Multimodal evidence for bone lymphatics in skeletal health and repair.

Previous studies predominantly associated lymphatics with skeletal disease and bone loss. However, building on our work, bone lymphatics are emerging as a paradigm-shifting component of the skeletal microenvironment, illustrating their role as positive regulators of bone mass and repair. Here, we present a comprehensive analysis integrating spatial transcriptomics, single-cell RNA sequencing, and imaging across murine and human bones. Spatial transcriptomics identifies Prox1+ endothelial cells embedded within bone. Reanalysis of multiple scRNA-seq datasets confirms Prox1+ lymphatic endothelial cells (LECs) in bones, despite their underrepresentation in soft-tissue endothelial cell atlases. Periosteum is an insufficient source for bone lymphatics because it contains only sparse LECs. Our analyses further demonstrate that certain mouse models lack the sensitivity required to detect bone lymphatics and highlight the importance of high-resolution imaging. Collectively, convergent multimodal evidence substantiates LECs as an integral functional component of the skeletal microenvironment. This Matters Arising Response paper addresses the Meng et al. (2026) Matters Arising paper, published concurrently in this issue.