Preprint: RANK signaling in mouse bone marrow blood vessel cells initiates age-related inflammation

Preprint: RANK signaling in mouse bone marrow blood vessel cells initiates age-related inflammation

On September 3, 2026, Yasuhiro Kobayashi's group posted a preprint describing how age-related inflammation begins in the bone marrow of mice. The authors traced a pathway from RANK, a signaling protein in the cellular lining of blood vessels, to IL‑1β, a protein that transmits inflammatory signals. In this model, IL‑1β promoted the senescence of stromal cells that form the structural framework of bone marrow and altered the balance of blood cell populations.

Bone marrow produces blood cells inside bones. Senescent cells accumulate there with age. These cells have stopped dividing but continue to release substances that sustain inflammation. At the same time, the bone marrow produces more myeloid cells of the innate immune system, including neutrophils, while lymphocyte numbers decline. The authors sought to identify which cell type sends the initial inflammatory signal.

They began with the RANKL, RANK, and OPG system. RANKL activates RANK, while OPG binds RANKL and weakens the signal. Eight-week-old mice lacking OPG had more cells with senescence markers, more neutrophils, and fewer lymphocytes, resembling 32-week-old control mice. An antibody against RANKL reduced the number of cells with senescence markers and attenuated the myeloid bias.

The authors then determined where this pathway operates. A 2025 study involving Kobayashi had already linked RANK/RANKL signaling to bone marrow blood vessel permeability and the passage of some immune cells through the vessel wall. This finding gave the authors a basis for examining the endothelium, the thin cellular lining of blood vessels. In 32-week-old mice, fluorescently labeled RANKL bound mainly to the endothelium. Deleting RANK only from these cells reduced the number of cells with senescence markers and attenuated the myeloid bias. After bone marrow removal, these animals formed more new bone tissue.

To identify the mediator, the authors compared RNA profiles, sorted cells, and stained tissue samples. All three analyses pointed to IL‑1β. RANK signaling in the endothelium increased production of this inflammatory protein. In laboratory-grown stromal cells that form the structural framework of bone marrow, IL‑1β increased markers of DNA damage and cellular senescence. In 32-week-old mice, an antibody against IL‑1β reduced the number of senescent cells and attenuated the myeloid bias, while bone regeneration improved.

In this mouse model, RANK signaling in the vascular lining initiates a pathway in which IL‑1β promotes stromal cell senescence and changes the composition of blood cell populations.