Old Blood, Young Bones: Identification of Middle-Aged Myeloid Cells That Limit Cortical Bone Loss

Although studies support disrupted bone remodelling within geriatric populations, mid-life changes are understudied. To investigate this, we performed bone marrow transplantation assays using either 8- or 40-week-old mice. Micro-CT analyses of lethally irradiated 8-week-old mice transplanted with 40-week-old bone marrow exhibited increased mid-shaft femoral cortical bone mass and thickness. Intensive bone marrow regeneration mirrors hematopoietic development in that erythro-myeloid progenitors (EMPs) first expand to support blood production before definitive hematopoietic stem cell (HSC) production. We hypothesized that reduced HSC capacity of 40-week-old bone marrow and compensatory expansion of EMPs may facilitate gains in cortical bone. Flow cytometry analyses revealed greater EMP to HSC ratios when mice were reconstituted with increasing percentages of middle-aged bone marrow. To identify cell types mediating these effects, we performed comparative scRNA-Seq analyses and identified CD11B⁺CD36⁺ myeloid cells exhibiting enriched expression of bone anabolic cytokines. Elevated levels of Wnt ligands, especially Wnt6, characterized these cells. In lineage tracing assays, CD11B⁺CD36⁺ cells were donor-derived myeloid cells. In functional assays, we demonstrate that soluble factors produced by CD11B⁺CD36⁺ cells enhance osteogenesis. Moreover, CD11B/CD36/Wnt6 exquisitely mark anabolic macrophages within human bone marrow. These findings reveal a myeloid population present during midlife that enhances cortical bone.