Degenerative musculoskeletal diseases are structural and functional failures of the musculoskeletal system, including osteoarthritis, osteoporosis, intervertebral disc degeneration (IVDD), and sarcopenia. As the global population ages, degenerative musculoskeletal diseases are becoming more prevalent. However, the pathogenesis of degenerative musculoskeletal diseases is not fully understood. Previous studies have revealed that endoplasmic reticulum (ER) stress is a stress response that occurs when impairment of the protein folding capacity of the ER leads to the accumulation of misfolded or unfolded proteins in the ER, contributing to degenerative musculoskeletal diseases. By affecting cartilage degeneration, synovitis, meniscal lesion, subchondral bone remodeling of osteoarthritis, bone remodeling and angiogenesis of osteoporosis, nucleus pulposus degeneration, annulus fibrosus rupture, cartilaginous endplate degeneration of IVDD, and sarcopenia, ER stress is involved in the pathogenesis of degenerative musculoskeletal diseases. Preclinical studies have found that regulation of ER stress can delay the progression of multiple degenerative musculoskeletal diseases. These pilot studies provide foundations for further evaluation of the feasibility, efficacy, and safety of ER stress modulators in the treatment of musculoskeletal degenerative diseases in clinical trials. In this review, we have integrated up-to-date research findings of ER stress into the pathogenesis of degenerative musculoskeletal diseases. In a future perspective, we have also discussed possible directions of ER stress in the investigation of degenerative musculoskeletal disease, potential therapeutic strategies for degenerative musculoskeletal diseases using ER stress modulators, as well as underlying challenges and obstacles in bench-to-beside research.

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深入了解退行性肌肉骨骼疾病中内质网应激的潜在发病机制和治疗潜力

退行性肌肉骨骼疾病是肌肉骨骼系统的结构和功能衰竭，包括骨关节炎、骨质疏松症、椎间盘退变（IVDD）和肌肉减少症。随着全球人口老龄化，退行性肌肉骨骼疾病变得越来越普遍。然而，退行性肌肉骨骼疾病的发病机制尚不完全清楚。先前的研究表明，内质网（ER）应激是一种应激反应，当内质网的蛋白质折叠能力受损导致错误折叠或未折叠的蛋白质在内质网中积累时，就会发生这种应激反应，从而导致退行性肌肉骨骼疾病。ER应激通过影响软骨变性、滑膜炎、半月板病变、骨关节炎的软骨下骨重塑、骨质疏松症的骨重塑和血管生成、髓核变性、纤维环破裂、IVDD的软骨终板变性和肌少症等，参与退行性肌肉骨骼的发病机制。疾病。临床前研究发现，调节内质网应激可以延缓多种退行性肌肉骨骼疾病的进展。这些试点研究为临床试验中进一步评估内质网应激调节剂治疗肌肉骨骼退行性疾病的可行性、有效性和安全性奠定了基础。在这篇综述中，我们将内质网应激的最新研究成果整合到退行性肌肉骨骼疾病的发病机制中。展望未来，我们还讨论了内质网应激在退行性肌肉骨骼疾病研究中的可能方向、使用内质网应激调节剂治疗退行性肌肉骨骼疾病的潜在治疗策略，以及实验室研究中潜在的挑战和障碍。