Immune–chondrocyte ligand–receptor axes in osteoarthritis: microenvironmental control of inflammation, matrix remodeling, and chondrocyte fate

Abstract

Osteoarthritis (OA) is increasingly recognized as a whole-joint disease shaped by chronic low-grade inflammation, matrix damage, mechanical stress, and failed tissue repair. Beyond the traditional view of cartilage wear, emerging evidence indicates that immune–chondrocyte ligand–receptor (LR) communication plays a central role in translating microenvironmental cues into disease-relevant chondrocyte phenotypes. In this narrative review, we summarize major immune-derived or inflammation-amplified LR axes that regulate OA progression, including cytokine pathways such as IL-1β–IL-1R, TNF-α–TNFR, IL-6–IL-6R/gp130, and IL-17–IL-17R; chemokine axes such as CXCL12–CXCR4 and CCL2–CCR2; DAMP–PRR pathways involving HMGB1, S100A8/A9, TLRs, and RAGE; and ECM-associated signaling through CD44 and integrins. These axes collectively drive chondrocyte catabolic activation, hypertrophic differentiation, senescence, inflammatory cell death, autophagy dysfunction, and impaired matrix repair. We further discuss how single-cell sequencing, spatial transcriptomics, multiplex imaging, and computational LR inference are redefining OA as a spatially organized disorder of immune–chondrocyte and multicellular joint communication. Finally, we highlight therapeutic opportunities, including receptor-level modulation, macrophage reprogramming, local intra-articular delivery, and LR-axis-based patient stratification. Understanding immune–chondrocyte LR networks may enable precision strategies that suppress pathological inflammation while preserving repair-oriented signaling in OA.