Revisiting the Chondrotoxicity of Intra-Articular Triamcinolone Acetonide in Osteoarthritis: Dose Dependence and Experimental Model Heterogeneity [Letter]

We have read with great interest the comprehensive review by Wan et al 1 on the efficacy and safety of intra-articular triamcinolone acetonide (TA) for osteoarthritis (OA).The authors systematically summarized its pharmacology, efficacy, and safety, providing valuable guidance for clinical practice.We commend their balanced discussion on TA-related chondrotoxicity.However, the controversy over TA's chondrotoxicity has not been fully explained by heterogeneity in existing evidence.As rehabilitation physicians routinely performing intra-articular injections, we wish to clarify this issue.Conflicting findings on TA's chondrotoxicity are primarily attributable to two key factors: heterogeneity of experimental model systems and dosedependent effects.A more granular analysis of these factors could help bridge the gap between preclinical findings and clinical practice.A major source of divergent findings lies in differences between in vitro systems.Most studies reporting significant chondrotoxicity have adopted monolayer chondrocyte cultures, in which cells are deprived of their native threedimensional extracellular matrix (ECM) environment. 2,3In contrast, when chondrocytes are maintained within intact cartilage explants-preserving the physiological ECM architecture and cellular heterogeneity-TA exerts substantially less detrimental effects.Porter et al 2 demonstrated that at physiologically relevant doses, TA had minimal negative impact on chondrocyte viability, proliferation, and ECM synthesis in full-thickness cartilage explants, even under inflammatory challenge with interleukin-1.Notably, TA not only failed to inhibit matrix synthesis but also mitigated glycosaminoglycan loss in inflamed cartilage, suggesting an anti-catabolic rather than chondrotoxic profile.Sherman et al 3 similarly reported that full-thickness cartilage explants exhibited reduced loss of cell viability compared to monolayer cultures when exposed to corticosteroids, attributing this difference to the protective effects of intact ECM and cellular heterogeneity.These consistent findings confirm that the intact ECM not only maintains chondrocyte physiology but also actively modulates their response to TA, explaining the divergent results between monolayer and explant models.The lack of physiological ECM in monolayer cultures artificially increases chondrocyte susceptibility to corticosteroids, leading to overestimation of chondrotoxic risk.Therefore, monolayer culture data should be interpreted cautiously, and explant or 3D models are preferred for preclinical safety assessment of TA.A second critical variable is the administered dose.As systematically reviewed in a landmark systematic review by Wernecke et al, 4 glucocorticoids exert time-and dose-dependent effects on articular cartilage, with beneficial antiinflammatory outcomes at lower doses or shorter durations and potential detrimental effects at higher doses or prolonged exposure.The dose-dependent effect of TA is likely related to its dual role: low doses suppress pro-inflammatory cytokines and catabolic activity, while high or repeated doses may disrupt chondrocyte metabolism and ECM synthesis.A 2023 noninferiority randomized controlled trial by Utamawatin et al 5 demonstrated that 10 mg of TA was non-inferior to 40 mg in