Network medicine-based discovery of therapeutics for knee osteoarthritis

ABSTRACT Knee osteoarthritis (KOA) represents a major public health burden, affecting more than 30 million individuals in the United States and typically leading to significant declines in physical mobility and compromised quality of life. Despite its profound impact on our aging population, the standard of care, including exercise and self- management through diet and nutrition, is currently limited to symptom management and functional improvement. To address the lack of disease-modifying interventions for KOA, we herein propose to investigate whether and how different mechanical loading protocols regulate knee joint health when applied in isolation (Aim 1) or combined with nutritional approaches (Aim 2) by using aged male and menopausal female murine models of age-related KOA. Specifically, in Aim 1, we aim to mechanistically interrogate how varying doses of exercise regulate cartilage health in age-related KOA according to sex. In Aim 2, we will determine whether and how exercise and nutritional approaches exert a synergistic effect in ameliorating age-related KOA. We will accomplish these aims using technically innovative approaches, including a menopausal murine model to better recapitulate female aging and an advanced network medicine approach integrated with machine learning algorithms to elucidate the molecular landscape of the disease-modifying impacts of exercise in isolation or combined with nutrition. These innovative studies will be carried out by an interdisciplinary team comprising a rehabilitation clinician and computational biologist (PI), a stem cell biologist (co-I), a bioengineer (co-I), and a registered dietitian nutritionist and exercise physiologist (consultant). The breadth of this team enhances feasibility, impact, and the likelihood of success. Successful completion of the proposed aims will provide mechanistic insights into how rehabilitation programs dictate knee joint health according to sex at both the symptom and disease levels. Ultimately, we anticipate that the innovative research studies proposed will aid in the development of exercise mimetics and mechano-active scaffolds designed to selectively induce anabolic responses in cells, considering sex-specific variables to the benefit our aging population.