Osteoarthritis (OA) is a painful disease that causes the progressive destruction of joint structures, and is the most common cause of disability among military service members who are removed from active duty for medical reasons. In preliminary work with a small number of animals, we have found that the natural product derivative halofuginone (HF) shows promise with respect to reducing cartilage damage in the destabilized medial meniscus (DMM) mouse model of PTOA. HF inhibits glutamyl- prolylt-RNA synthetase (EPRS), the enzyme responsible for charging tRNAs with the amino acid proline. The goal of this grant is to test the hypothesis that EPRS inhibitors will provide the basis for a new therapeutic strategy for PTOA. We report here: 1) Data demonstrating that the EPRS inhibitors HF and its less toxic derivative HFol, are effective as therapeutics for PTOA in mice, using the DMM model; 2) Detailed immunohistochemical data examining the effect of HF/Hfol on effectors of OA 3) A new ex vivo assay using intact joint cartilage to test ex vivo efficacy of EPRS inhibitors as therapeutics for OA.