Osteoarthritis (OA) is a full-joint, multifactorial, degenerative and inflammatory disease that seriously affects the quality of life of patients due to its disabling and pain-causing properties. ER stress has been reported to be closely related to the progression of OA. The inositol-requiring enzyme 1α/X-box-binding protein-1 spliced (IRE1α/XBP1s) pathway, which is highly expressed in the chondrocytes of OA patients, promotes the degradation and refolding of abnormal proteins during ER stress and maintains the stability of the ER environment of chondrocytes, but its function and the underlying mechanisms of how it contributes to the progression of OA remain unclear. This study investigates the role of IRE1α/ERN1 in OA. Specific deficiency of ERN1 in chondrocytes spontaneously resulted in OA-like cartilage destruction and accelerated OA progression in a surgically induced arthritis model. Local delivery of AdERN1 relieved degradation of the cartilage matrix and prevented OA development in an ACLT-mediated model. Mechanistically, progranulin (PGRN), an intracellular chaperone, binds to IRE1α, promoting its phosphorylation and splicing of XBP1u to generate XBP1s. XBP1s protects articular cartilage through TNF-α/ERK1/2 signaling and further maintains collagen homeostasis by regulating type II collagen expression. The chondroprotective effect of IRE1α/ERN1 is dependent on PGRN and XBP1s splicing. ERN1 deficiency accelerated cartilage degeneration in OA by reducing PGRN expression and XBP1s splicing, subsequently decreasing collagen II expression and triggering collagen structural abnormalities and an imbalance in collagen homeostasis. This study provides new insights into OA pathogenesis and the UPR and suggests that IRE1α/ERN1 may serve as a potential target for the treatment of joint degenerative diseases, including OA.

骨关节炎（OA）是一种全关节、多因素、退行性和炎症性疾病，由于其致残和引起疼痛的特性，严重影响患者的生活质量。据报道，ER 应激与 OA 的进展密切相关。肌醇需求酶1α/X-box结合蛋白1剪接（IRE1α/XBP1s）途径在OA患者的软骨细胞中高表达，促进内质网应激期间异常蛋白的降解和重折叠，维持细胞的稳定性。软骨细胞的 ER 环境，但其功能及其如何促进 OA 进展的潜在机制仍不清楚。本研究探讨了 IRE1α/ ERN1在 OA 中的作用。在手术诱导的关节炎模型中，软骨细胞中ERN1的特异性缺陷会自发导致类 OA 软骨破坏并加速 OA 进展。在 ACLT 介导的模型中，Ad ERN1的局部递送缓解了软骨基质的降解并阻止了 OA 的发展。从机制上讲，颗粒体蛋白前体（PGRN）是一种细胞内伴侣，与 IRE1α 结合，促进其磷酸化并剪接 XBP1u 生成 XBP1。 XBP1s 通过 TNF-α/ERK1/2 信号传导保护关节软骨，并通过调节 II 型胶原蛋白表达进一步维持胶原蛋白稳态。 IRE1α/ ERN1的软骨保护作用依赖于 PGRN 和 XBP1s 剪接。 ERN1缺陷通过减少PGRN表达和XBP1s剪接加速OA中的软骨退化，随后减少II型胶原蛋白表达并引发胶原蛋白结构异常和胶原蛋白稳态失衡。 这项研究为 OA 发病机制和 UPR 提供了新的见解，并表明 IRE1α/ ERN1可能作为治疗关节退行性疾病（包括 OA）的潜在靶点。