Cartilage Extracellular Matrix Homeostasis in Knee Osteoarthritis: Pathomechanisms and Therapeutic Targeting

ABSTRACT Knee osteoarthritis (KOA) is a degenerative joint disease primarily driven by the disruption of homeostasis in the chondrocyte extracellular matrix (CECM). This review systematically examines the central role of CECM homeostasis in KOA pathogenesis and summarizes recent advances in this field. We synthesized contemporary basic and clinical research to analyse the mechanisms underlying CECM homeostatic imbalance. These include biomechanical stress, inflammatory responses, programmed cell death (e.g., apoptosis, pyroptosis, ferroptosis), impaired autophagy, and cellular senescence. We also evaluated intrinsic risk factors and the application of related biomarkers for diagnosis and prognosis. Our analysis identifies multifaceted pathways driving CECM imbalance and highlights promising multi‐modal therapeutic strategies. These include novel pharmacological agents (e.g., high‐purity chondroitin sulphate, natural active monomers), physical and regenerative therapies (e.g., stem cells, platelet‐rich plasma), precision interventions (e.g., gene editing, RNA interference), and tissue engineering approaches (e.g., smart biomaterials, biomimetic scaffolds). The evidence demonstrates that these strategies can effectively modulate CECM metabolism, promote cartilage repair, and slow disease progression. Targeting CECM homeostasis is a core strategy for developing disease‐modifying therapies for KOA. Future efforts should focus on interdisciplinary integration, individualized precision medicine, and multi‐site synergistic interventions. This review provides a comprehensive foundation for innovating strategies to delay or reverse KOA progression by restoring CECM balance.