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Objectives A major hurdle in osteoarthritis (OA) research is the lack of sensitive detection and monitoring methods. It is hypothesized that proteases, such as matrix metalloproteinases (MMPs), are upregulated at early stages of OA development. The aim of this study was to investigate if a near infrared fluorescence (NIRF) probe activated by MMPs could visualize in vivo OA progression starting from its early stages. Methods Using an MMP activatable NIRF probe (MMPSense680), we assessed the upregulation of MMP activity in vitro by incubating human chondrocytes with the pro-inflammatory cytokine IL-1β. MMP activity was then evaluated in vivo serially in a chronic, injury-induced OA mouse model. For tracking MMP activity over time, mice were imaged 1 – 8 weeks post OA inducing surgery. Imaging results were correlated with histology. Results In vitro studies confirmed that NIRF imaging could identify enhanced MMP activity in IL-1β-treated human chondrocytes. In vivo imaging showed significantly higher fluorescent intensity in OA knees compared to sham knees (control) of the same mice. Additionally, the total emitted fluorescence intensity steadily increased over the entire course of OA progression that was examined. NIRF imaging results correlated with histological analysis, which showed an increase in articular cartilage structural damage over time. Conclusions Imaging of MMP activity in an OA mouse model provided sensitive and consistent visualization of OA progression, beginning from the early stages of OA. In addition to facilitating the preclinical study of OA modulators, this approach has the potential for future human translation.

Background:The molecular mechanisms for islet ␤-cell compensation and failure are not fully known. Results: FoxO1/PPAR␥ signaling regulates key ␤-cell genes, with this network being up-regulated in nondiabetic insulinresistant rats and impaired in rodents with diabetes. Conclusion: We examine the potential for the FoxO1/PPAR␥ network as a feature of ␤-cell compensation and failure. Significance: We identify targets for prevention of type 2 diabetes.