ABSTRACT Knee osteoarthritis (OA) is the leading cause of disability in adults, with a substantial fiscal impact. Furthermore, patellofemoral joint OA is a major source of pain and dysfunction. A hypothetical model for OA pathogenesis has been proposed whereby repetitive joint loading causes an initial increase in bone remodeling, which is associated with increased vascular invasion of the deep layers of cartilage. Emerging Proton Emission Tomography and Magnetic Resonance Imaging simultaneous systems (PET-MRI) offer an exciting new modality to simultaneously acquire numerous functional measures as well as high-resolution morphology to study this complex phenomenon. Joint loading is integral to OA progression yet currently, very little is known regarding the biomechanical factors associated with PFJOA progression. Therefore, our overall goal is to: (i) identify cross- sectional and longitudinal local patterns of cartilage and bone interactions unique to PFJOA, and (ii) determine the mediation effects of gait biomechanics and bone morphology on PFJOA progression. We will conduct a longitudinal cohort study investigating 100 people with isolated PFJOA, followed for 2 time points. Simultaneous PET-MRI and gait biomechanics will be collected for all subjects at baseline and 2-year follow-up. Aim 1: To study the cross-sectional relationships between bone and cartilage imaging biomarkers and to investigate how the patterns of interactions are mediated by gait biomechanics and bone morphology. Hypothesis 1: Elevated SUV in subjects with PFJOA will be colocalized with prolongation of T1ρ and T2 relaxation times. Complex bone-cartilage interactions mediated by change in loading as a result of abnormal gait biomechanics and bone morphology will show non-colocalized associations between bone and cartilage. Aim 2: To study the longitudinal relationships between bone and cartilage imaging biomarkers and to investigate how the patterns of interactions are mediated by gait biomechanics and morphology: Hypothesis 2: Early changes in bone metabolic activity (SUV) are a precursor to cartilage compositional changes (T1ρ and T2). Subjects with specific abnormal gait biomechanics and bone shape features will show accelerated compositional changes. Aim 3: To determine the ability of bone-cartilage interactions to predict longitudinal trajectories of structural and symptomatic PFJOA progression. Hypothesis 3: Both colocalized and non-colocalized bone-cartilage interaction patterns mediated by joint biomechanics and bone shape will be significant predictors of structural and symptomatic PJOA progression. Cross-sectional and longitudinal evaluations of cartilage composition and bone remodeling mediated by gait biomechanics as likely contributors to PFJOA progression, are vital to determine the individual and combined effects of the disease.