Ciprofloxacin Treatment in Juvenile Mice Involves Neuronal Activation and Mimics Physical Features of Human Disease.

Abstract

Tendinopathy is a complex, painful condition that affects up to 5% of the general population in their lifetime. Antibiotic treatment with fluoroquinolones has been associated with the onset of tendinopathy and tendon rupture. The mechanisms behind fluoroquinolone induced tendinopathy remain unclear. To probe activation of potentially causative pathways, we treated juvenile mice with ciprofloxacin in drinking water for 4 weeks and performed RNA sequencing on tail tendons. We discovered that ciprofloxacin-treated mice had upregulated genes relating to nerve development. Additionally, treated mice showed downregulation of genes associated with extracellular matrix (ECM) processes. We further explored ECM changes using histological and mechanical testing methods on patellar tendons. We found that ciprofloxacin treatment led to altered cell morphology and proteoglycan density. These changes translated to a decrease in mechanical properties of the patellar tendons. Furthermore, ciprofloxacin-treated mice had a higher percentage of apoptotic cells, and we confirmed increased presence of nerve cells (Plexin B1) in the patellar tendons compared to controls. Taken together, we showed that ciprofloxacin treatment in juvenile mice induces structural and biological phenotypes commonly associated with fluoroquinolone-induced tendinopathy and identify the axis of pathological neural activation as a promising area for further exploration. Clinical significance: Oral administration of ciprofloxacin in mice presents a clinically relevant model for studying mechanisms of tendinopathy in humans.