Endothelial RANK signaling triggers bone marrow inflammaging

Senescent cell accumulation in the bone marrow promotes inflammaging, hematopoietic stem cell dysfunction, and myeloid-biased hematopoiesis, contributing to the onset of age-related diseases. However, the mechanisms underlying the emergence of senescent cells in the bone marrow remain poorly understood. Here, we identify endothelial RANK signaling as a key regulator of bone marrow senescence. Young Tnfrsf11b (osteoprotegerin, OPG)-deficient mice exhibited premature accumulation of senescent cells and myeloid-biased hematopoiesis, phenocopying middle-aged wild-type mice. Endothelial-specific deletion of Tnfrsf11a (RANK), blockade of RANKL, and in vivo tracing with fluorescent-labelled RANKL revealed that RANK signaling in endothelial cells drives senescent cell accumulation in the bone marrow. Bulk and single-cell RNA sequencing, and IL-1β neutralization demonstrate that RANK signaling induces IL-1β expression in endothelial cells, which in turn promotes bone marrow inflammaging. These findings identify endothelial RANK as a critical initiator of bone marrow senescence, thereby driving inflammaging, a potential therapeutic target for age-related diseases.