Longevity & AgingESCRT Protein CHMP5 Drives Bone Overgrowth Through Cellular Senescence
Researchers discovered that CHMP5, an ESCRT-III protein, normally restrains bone formation in osteogenic cells. When CHMP5 is genetically deleted in mice, endolysosomal function breaks down due to reduced VPS4A protein levels. This dysfunction impairs mitochondria, elevates reactive oxygen species (ROS), and drives skeletal cell senescence. Senescent cells then promote abnormal bone overgrowth through both direct (cell-autonomous) and indirect (paracrine) mechanisms, causing joint stiffness, skeletal deformity, and muscle loss. Critically, treating mice with senolytic drugs — which selectively eliminate senescent cells — significantly alleviated these musculoskeletal abnormalities, pointing to a potential therapeutic strategy for lysosomal storage diseases affecting the skeleton.
