorates osteoarthritis development via dual inhibition of TNF-α-driven inflammation and ER stress
复制标题
PCAF 的药理学阻断通过双重抑制 TNF-α 驱动的炎症和 ER 应激改善骨关节炎的发展
DOI：
10.1016/j.ebiom.2019.10.054
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发表时间：
2019-12-01
期刊：
影响因子：
11.1
通讯作者：
Pan, Xiaoyun
中科院分区：
文献类型：
--
作者：
Chen, Deheng;Lu, Di;Pan, Xiaoyun
背景：据报道，表观遗传机制在骨关节炎（OA）的发展中起关键作用。P300/ cbp相关因子（PCAF）是组蛋白乙酰转移酶的一员，与内质网（ER）应激和转录因子核因子κ B （nf - κ B）信号密切相关。红景天苷是一种天然的组蛋白乙酰化抑制剂，在脂多糖刺激的小胶质细胞中显示出抗炎和抗凋亡的作用。然而，Sal是否对OA具有保护作用尚不清楚，其与PCAF、NF-kappa B和内质网应激途径的关系有待进一步探讨。方法：我们确定了PCAF在OA发病机制中的作用，并确定了Sal对肿瘤坏死因子α (tnf - α)处理的人软骨细胞和不稳定的内侧半月板（DMM）小鼠OA模型的软骨保护作用。结果：我们发现PCAF在人OA软骨和tnf - α驱动的软骨细胞中的表达增加。同时，PCAF的沉默降低了tnf刺激下软骨细胞中核p65和C/EBP同源蛋白的水平。此外，Sal被发现特异性结合PCAF蛋白结构的抑制位点，随后逆转tnf α诱导的nf - κ B信号激活和内质网应激相关的软骨细胞凋亡。此外，我们还在小鼠DMM模型中观察了Sal对PCAF以及炎症和内质网应激相关标志物的保护作用和抑制作用。解释：Sal通过抑制炎症和内质网应激来阻断PCAF，改善OA的发展，这使Sal成为治疗OA的有希望的药物。(C) 2019作者。Elsevier B.V.出版
Background: Epigenetic mechanisms have been reported to play key roles in osteoarthritis (OA) development. P300/CBP-associated factor (PCAF) is a member of the histone acetyltransferases, which exhibits a strong relationship with endoplasmic reticulum (ER) stress and transcription factor nuclear factor kappa B (NF-kappa B) signals. Salidroside, a natural histone acetylation inhibitor, showed its anti-inflammatory and anti-apoptotic effects in lipopolysaccharide (LPS)-stimulated microglia cells in our previous study. However, whether Sal has a protective effect against OA remains unknown, and its relationships to PCAF, NF-kappa B, and the ER stress pathway should be explored further.Methods: We identified the role of PCAF in the pathogenesis of OA and determined the chondroprotective effect of Sal on both tumor necrosis factor alpha (TNF-alpha)-treated human chondrocytes and a destabilized medial meniscus (DMM) mouse OA model.Findings: We found increased PCAF expression in human OA cartilage and TNF-alpha-driven chondrocytes. Meanwhile, silencing of PCAF attenuated nuclear p65 and C/EBP homologous protein levels in chondrocytes upon TNF-astimulation. Furthermore, Sal was found to specifically bind to the inhibitory site of the PCAF protein structure, which subsequently reversed the TNF-alpha-induced activation of NF-kappa B signal and ER stress-related apoptosis in chondrocytes. In addition, the protective effect of Sal and its inhibitory effects on PCAF as well as inflammatory- and ER stress-related markers were also observed in the mouse DMM model.Interpretation: Pharmacological blockade of PCAF by Sal ameliorates OA development via inhibition of inflammation and ER stress, which makes Sal a promising therapeutic agents for the treatment of OA. (C) 2019 The Author(s). Published by Elsevier B.V.