破骨细胞在骨关节炎中的作用及其调控机制

The Role of Osteoclasts in Osteoarthritis and Their Regulatory Mechanisms

摘要: 骨关节炎(Osteoarthritis, OA)是全球最常见的关节疾病，其发病机制复杂，涉及多种致病因素，导致治疗效果常不理想。经过多年的研究与探索，学者们逐渐认识到软骨下骨在OA发病中的关键作用。研究表明，在关节软骨病变显现之前，软骨下骨已发生显著的病理变化。作为调控骨吸收的主要细胞，破骨细胞在软骨下骨的病理过程中发挥着至关重要的作用。软骨下破骨细胞通过分泌降解酶、参与免疫调节以及调控细胞信号通路，维持软骨下骨的稳态。然而，在OA病理状态下，破骨细胞活性受到自噬、RANKL/RANK/OPG信号通路、炎症信号通路以及非编码RNA (ncRNA)等的异常激活，导致骨吸收过度，破坏了骨重塑的动态平衡，引发软骨下骨质流失、骨密度下降，继而导致关节软骨结构损伤和关节疼痛的加剧。随着骨生物学和靶向治疗研究的深入，学者们发现软骨下破骨细胞的活性和功能受多种途径的精细调控。本文系统综述了软骨下破骨细胞在OA中的作用机制，并总结了针对其功能特性开发的最新治疗进展。展望未来，软骨下破骨细胞靶向治疗在临床应用中的发展趋势备受关注。这一领域的研究旨在填补当前OA治疗知识的空白，为制定创新的治疗策略提供科学依据。

Abstract: Osteoarthritis (OA) is the most common joint disease worldwide, characterized by a complex pathophysiology involving multiple pathogenic factors, which often leads to suboptimal treatment outcomes. After years of research and exploration, the pivotal role of the subchondral bone in OA pathogenesis has been increasingly recognized. Studies have demonstrated that significant pathological alterations occur in the subchondral bone prior to the manifestation of articular cartilage lesions. As the primary cells responsible for regulating bone resorption, osteoclasts play a crucial role in the pathological processes within the subchondral bone. Subchondral osteoclasts maintain bone homeostasis through the secretion of degrading enzymes, participation in immune regulation, and modulation of cellular signaling pathways. However, under OA pathological conditions, osteoclast activity is aberrantly activated by mechanisms such as autophagy, the RANKL/RANK/OPG signaling pathway, inflammatory signaling pathways, and non-coding RNAs (ncRNAs). This aberrant activation leads to excessive bone resorption, disrupts the dynamic balance of bone remodeling, and subsequently induces subchondral bone loss, reduced bone density, structural damage to the articular cartilage, and exacerbation of joint pain. With advances in bone biology and targeted therapy research, it has been revealed that the activity and function of subchondral osteoclasts are finely regulated by multiple pathways. This article systematically reviews the mechanisms of action of subchondral osteoclasts in OA and summarizes recent therapeutic advances developed to target their functional properties. Looking forward, the development trends of subchondral osteoclast-targeted therapies for clinical application are of significant interest. Research in this field aims to address current gaps in knowledge regarding OA treatment and provide a scientific basis for developing innovative therapeutic strategies.