PROJECT SUMMARY/ABSTRACT Osteoarthritis (OA) costs more than $81 billion per year in the United States, a burden similar to cancer. OA most commonly affects the knee joint and is associated with increased mortality. There are currently no effective therapies to prevent or treat this serious disease. Patellofemoral (PF) OA, which refers to OA in the PF joint, is a distinct subgroup of knee OA with substantial morbidity and is present in 39% of individuals with knee pain. Anterior knee pain (AKP) is one of the most common chronic pain conditions across the lifespan. AKP is persistent and affects a person?s function and quality of life. AKP and PFOA may represent a continuum of PF disease. However, longitudinal data is lacking on the relation of AKP to incident PFOA. By identifying risk factors for AKP, we could not only reduce the burden of this common condition, but potentially alter the natural history of knee pain and OA. The current proposal aims to understand risk factors for AKP and the relation of AKP to incident PFOA and functional limitations. Understanding risk factors for AKP in can improve clinicians? abilities to address these symptoms and slow their progression. We will leverage data from the NIH-funded Multicenter Osteoarthritis (MOST) study to answer our proposed research questions. In the recent renewal of MOST, a cohort without established OA was recruited. This offers us a tremendous opportunity to study AKP and PFOA development, which is the first key step in identifying targets for rehabilitation strategies. MOST is the only large cohort in the world that has the necessary longitudinal data on knee pain location, functional limitations, potential modifiable risk factors that may influence PF joint loading, and PF joint imaging with OA features assessed, making our proposal feasible by leveraging this rich resource. Our specific aims are as follows: Aim 1: Determine the extent to which modifiable risk factors (e.g., lower extremity strength, gait mechanics, PF alignment, body mass index) are associated with prevalent and incident AKP over 2 years; Aim 2: Determine the relation of AKP to incident PFOA and functional limitations over 2 years. The proposed research is highly significant in that it will identify modifiable risk factors for AKP development and its downstream effects (e.g., PFOA, tibiofemoral OA, TKR). It is innovative in that, instead of taking the typical approach of managing disease after it occurs, the current proposal will allow us to develop strategies to intervene when we have the potential for the greatest impact on changing the natural history of PF disease, and subsequently minimizing the burden of OA.