Primary Osteoarthritis Early Joint Degeneration Induced by Endoplasmic Reticulum Stress Is Mitigated by Resveratrol
Primary Osteoarthritis Early Joint Degeneration Induced by Endoplasmic Reticulum Stress Is Mitigated by Resveratrol
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白藜芦醇可减轻内质网应激引起的原发性骨关节炎早期关节退变
DOI：
10.1016/j.ajpath.2021.05.016
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发表时间：
2021-08-20
影响因子：
6
通讯作者：
Posey, Karen L.
中科院分区：
文献类型：
--
作者：
Hecht, Jacqueline T.;Veerisetty, Alka C.;Posey, Karen L.
由于衰老和肥胖，越来越多的人患有骨关节炎，迫切需要有效的治疗和预防。OA的两个最大风险因素，年龄和肥胖，与内质网(ER)压力有关。建立内质网应激驱动的原发性骨性关节炎模型I-ERS小鼠，研究内质网应激在骨性关节炎易感性中的作用。I-ERS小鼠具有独特的能力，可以在健康的成人关节软骨细胞和软骨中诱导内质网应激，推动关节退变，模拟早期原发骨性关节炎。在本研究中，内质网应激诱导的损伤逐渐发生，并刺激关节退变，其特征包括基质金属蛋白酶活性增加、炎症、衰老、软骨细胞死亡、蛋白多糖减少、自噬障碍和步态功能障碍。与人类骨性关节炎一样，剧烈运动加速并增加了内质网应激诱导的关节损伤水平。值得注意的是，关键的内质网应激反应蛋白(CHOP)的丢失在很大程度上改善了内质网应激刺激的骨性关节炎的结果，包括保留蛋白多糖含量、减少炎症和解除自噬障碍。白藜芦醇通过减少CHOP、TNFa、IL-1b、MMP-13、pS6、TUNEL阳性软骨细胞数和衰老标记物p16INK4a而减轻内质网应激诱导的关节退变。这一发现，即膳食补充剂可以防止内质网应激诱导的小鼠关节退行性变，为潜在地为那些患有骨性关节炎的高危人群制定预防策略提供了临床前基础。(Am J Pathol2021年，19116241637；https：//doi.org/10.1016/j.ajpath.2021.05.016)
Increasing numbers of people are living with osteoarthritis (OA) due to aging and obesity, creating an urgent need for effective treatment and preventions. Two top risk factors for OA, age and obesity, are associated with endoplasmic reticulum (ER) stress. The I-ERS mouse, an ER stress-driven model of primary OA, was developed to study the role of ER stress in primary OA susceptibility. The I-ERS mouse has the unique ability to induce ER stress in healthy adult articular chondrocytes and cartilage, driving joint degeneration that mimics early primary OA. In this study, ER stress-induced damage occurred gradually and stimulated joint degeneration with OA characteristics including increased matrix metalloproteinase activity, inflammation, senescence, chondrocyte death, decreased proteoglycans, autophagy block, and gait dysfunction. Consistent with human OA, intense exercise hastened and increased the level of ER stress-induced joint damage. Notably, loss of a critical ER stress response protein (CHOP) largely ameliorated ER stress-stimulated OA outcomes including preserving proteoglycan content, reducing inflammation, and relieving autophagy block. Resveratrol diminished ER stress -induced joint degeneration by decreasing CHOP, TNFa, IL-1b, MMP-13, pS6, number of TUNEL-positive chondrocytes, and senescence marker p16 INK4a. The finding, that a dietary supplement can prevent ER stressed-induced joint degeneration in mice, provides a preclinical foundation to potentially develop a prevention strategy for those at high risk to develop OA. (Am J Pathol 2021, 191: 1624-1637; https:// doi.org/10.1016/j.ajpath.2021.05.016)