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

Abstract

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.