Effects of fluoroquinolone antibiotics on extracellular matrix-related phenotypes in tendon cells

Fluoroquinolones (FQ) are amongst the most widely prescribed antibiotics used to treat a wide range of infections because of their excellent gastrointestinal absorption, superior tissue penetration and broad-spectrum activity. However, FQs can cause rare, though serious, collagen-associated adverse reactions, including tendinopathy, and there is still no clear framework for understanding the phenotypes relating to how tenocyte-produced extracellular matrix (ECM) and related molecules change in response to FQs. Here, we show carrier-mediated intracellular uptake of the FQ ciprofloxacin by mouse tendon cells in vitro. FQ antibiotics downregulated not only the production of the main component of tendon ECM, type I collagen, but also its assembly capacity and hydroxyproline content, which was accompanied by reduced fibronectin production. Treatment of tendon cells with ciprofloxacin downregulated the enzymatic activity of lysyl oxidase and the stiffness and diameter of collagen fibrils in vitro. Furthermore, ciprofloxacin-treated tendon cells exhibited decreased expression of active β1-integrin, the key ECM receptor. Thus, the reduction in fibronectin production and active β1-integrin expression support the notion that anoikis could be the pathological basis for FQ-induced tendinopathy together with adverse phenotypes that involve type I collagen.