Pathogenesis and therapeutic strategies of osteoarthritis: roles of immune cells, inflammatory mediators, and pathogenic signaling pathways
Zhenglin He, Hanming Hao, Baoer Chen, Xuechao Li, Dezhi Mao, Yi Jin, Kai Zhao, Guanyu Chen
Abstract
Osteoarthritis (OA), the leading global cause of joint-related disability, is increasingly viewed as an immune-mediated disorder rather than mere mechanical wear-and-tear. Yet how resident and infiltrating immune cells, inflammatory mediators and dysregulated signaling networks act in concert to perpetuate synovitis, erode cartilage and remodel subchondral bone remains a central enigma. This review dissects the cellular and molecular choreography underlying OA pathology. We detail how macrophages, dendritic cells (DCs), neutrophils, mast cells (MCs), natural killer cells (NK cells), T cells, and B cells orchestrate destructive immune-bone crosstalk within the joint microenvironment. Key inflammatory mediators such as tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta (TGF-β), interleukins (e.g., interleukin (IL)-1β, IL-6), and chemokines sustain this inflammatory loop, further perpetuating inflammation and cartilage damage. Dysregulated signaling pathways, such as nuclear factor-kappa B (NF-κB) and Wingless-type (Wnt)/β-catenin, are coordinated with inflammatory mediators, thereby contributing to the pathophysiology of OA. Beyond mechanism, we critically evaluate cutting-edge therapeutic strategies targeting these osteoimmunological and molecular mechanisms, such as immunomodulatory therapy, mesenchymal stem cell (MSC) therapy and small-molecule pathway inhibitors. Preclinical successes underscore the feasibility of targeting immune-signaling axes to halt or reverse OA progression. By elucidating these mechanisms and therapeutic targets, this review aims to advance the development of disease-modifying therapies and improve outcomes for OA patients.