《生命科学》 2026, 38(4): 753-767
靶向巨噬细胞防治骨关节炎的研究进展
摘 要：
近年来，巨噬细胞在骨关节炎（osteoarthritis，OA）发生发展中的作用受到广泛关注。作为关节滑膜中最主要的免疫细胞群体，巨噬细胞具有高度可塑性，其极化失衡、焦亡异常激活、胞葬功能受损及活化状态紊乱等特征，是驱动OA关节慢性低度炎症、软骨基质降解及组织修复障碍的核心机制。尽管调控巨噬细胞在OA治疗中展现出广阔前景，但仍面临巨噬细胞异质性、时空动态性等诸多挑战。该综述系统性地总结了干预OA中巨噬细胞不同途径的研究现状，结合单细胞测序、空间转录组等前沿技术解析巨噬细胞亚群特征与功能网络，并深入探讨了损伤相关分子模式、代谢产物、力学信号等微环境因素调控巨噬细胞表型转换的分子机制，同时分析了干预巨噬细胞在治疗OA中所面临的挑战及未来发展前景，旨在为治疗OA提供新的思路与见解。
通讯作者：张晓玲 , Email:xlzhang@shsmu.edu.cn
Abstract:
Osteoarthritis (OA) represents a globally prevalent joint disorder affecting more than 654 million individuals, and its pathological essence has been reconceptualized from a mere mechanical degenerative disease of cartilage to a chronic immune mediated metabolic disorder featured by persistent lowgrade inflammation. As the most numerous and functionally plastic innate immune cells in the synovium, macrophages serve as a pivotal regulatory hub in the onset and progression of OA, thereby offering a promising target for developing disease modifying therapeutic interventions. This review is designed to systematically synthesize recent advances in macrophage targeted strategies for OA prophylaxis and treatment, dissect the core regulatory mechanisms, and address translational challenges and future perspectives. The review first delineates the ontogeny and phenotypic heterogeneity of articular macrophages, which encompass embryo-derived resident tissue macrophages and bone marrow recruited monocytes that infiltrate into synovium during inflammatory conditions. It highlights that macrophage polarization follows a continuous phenotypic spectrum rather than a simplistic M1/M2 dichotomy, and is dynamically modulated by damage associated molecular patterns, metabolites, mechanical stress, and paracrine or autocrine signaling networks. Pathologically, polarization imbalance, aberrant pyroptosis, defective efferocytosis, and uncontrolled activation of macrophages collectively trigger and sustain synovial inflammation, accelerate extracellular matrix degradation, impair tissue regeneration, and thereby promote OA progression. Furthermore, the review summarizes five major interventional approaches targeting macrophages: reprogramming macrophage polarization toward an anti-inflammatory and reparative phenotype; selectively eliminating proinflammatory macrophage subsets to avoid global immunosuppression; restraining caspase1/GSDMD dependent macrophage pyroptosis to mitigate inflammatory cascades; enhancing efferocytotic capacity to clear apoptotic debris and resolve chronic inflammation; and inhibiting abnormal macrophage activation to alleviate cartilage and subchondral lesions. Promising preclinical evidence has been obtained using nanocarriers, injectable hydrogels, stem cell secretomes, small molecular compounds, and targeted biological agents. In conclusion, although macrophage targeted therapy has demonstrated considerable potential, its clinical translation is hindered by cellular heterogeneity, spatiotemporal variability, and limited targeting specificity. Future investigations should prioritize high resolution macrophage subpopulation mapping, stimuli responsive intelligent delivery systems, metabolic and epigenetic modulation, and subtype stratified personalized regimens. Harnessing macrophages to restore immune homeostasis represents a fundamental paradigm shift in OA management and may ultimately achieve durable disease modification.
Communication Author：ZHANG Xiao-Ling , Email:xlzhang@shsmu.edu.cn
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