Dexamethasone: a double-edged sword in the treatment of osteoarthritis.

Glucocorticoids are widely used to manage osteoarthritis (OA) symptoms, but long-term safety concerns exist. This study investigates the therapeutic potential of dexamethasone (DEX) and triamcinolone acetonide (TA) in chondrocytes, evaluating their anti-inflammatory effects and potential detrimental actions. This study evaluated the effects of DEX and TA on the expression of pro-inflammatory genes in inflamed chondrocytes. In addition, the effects of DEX treatment on chondrocytes were analyzed using next-generation sequencing, high-resolution mass spectrometry, proliferation and metabolic rate, wound healing capacity and senescence-associated B-galactosidase assays. A single therapeutic dose of DEX (40nM) effectively reduced the expression of inflammatory genes in chondrocytes, while TA showed no such effect. DEX significantly reduced inflammation but also ECM production in inflamed chondrocytes. At 24 h, DEX treatment led to 168 differentially expressed genes (DEGs) compared to untreated inflamed cells, decreasing to 5 DEGs by 48 h, indicating a rapidly diminishing anti-inflammatory effect. Conversely, the difference between DEX-treated and healthy cells increased over time, from 666 DEGs at 24 h to 1317 DEGs at 48 h. Pathway analysis revealed potential disruptions in cell cycle, mitosis, and ECM homeostasis in DEX-treated cells compared to both healthy and inflamed controls. Interestingly, repeated DEX administration at both a therapeutic (40nM) and a high dose (1µM) induced senescence in healthy cells but not in inflamed cells. In contrast, repeated high-dose DEX reduced apoptosis marker Caspase 3/7 in inflamed but not healthy cells. Despite the transient suppression of inflammation achieved with DEX treatment, the observed decrease in ECM production and induction of senescence in healthy chondrocytes at therapeutic doses, along with apoptosis in inflamed cells at higher doses, underscore the need for caution in its intra-articular administration.