Section of Molecular Medicine, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota, USA.
FASEB J. 2023 Sep;37(9):e23133. doi: 10.1096/fj.202201700RR.
Pathways leading to osteoarthritis (OA) are diverse depending on the risk factors involved; thus, developing OA therapeutics has been challenging. Here we report that nuclear protein-1 (Nupr1), a stress-inducible protein/transcription factor, is activated by pathways associated with obesity and aging in chondrocytes. Treatment of human chondrocytes with free fatty acids (palmitate and oleate; a model for high-fat diet/obesity) induced PERK signaling and increased expression of caspase-3, TRB3, and Nupr1. On the other hand, treatment of chondrocytes with menadione (oxidative stress inducer) induced oxidation of IRE1, activated antioxidant response (higher Nrf2 expression), and increased expression of Nupr1 and matrix metalloproteinases. Experimental OA was induced by destabilization of the medial meniscus (DMM) in the knee joints of Nupr1 and Nupr1 mice. Loss of Nupr1 expression reduced the severity of cartilage lesions in this model. Together, our findings suggest that Nupr1 is a common factor activated by signaling pathways activated by obesity (ER stress) and age (oxidative stress) and a potential drug target for OA resulting from various risk factors.
导致骨关节炎（OA）的途径因涉及的危险因素而异；因此，开发 OA 治疗方法一直具有挑战性。在这里，我们报告核蛋白-1（Nupr1），一种应激诱导蛋白/转录因子，在软骨细胞中由与肥胖和衰老相关的途径激活。用游离脂肪酸（棕榈酸和油酸；高脂肪饮食/肥胖模型）处理人软骨细胞可诱导 PERK 信号转导，并增加 caspase-3、TRB3 和 Nupr1 的表达。另一方面，用 menadione（氧化应激诱导剂）处理软骨细胞可诱导 IRE1 的氧化，激活抗氧化反应（更高的 Nrf2 表达），并增加 Nupr1 和基质金属蛋白酶的表达。通过膝关节内侧半月板（DMM）不稳定在 Nupr1 和 Nupr1 小鼠中诱导实验性 OA。Nupr1 表达的丧失降低了该模型中软骨损伤的严重程度。总之，我们的研究结果表明，Nupr1 是由肥胖（内质网应激）和年龄（氧化应激）激活的信号通路激活的共同因素，也是由各种危险因素引起的 OA 的潜在药物靶点。
