Osteoarthritis (OA) is a prevalent age-associated joint disease marked by progressive cartilage loss, subchondral bone remodeling, osteophyte formation, and low-grade inflammation. In OA, articular chondrocytes shift from a stable extracellular matrix (ECM)-maintaining state toward a hypertrophy-like program with increased collagen type X alpha 1 chain (COL10A1), runt-related transcription factor 2 (RUNX2), and matrix metalloproteinase 13 (MMP-13), promoting ECM degradation, calcification, and pro-angiogenic remodeling. Ageing lowers the threshold for this conversion by reshaping stress responses and signaling through senescence and the senescence-associated secretory phenotype (SASP), oxidative stress, mitochondrial dysfunction, impaired autophagy, and epigenetic drift. Context-dependent modules including Wnt/β-catenin, transforming growth factor-β and bone morphogenetic protein (TGF-β and BMP), Indian hedgehog and parathyroid hormone-related protein (IHH and PTHrP), hypoxia-inducible factor 1α and hypoxia-inducible factor 2α (HIF-1α and HIF-2α), Notch, nuclear factor κB (NF-κB), and metabolic regulators such as fibroblast growth factor 19 (FGF19) and AMP-activated protein kinase (AMPK) interact and converge on shared executors. We synthesize primary mechanistic evidence using a trigger, gate, and executor framework that highlights crosstalk and convergence, and we critically appraise in vivo, ex vivo, and three-dimensional in vitro platforms, emphasizing age mismatch as a major translational bias. We also evaluate therapeutic strategies and constraints that determine clinical interpretability, including cartilage-restricted delivery, patient stratification, and mechanism-aligned structural and molecular outcome metrics alongside symptom assessment. This evidence-tiered network perspective positions chondrocyte hypertrophy as a tractable phenotype-level node for advancing disease-modifying OA drugs (DMOADs).
