title: Synergistic effects of dexamethasone and quinolones on human-derived tendon cells.
abstract: Quinolones and glucocorticoids are frequently used drugs that may cause tendinopathy as a rare adverse effect. We exposed human tenocyte cultures to the steroid dexamethasone alone or in combination with either ciprofloxacin or levofloxacin at concentrations of 3mg/L and 10mg/L. At concentrations corresponding to peak levels in plasma and tissues during therapy (ca. 3-10mg/L), ciprofloxacin caused a significant decrease in collagen type I and the beta(1)-integrin receptor. In contrast, no corresponding effect was induced by 3mg/L levofloxacin. With both quinolones at 3mg/L and 10mg/L, the amount of matrix metalloproteinase-1 (MMP-1) and MMP-13 was increased. In addition, 3mg/L ciprofloxacin and 10mg/L levofloxacin activated caspase-3. Apoptotic changes were confirmed by electron microscopy. Incubation of human tenocytes with dexamethasone decreased the main matrix protein collagen type I, the transmembrane beta(1)-integrin receptor and the cytoskeleton protein vinculin, but only at the high concentrations tested (0.1 microM or 10 microM). Concentrations of 0.1 microM and 10 microM dexamethasone increased the amount of MMPs and activated caspase-3 as an indicator of apoptosis. Combined exposure to quinolones and dexamethasone led to more pronounced effects in tenocyte cultures at most of the analysed endpoints. The clinical observations of an increased risk of quinolone-induced tendinopathy by glucocorticoids are supported by these in vitro data.
authors.affiliation: Institute of Clinical Pharmacology and Toxicology, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Garystr. 5, 14195 Berlin, Germany.
authors.forename: Judith
authors.initials: J
authors.lastname: Sendzik
authors.forename: Mehdi
authors.initials: M
authors.lastname: Shakibaei
authors.forename: Monika
authors.initials: M
authors.lastname: Schäfer-Korting
authors.forename: Hartmut
authors.initials: H
authors.lastname: Lode
authors.forename: Ralf
authors.initials: R
authors.lastname: Stahlmann
mesh_terms: D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000633:toxicity*; D000893:Anti-Inflammatory Agents / Q000009:adverse effects / Q000633:toxicity*; D017209:Apoptosis; D002460:Cell Line; D024042:Collagen Type I / Q000096:biosynthesis; D003907:Dexamethasone / Q000633:toxicity*; D015536:Down-Regulation; D006801:Humans; D019012:Integrin beta1 / Q000096:biosynthesis; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis; D053509:Matrix Metalloproteinase 13 / Q000096:biosynthesis; D015363:Quinolones / Q000633:toxicity*; D013710:Tendons / Q000187:drug effects*; D015854:Up-Regulation
chemical_list: D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D024042:Collagen Type I; D019012:Integrin beta1; D015363:Quinolones; D003907:Dexamethasone; D053509:Matrix Metalloproteinase 13; D020781:Matrix Metalloproteinase 1