RUNX2 Activation in Fibro/Adipogenic Progenitors Promotes Muscle Fibrosis in Muscular Dystrophy

ABSTRACT Clinical evidence indicates concurrent muscle inflammation and fibrosis in muscular dystrophies (MDs); however, the molecular mechanisms underlying inflammation‐mediated fibrosis in skeletal muscle remain inadequately understood. This study revealed a molecular link between macrophages and fibro‐adipogenic progenitors (FAPs) in both human subjects and mice via the transforming growth factor‐beta (TGF‐β)‐RUNX family transcription factor‐2 (RUNX2) axis. RUNX2 mRNA levels correlated positively with both the expression of fibrotic genes and the fibrosis area of MD patients. We demonstrated that specific ablation of RUNX2 in FAPs alleviated muscle fibrosis in an animal model of MD. Mechanistically, injured myofibers activated the transcription of chemokine genes, enhancing macrophage recruitment and the release of TGF‐β, which subsequently triggered RUNX2‐mediated transcription of fibrogenic genes in FAPs, promoting muscle fibrosis. Additionally, we demonstrated that CADD522, a RUNX2 inhibitor, protects against muscle fibrosis in both dystrophic and denervated mice. Importantly, the anti‐inflammatory drug prednisolone alleviated muscle fibrosis in MD patients by inhibiting inflammatory cytokine‐mediated RUNX2 activation. Collectively, our findings indicated that the TGF‐β‐RUNX2 axis is a viable target for alleviating muscle fibrosis and related diseases, highlighting potential future research directions.