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Several non\u2010invasive mouse models mimicking human PTOA investigate molecular mechanisms of disease development; none have characterized the inflammatory response to this acute traumatic injury. Our aim was to characterize the early inflammatory phase and later degenerative component in our in vivo non\u2010invasive murine model of PTOA induced by anterior cruciate ligament (ACL) rupture. Right knees of 12\u2010week\u2010old C57Bl6 mice were placed in flexion at a 30\u00b0 offset position and subjected to a single compressive load (12N, 1.4\u2009mm\/s) to induce ACL rupture with no obvious damage to surrounding tissues. Tissue was harvested 4\u2009h post\u2010injury and on days 3, 14, and 21; contralateral left knees served as controls. Histological, immunohistochemical, and gene analyzes were performed to evaluate inflammatory and degenerative changes. Immunohistochemistry revealed time\u2010dependent expression of mature (F4\/80 positive) and inflammatory (CD11b positive) macrophage populations within the sub\u2010synovial infiltrate, developing osteophytes, and inflammation surrounding the ACL in response to injury. Up\u2010regulation of genes encoding acute pro\u2010inflammatory markers, inducible nitric oxide synthase, interleukin\u20106 and interleukin\u201017, and the matrix degrading enzymes, ADAMTS\u20104 and MMP3 was detected in femoral cartilage, concomitant with extensive cartilage damage and bone remodelling over 21\u2010days post\u2010injury. Our non\u2010invasive model describes pathologically distinct phases of the disease, increasing our understanding of inflammatory episodes, the tissues\/cells producing inflammatory mediators and the early molecular changes in the joint, thereby defining the early phenotype of PTOA. This knowledge will guide appropriate interventions to delay or arrest disease progression following joint injury. \u00a9 2018 The Authors.<jats:italic>Journal of Orthopaedic Research<\/jats:italic>\u00ae Published by Wiley Periodicals, Inc. on behalf of the Orthopaedic Research Society. 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