Novel Insights into Osteoarthritis, Pain and Function: MOST4

OVERALL ABSTRACT The Multicenter Osteoarthritis (MOST) Study has been a major source of new knowledge about the course of OA and factors that affect it, having published over 180 articles ranging from studies of pain and pain sensitization, to investigations of biomechanics, to inquiries into structural joint pathology as visualized by MRI,

and to studies of decline in function, buckling and falls, among others. The initial cohort enrolled 3026 participants with or at risk of knee OA; a new cohort consisting of 1525 subjects was recruited at the last cycle (MOST3) who were slightly younger and unlikely to have advanced disease. We will recruit an additional 150 participants from

underrepresented minority groups for a total projected sample size of 2293 in this next cycle of MOST (MOST4). In addition to its scientific output, the study has been remarkable in recruiting and encouraging talented young investigators to take on career defining investigations within MOST, having served as the basis for 31 career

development awards. Our overall goal is to advance our understanding of OA and its consequences to open doors to new treatment approaches including stratified approaches to treatments. We will use an integrated approach in the next cycle of MOST (MOST4) overseen by an Administrative Core, involving a Clinical Data

Collection and Management Core, Analysis Core, and Imaging Core, with guidance from an Observational Safety Monitoring Board and input from a Community Advisory Board, to efficiently address key knowledge gaps through the conduct of three Projects. Our Specific Aims are to: 1. Evaluate impaired exercise-induced

hypoalgesia (EIH) in knee OA, evaluate the relation of nervous system alterations to EIH, and determine the impact of EIH on pain, function, physical activity, and fear-avoidance related to exercise (Project 1); 2. Carry out proteomics analysis of synovial fluid to determine networks of proteins associated with generalized vs. localized

OA, pain and disease progression (Project 2); 3. Differentiate types of calcium crystals deposited in the joint and, for each of them, understand the clinical and structural consequences of crystal deposition (Project 3); 4. Take advantage of comprehensive longitudinal data already collected in MOST to address a wide range of questions

related to OA and its impact on outcomes; 5. Bring a multidisciplinary approach to bear on this complex disease and offer career development opportunities to investigators including pilot project grants in this understudied condition. MOST4 will introduce new approaches to understanding disease and will continue to comprehensively

assess pain, structural, and functional outcomes so that the specific effects of the factors proposed in the Projects and other risk factors can be examined. This work will produce new actionable insights regarding pain, structural deterioration and function loss in knee OA.