Wu Yuangang, Sun Kaibo, Li Mingyang, Yang Yang, Liu Yuan, Wu Limin, Ding Yang, Zeng Yi, Shen Bin
Orthopedic Research Institute and Department of Orthopedics Surgery, West China Hospital, Sichuan University, Chengdu, China.
Orthop Surg. 2025 Jun;17(6):1604-1619. doi: 10.1111/os.70035. Epub 2025 Apr 2.
Osteoarthritis (OA) is a degenerative disease characterized by cartilage abrasion and pain, affecting millions globally. However, current treatments focus on symptom management rather than modifying disease development. Recent studies have indicated that low-density lipoprotein receptor-related protein 1 (LRP1) is associated with maintaining cartilage homeostasis through its involvement in endocytosis and signaling pathways. LRP1 facilitates the removal of extracellular matrix (ECM)-degrading enzymes, including a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) and matrix metalloproteinases (MMPs), thereby protecting against excessive cartilage breakdown. However, OA cartilage shows increased shedding of LRP1, leading to reduced endocytic capacity and elevated levels of these enzymes, contributing to accelerated ECM breakdown. LRP1 is also involved in key signaling pathways, such as Wnt/β-catenin, transforming growth factor-beta (TGF-β), and nuclear factor-kappa B (NF-κB), which regulate processes like chondrocyte proliferation, apoptosis, differentiation, and autophagy. Dysregulation of these pathways, combined with impaired LRP1-mediated endocytosis, fosters a catabolic environment in osteoarthritic cartilage. Emerging therapies targeting LRP1, such as gene interventions, exosome-based therapies, and small-molecule modulators, show potential in restoring LRP1 function, reducing cartilage degradation, and promoting joint repair. This review emphasizes the significance of LRP1 in the development of OA and explores its potential as a therapeutic target for creating disease-modifying strategies to maintain joint integrity and enhance patient well-being.
骨关节炎（OA）是一种以软骨磨损和疼痛为特征的退行性疾病，全球数百万人受其影响。然而，目前的治疗方法侧重于症状管理，而非改变疾病发展进程。最近的研究表明，低密度脂蛋白受体相关蛋白1（LRP1）通过参与内吞作用和信号通路，与维持软骨内环境稳定相关。LRP1有助于清除细胞外基质（ECM）降解酶，包括含血小板反应蛋白基序的解聚素和金属蛋白酶（ADAMTSs）以及基质金属蛋白酶（MMPs），从而防止软骨过度分解。然而，骨关节炎软骨中LRP1的脱落增加，导致内吞能力下降以及这些酶水平升高，促使ECM加速分解。LRP1还参与关键信号通路，如Wnt/β-连环蛋白、转化生长因子-β（TGF-β）和核因子-κB（NF-κB），这些信号通路调节软骨细胞增殖、凋亡、分化和自噬等过程。这些信号通路失调，再加上LRP1介导的内吞作用受损，在骨关节炎软骨中形成了一种分解代谢环境。针对LRP1的新兴疗法，如基因干预、基于外泌体的疗法和小分子调节剂，在恢复LRP1功能、减少软骨降解和促进关节修复方面显示出潜力。本综述强调了LRP1在骨关节炎发展中的重要性，并探讨了其作为治疗靶点的潜力，以制定疾病修饰策略来维持关节完整性并提高患者健康水平。
