PROJECT SUMMARY/ABSTRACT Despite the tremendous public health burden of OA, trials have largely been negative to date and there are no effective approved treatments that can prevent structural progression. There is increasing interest in refining the phenotype of people enrolled into OA trials to better match the known mechanisms of the interventions to relevant patients to increase likelihood of successfully detecting treatment effects. Vitamin K is a promising therapeutic option in knee OA given its association with structural outcomes, and the high prevalence of inadequate dietary vitamin K intake among older adults. Prior work has demonstrated associations between lower vitamin K levels and cartilage loss on knee MRI. Whether the vitamin K-dependent matrix Gla protein (MGP), which functions to inhibit bone and cartilage mineralization when activated, may provide insights into how vitamin K affects OA structure is not known. Further, whether MGP could be used as a biomarker of vitamin K’s effects on structural outcomes to potentially reduce trial durations merits investigation. Beyond the impact of lower vitamin K levels on structural OA outcomes, an improved understanding of its impact on clinical outcomes, including pain and physical function, is needed as vitamin K supplementation may be an effective intervention targeting both symptoms and structure. Finally, although there is increasing interest in testing vitamin K supplementation in OA trials, the appropriate form and dosing have not been determined, nor what therapeutic threshold needs to be targeted to obtain anticipated beneficial effects. I will leverage data collected in the Multicenter Osteoarthritis Study, including previously collected knee radiographs and MRIs and stored blood biospecimens to evaluate the following: 1) blood thresholds of vitamin K associated with increased risk of structural OA outcomes (cartilage damage, bone marrow lesions, and synovitis), and the role of MGP as an intermediate in this pathway to assess its potential as a serum biomarker; 2) association of vitamin K levels and MGP on knee pain and physical function in knee OA; and blood thresholds of vitamin K associated with increased risk of poor clinical outcomes. As a third aim, I will perform a pilot trial testing different forms and dosing of vitamin K supplementation on plasma levels of vitamin K and inactive MGP in older adults with knee OA. These proposed studies are innovative as they will provide novel insights into the relationships between vitamin K levels and both structural and symptomatic outcomes. The proposed research is significant as these insights would lay the foundation for identifying an important phenotype (those with lower vitamin K levels) for testing a potential intervention (vitamin K supplementation) for OA structure and/or symptom modification. This project will importantly provide the necessary protected time, essential training, and mentorship to support my transition to beco...