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PTOA progression can be exacerbated by repeated injury and systemic inflammation. Few studies have examined approaches for blunting or slowing down PTOA progression with emphasis on systemic inflammation; most arthritis studies focused on the immune system have been in the context of rheumatoid arthritis. To examine how the gut microbiome affects systemic inflammation during PTOA development, we used a chronic antibiotic treatment regimen starting at weaning for 6\u2009weeks before anterior cruciate ligament (ACL) rupture in\n                    <jats:italic>STR\/ort<\/jats:italic>\n                    mice combined with lipopolysaccharide (LPS)\u2010induced systemic inflammation.\n                    <jats:italic>STR\/ort<\/jats:italic>\n                    mice develop spontaneous OA as well as a more severe PTOA phenotype than\n                    <jats:italic>C57Bl\/6J<\/jats:italic>\n                    mice. By 6\u2009weeks post injury, histological examination showed a more robust cartilage staining in the antibiotic\u2010treated (AB)\n                    <jats:italic>STR\/ort<\/jats:italic>\n                    mice than in the untreated\n                    <jats:italic>STR\/ort<\/jats:italic>\n                    controls. Furthermore, we also examined the effects of AB treatment on systemic inflammation and found that the effects of LPS administration before injury are also blunted by AB treatment in\n                    <jats:italic>STR\/ort<\/jats:italic>\n                    mice. The AB\u2010 or AB+LPS\u2010treated\n                    <jats:italic>STR\/ort<\/jats:italic>\n                    injured joints more closely resembled the\n                    <jats:italic>C57Bl\/6J<\/jats:italic>\n                    VEH OA phenotypes than the vehicle\u2010 or LPS\u2010treated\n                    <jats:italic>STR\/ort<\/jats:italic>\n                    , suggesting that antibiotic treatment has the potential to slow disease progression and should be further explored therapeutically as prophylactic post injury. \u00a9 2023 The Authors.\n                    <jats:italic>JBMR Plus<\/jats:italic>\n                    published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.\n                  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