Mechano-regulation of circulating extracellular vesicle cargoes to enhance knee joint health

ABSTRACT Knee osteoarthritis (KOA) represents a major public health burden affecting more than 30 million older individuals in the United States alone. Standard of care, including rehabilitative programs, is currently limited to symptom management. To address the lack of disease-modifying interventions for KOA, we herein aim to provide an integrated view of the complex pathophysiology of KOA as “a disease of the organ”, and mechanistically investigate how physiological exercise regulates molecular circuitry in cartilage and the surrounding the knee joint in the setting of KOA. Two inter-related yet independent aims will test the central hypotheses that mechanotransductive pathways stimulated by exercise promote more youthful molecular cargoes within circulating extracellular vesicles that promote cartilage integrity directly (Aim 1) and/or indirectly via alterations in the secreted proteins of the infrapatellar fat pad /synovium complex (Aim 2). We will accomplish these aims using technically innovative approaches, including (1) an advanced network medicine framework for multi-tissue multi-omics datasets in order to disentangle the multi-dimensional contribution of circulating factors on knee joint health at single cell resolution, and (2) a physiologically relevant model of female aging by which menopause is chemically-induced in middle-aged mice. These conceptually and technically innovative studies will be carried out by an interdisciplinary team comprising an exercise physiologist and computational biologist (PI), a stem cell biologist (co-PI), and a bioengineer (co-I). The breadth of this team enhances feasibility, impact, and the likelihood of success. Successful completion of the aims as proposed will provide mechanistic insights into how molecular cargo in blood impacts on osteoarthritic knee joint health in sex- and activity-dependent manner. Ultimately, we anticipate that the studies proposed will aid in the development of innovative diagnostic and prognostic nano-biomarkers and effective interventions to the benefit of an aging population.