Lymphatic Vessels Enter Bone in Disease, Not Repair

LYMPHATIC vessels were absent from healthy and regenerating bone but invaded bone in rare disease models.

Using highly specific genetic tracing methods, investigators found lymphatic endothelial cells in the periosteum and connective tissues surrounding bone, but not within cortical bone, the endosteum, or bone marrow. The findings challenge previous evidence suggesting that lymphatic vessels normally reside inside bone and support regeneration after injury.

Lymphatic Vessels in Bone Absent During Repair

Researchers used a PROX1 based genetic tool and a dual recombinase system designed to label lymphatic endothelial cells more specifically. Serial bone sections, whole bone immunostaining, and three-dimensional imaging consistently localized the labeled cells to the outer bone surface.

Following irradiation and bone marrow transplantation, lymphatic endothelial cells remained confined to the periosteum and surrounding connective tissue. No cells were detected within bone during recovery periods extending to 66 days.

A femur fracture model produced a substantial expansion of lymphatic endothelial cells within the periosteum and fibrous callus. However, the cells did not enter disrupted bone, cartilage within the callus, or newly formed bone during the first 2 weeks of fracture healing.

These results suggest that lymphatic expansion near an injury should not automatically be interpreted as evidence of lymphatic participation within regenerating bone.

Disease Models Reveal Pathological Invasion

A different pattern emerged in mouse models of generalized lymphatic anomaly and Gorham–Stout disease. Hyperplastic lymphatic endothelial cells progressively approached cortical bone, breached the periosteum, and ultimately infiltrated bone marrow as disease advanced.

This pathological invasion provided a positive control demonstrating that the tracing methods could detect lymphatic vessels inside bone when they were genuinely present. It also supports a distinction between normal periosteal lymphatics and disease associated intraosseous invasion.

The investigators additionally reanalyzed previously reported human single cell RNA sequencing data. They concluded that the dataset contained extensive nonendothelial contamination and did not establish the presence of lymphatic endothelial cells in human bone.

Clinically, the findings refine current understanding of rare disorders characterized by abnormal lymphatic proliferation and osteolysis. However, the experiments were conducted primarily in mice, evaluated only irradiation and fracture injury, and did not determine how pathological lymphatic cells breach the periosteum. The long term fate and function of lymphatic cells expanding around a healing fracture also remain uncertain.

Reference
Meng X et al. Lymphatic vessels invade bone in disease but are absent in health and regeneration. Cell. 2026;189(17):5449-5465.e5.

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