Bone marrow AdipoQ-lineage progenitors are a major cellular source of M-CSF that dominates bone marrow macrophage development, osteoclastogenesis and bone mass

M-CSF is a critical growth factor for myeloid lineage cells, including monocytes, macrophages and osteoclasts. Tissue resident macrophages in most organs rely on local M-CSF. However, it is unclear what specific cells in bone marrow produce M-CSF to maintain myeloid homeostasis. Here, we identify bone marrow AdipoQ-lineage progenitors, but not bone marrow mature adipocytes or peripheral adipose tissue, as a major cellular source of M-CSF, with these AdipoQ-lineage progenitors producing M-CSF at levels much higher than those produced by osteoblast lineage cells. Deficiency of M-CSF in bone marrow AdipoQ-lineage progenitors drastically reduces the generation of bone marrow macrophages and osteoclasts, leading to severe osteopetrosis in mice. Furthermore, the postmenopausal osteoporosis in a mouse model can be significantly alleviated by the lack of M-CSF in bone marrow AdipoQ-lineage progenitors. Our findings identify bone marrow AdipoQ-lineage progenitors as a major cellular source of M-CSF in bone marrow and reveal their crucial contribution to bone marrow macrophage development, osteoclastogenesis, bone homeostasis and pathological bone loss.