Koroth, J. | bioRxiv Science

bioRxiv2026

Sex-specific bone marrow populations regulate skeletal phenotype and identify CD74-marked osteoclast precursor subsets

While there are clear differences in bone accrual and maintenance between men and women due to hormonal regulation, the potential cell-intrinsic factors governing this difference are poorly understood. To investigate this, we performed bone marrow transplantation assays using male or female bone marrow transplantation into male hosts. Micro-CT analyses of lethally irradiated 8-week-old male mice transplanted with female bone marrow exhibited increased vertebral body trabecular and cortical bone mass. To identify cell types mediating these effects, we performed comparative single cell sequencing analyses and identified several CD11B+CD74+ myeloid cell clusters. Male donor BM chimeric mice had a higher proportion of Cd74-expressing clusters compared to female donor BM chimeric mice. We confirmed that males have greater numbers of bone marrow-resident CD11B+CD74+ cells under physiological conditions. Elevated expression of X-linked genes Tlr7 and Kdm6a marked a population of CD11B+CD74+ cells. Lastly, we show that female CD11B+CD74+ cells exhibit diminished osteoclastogenesis. These findings demonstrate that male and female bone marrow-resident cells have cell-intrinsic differences that regulate bone mass and that CD74 marks a subset of osteoclast precursor-enriched myeloid populations.

cell biology↗

bioRxiv2024

CD11B+CD36+ cells are bone anabolic macrophages that limit age-associated bone loss

Disruptions in the bone remodeling cycle that occur with increasing age lead to degeneration of the skeleton and increased risk of fragility fractures. Our understanding of how bone remodeling within cortical bone is controlled and altered with age in males and females is limited. Here, we generated bone marrow chimeric mice to understand the impacts of age and sex on bone remodeling. We demonstrate that transplantation of aged male or female bone marrow into young, lethally irradiated male hosts unexpectedly enhances cortical bone mass without impacting cancellous bone. Our single cell RNA-sequencing data show that mice reconstituted with aged bone marrow exhibited subsets of cells marked by CD11B/CD36 expression that demonstrate enhanced production of anabolic cytokines as compared to young counterparts, and that these myeloid subsets exist under conditions of normal physiology in aged mice. Importantly, CD11B+CD36+ cells do not differentiate into osteoclasts in vitro, and CD36 does not mark TRAP+ cells in vivo. Instead, CD36+ cells localize to resorption sites, including within cortical bone defects, suggesting their involvement in cortical bone remodeling and healing. CD11B+CD36+ cells also express elevated levels of bone anabolic WNT ligands, especially Wnt6. In functional assays, we demonstrate that soluble factors produced by CD11B+CD36+ cells enhance osteoblast progenitor commitment, mineralization, and activation of WNT signaling in vitro. Moreover, CD11B/CD36 exquisitely mark a subset of anabolic myeloid cells within human bone marrow. In conclusion, our studies identified a novel population of aged macrophages that limit cortical bone loss.

cell biology↗