Purpose: Although the etiology of osteoarthritis (OA) is unknown, it is often associated with joint injuries. For example, ∼50% of people with knee injuries, such as an ACL tear, develop post traumatic osteoarthritis (PTOA) within 10-20 years. Immediately upon injury, the mechanical damage causes cell death and physical damage to the surrounding tissues. This is followed by an acute cellular response, which occurs within a time-scale of minutes to hours. Based on studies of injury in other tissues, the acute response phase is characterized by the release of inflammatory mediators, including IL-1, IL-6, and TNFa. In chondrocytes, exposure to these cytokines can cause the transcriptional activation of primary response genes (or inflammatory genes), and lead to increased production of matrix degrading enzymes such as MMPs, collagenases and aggrecanases. This enzymatic degradation of matrix contributes to OA via a cascade of destructive events. We believe that a window for therapeutic intervention exists shortly after injury, during which attenuating the acute cellular response will decrease the production of matrix degrading enzymes and thus decrease the likelihood of developing PTOA. The acute cellular response within hours of knee injury has not been studied in detail in a mouse model. We have developed a non-invasive knee injury mouse model, in which the knee joint is injured by a single mechanical compression. These mice consistently develop osteoarthritis in the injured knees within 2-3 months. We examined the temporal expression of IL-1b, IL-6, and TNFa and their downstream target MMP13. Our study characterizes the temporal changes in gene expression shortly after knee trauma and identifies a window of opportunity for therapeutic intervention. Methods: The acute cellular response within hours of knee injury has not been studied in detail in a mouse model. We have developed a non-invasive knee injury mouse model, in which the knee joint is injured by a single mechanical compression. These mice consistently develop osteoarthritis in the injured knees within 2-3 months. We examined the temporal expression of IL-1b, IL-6, and TNFa and their downstream target MMP13. Our study characterizes the temporal changes in gene expression shortly after knee trauma and identifies a window of opportunity for therapeutic intervention. Results: IL-6 mRNA expression peaked at 8-hours (∼8.5-fold over control) and returned to base line at 3-day post-injury (Fig. 2). IL-6 Receptor expression was detectable in all samples but remained largely unchanged relative to control. On the other hand, IL-1b mRNA increased only slightly (∼1.6-fold) but significantly at 8 and 24 hours post-injury and also returned to base line after 3 days. Unexpectedly, the expression of MMP13, which degrades cartilage matrix and is a downstream target of IL-1b and TNFa, showed no significant change. In contrast, TNFa expression did not change significantly throughout the entire 7-days time course. Taken together, results from our mouse PTOA model indicated that IL-6 mRNA is transiently but markedly elevated in cartilage/sub-chondral bone tissues shortly after knee injury. Conclusions: IL-6 may play an important role in the acute phase response to joint injury and the subsequent development of PTOA. IL-6 has been shown by others to activate various signal pathways that cause cartilage destruction, sub-chondral bone remodeling, and osteoarthritis (Fig. 3).View Large Image Figure ViewerDownload Hi-res image Download (PPT)View Large Image Figure ViewerDownload Hi-res image Download (PPT)