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Updated: Jan 12, 2026

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The RANK/RANKL axis controls vascular dynamics in the bone marrow.

Takeshi Kaneko1,2,3, Shinya Yari1, Junichi Kikuta1,3,4

  • 1Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, The University of Osaka, Osaka 565-0871, Japan.

Proceedings of the National Academy of Sciences of the United States of America
|November 3, 2025
PubMed
Summary
This summary is machine-generated.

Receptor activator of nuclear factor kappa B ligand (RANKL) controls bone marrow vascular permeability, facilitating hematopoietic cell mobilization and regulating bone metabolism. This RANK/RANKL signaling acts as a gatekeeper for bone marrow sinusoids.

Keywords:
RANK/RANKL axisbone marrowbone metabolismintravital imagingvascular permeability

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Area of Science:

  • Immunology
  • Vascular Biology
  • Bone Metabolism

Background:

  • Receptor activator of nuclear factor kappa B ligand (RANKL) is crucial for osteoclast differentiation.
  • RANKL's role beyond osteoclastogenesis in bone marrow homeostasis is not fully understood.

Purpose of the Study:

  • To investigate the novel function of RANKL in regulating bone marrow vascular permeability.
  • To elucidate the mechanism by which RANKL influences hematopoietic cell mobilization and bone metabolism.

Main Methods:

  • Utilized genetic mouse models with specific gene deletions.
  • Analyzed vascular permeability using in vivo and ex vivo assays.
  • Examined the expression of adhesion molecules and RANK/RANKL signaling pathways.

Main Results:

  • RANKL was found to control vascular permeability in the bone marrow, independent of its role in osteoclastogenesis.
  • RANK, expressed on sinusoidal endothelial cells, mediates vascular permeability by regulating intercellular adhesion molecule 1 and vascular cell adhesion molecule 1.
  • Perivascular C-X-C motif chemokine ligand 12-abundant reticular (CAR) stromal cells highly express RANKL, and its deletion abrogates vascular leakage.

Conclusions:

  • RANK/RANKL signaling acts as a critical regulator of bone marrow sinusoidal permeability.
  • This pathway facilitates the mobilization of hematopoietic monocytic cells, impacting bone metabolism.
  • RANK/RANKL signaling functions as a gatekeeper for bone marrow sinusoids in vivo.