PROJECT SUMMARY Osteoarthritis (OA) is a leading cause of pain and disability worldwide and results in a reduced quality of life due to pain from common tasks such as walking or climbing and descending stairs, which greatly limit function. Knee pain plays a critical role in OA. Knee pain also presents in younger patients without features of OA. In this population, beyond its effects on patient performance and quality of life, knee pain may be a precursor of future OA onset or progression. While this offers an early target to both treat patient pain as well as potentially prevent future OA onset, identification of pain phenotypes and especially specific pain sources in knee pain remains challenging. MRI is most often utilized to try to identify sources of knee pain, but has poor specificity, partly due to the heterogeneity of fluid signal that appears across subjects. Further, current imaging methods are performed in a static fashion and have shown limited sensitivity to evaluation of tissue response to acute changes due to joint loading activities such as walking, or stair climbing which often are the stressor of the patient’s pain. PET-MRI offers potential to simultaneously evaluate multiple early markers of OA in all joint tissues. In particular, [18F]-sodium fluoride ([18F]NaF) uptake can be used to study bone metabolism. [18F]NaF uptake has shown correlation with pain in patellofemoral (PF) pain patients. Further, we have observed that joint loading acutely alters the bone physiology affecting [18F]NaF uptake which suggests it may be sensitive to the metabolic response of bone where there is breakdown of the whole-joint unit that results in focal increases in bone loading. The scientific premise of this supplement is the application of an imaging “stress test,” based on [18F]NaF PET-MRI, to evaluate the function response of the whole-joint unit after physiological joint loading in patients with knee pain. Our supplemental Aim will scan 20 subjects with unilateral PF pain and no history of OA or joint injury with [18F]NaF PET-MRI to quantitatively assess changes in bone perfusion and mineralization [PET] as well as cartilage and meniscus morphology and microstructure(T2, UTE-T2*) [MRI] in response to a stair ascent/descent “stress” test. We hypothesize that focal increases in [18F]NaF bone uptake after a baseline stair ascent/descent task will be larger in the painful knee compared with non-painful contralateral knee, suggestive of mechanical-derived pain. We will explore if PF pain exhibits focally high areas of bone load which may be targets for conservative interventions. We will also explore how this functional response to loading is in the painful knee will compare to age-matched controls as well as to an OA population. Our investigative team includes experts in [18F]NaF kinetic modeling, imaging technology, and bone physiology, as well as musculoskeletal clinicians. Our environment provides all the necessary tools, including a leading im...