phaidra.vetmeduni.ac.at o:4102 DOI 10.1038/s41598-025-96050-2 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. eng Dexamethasone Pharmacology Dexamethasone Therapeutic Use Chondrocytes Drug Effects Chondrocytes Metabolism Chondrocytes Pathology Osteoarthritis Drug Therapy Osteoarthritis Pathology Osteoarthritis Metabolism Humans Anti-Inflammatory Agents Pharmacology Cell Proliferation Drug Effects Triamcinolone Acetonide Pharmacology Cells, Cultured Apoptosis Drug Effects Gene Expression Regulation Drug Effects Cellular Senescence Drug Effects Glucocorticoids Pharmacology Inflammation Drug Therapy Gene Expression Profiling 2025-05-02T08:20:44.722Z LOMv1.0 Author BEGIN:VCARD VERSION:3.0 N:Tarasova;Karyna; FN:Karyna Tarasova END:VCARD BEGIN:VCARD VERSION:3.0 N:Arteaga;Maria Belen; FN:Maria Belen Arteaga END:VCARD BEGIN:VCARD VERSION:3.0 N:Kidtiwong;Angkana; FN:Angkana Kidtiwong END:VCARD BEGIN:VCARD VERSION:3.0 N:Gueltekin;Sinan; FN:Sinan Gueltekin X-ORCID:https://orcid.org/0000-0002-4962-8451 END:VCARD BEGIN:VCARD VERSION:3.0 N:Bileck;Andrea; FN:Andrea Bileck END:VCARD BEGIN:VCARD VERSION:3.0 N:Gerner;Christopher; FN:Christopher Gerner END:VCARD BEGIN:VCARD VERSION:3.0 N:Gerner;Iris; FN:Iris Gerner X-ORCID:https://orcid.org/0000-0001-6618-2669 END:VCARD BEGIN:VCARD VERSION:3.0 N:Jenner;Florien; FN:Florien Jenner X-ORCID:https://orcid.org/0000-0002-6977-1984 END:VCARD https://w3id.org/kim/hcrt/scheme https://w3id.org/kim/hcrt/text Textdokument Text LOMv1.0 yes https://creativecommons.org/licenses/by/4.0 application/pdf 3710982 https://phaidra.vetmeduni.ac.at/o:4102 https://phaidra.vetmeduni.ac.at/api/object/o:4102/thumbnail LOMv1.0 discipline