In Silico Exercise: A Network Medicine Paradigm To Interrogate A Dose-dependent Effect Of Exercise On Osteoarthritis

PURPOSE: An enhanced understanding of the potential dose-dependent effects of exercise on cartilage health represents an essential step towards promoting the clinical success of exercise interventions for people with knee osteoarthritis (KOA). Using a series of computational approaches, this study interrogates how exercise regulates cartilage health in the setting of KOA in a dose-dependent manner. METHODS: A systematic review with meta-analysis first summarized the current knowledge of the dose-dependent impacts of exercise on cartilage health in experimental models of KOA. We then developed network medicine paradigms, "in silico exercise", and applied to publicly available transcriptomic data of healthy and KOA cartilage (GSE114007) in order to simulate the molecular responses of cartilage to physical exercise at moderate versus intense doses in individuals with KOA (Figure 1). RESULTS: Integrated findings across in vivo, ex vivo, and in vitro KOA models revealed that moderate and intense exercise demonstrated opposing effects on inflammatory signals and chondrocyte health, partly through selective regulation on Trpv4 and Piezo1/Piezo2 ion channels. Building on the mechanistic framework identified through these studies, we developed a novel network medicine paradigm, “in silico exercise”, which discovered that exercise at moderate and intense levels exhibited distinct transcriptional impacts on chondrocytes, which was due, at least in part, to the differential regulation of estrogen signaling. CONCLUSION: These studies provide a novel, mechanistic insight into exercise as a modality to improve joint structural integrity in a dose-dependent manner. The findings of the current study also offer translational opportunities towards the establishment of effective rehabilitation strategies as well as exercise mimetics for treating people with KOA.Figure 1.: In silico exercise to interrogate dose-dependent impacts of exercise on cartilage healthNIA R01AG061005