Megakaryocytes promote bone formation through coupling osteogenesis with angiogenesis by secreting TGF-β1

Rationale: The hematopoietic system and skeletal system have a close relationship, and megakaryocytes (MKs) may be involved in maintaining bone homeostasis. However, the exact role and underlying mechanism of MKs in bone formation during steady-state and stress conditions are still unclear. Methods: We first evaluated the bone phenotype with MKs deficiency in bone marrow by using c-Mpl-deficient mice and MKs-conditionally deleted mice. Then, osteoblasts (OBs) proliferation and differentiation and CD31^hiEmcn^hi tube formation were assessed. The expression of growth factors related to bone formation in MKs was detected by RNA-sequencing and enzyme-linked immunosorbent assays (ELISAs). Mice with specific depletion of TGF-β1 in MKs were used to further verify the effect of MKs on osteogenesis and angiogenesis. Finally, MKs treatment of irradiation-induced bone injury was tested in a mouse model. Results: We found that MKs deficiency significantly impaired bone formation. Further investigations revealed that MKs could promote OBs proliferation and differentiation, as well as CD31^hiEmcn^hi vessels formation, by secreting high levels of TGF-β1. Consistent with these findings, mice with specific depletion of TGF-β1 in MKs displayed significantly decreased bone mass and strength. Importantly, treatment with MKs or thrombopoietin (TPO) substantially attenuated radioactive bone injury in mice by directly or indirectly increasing the level of TGF-β1 in bone marrow. MKs-derived TGF-β1 was also involved in suppressing apoptosis and promoting DNA damage repair in OBs after irradiation exposure. Conclusions: Our findings demonstrate that MKs contribute to bone formation through coupling osteogenesis with angiogenesis by secreting TGF-β1, which may offer a potential therapeutic strategy for the treatment of irradiation-induced osteoporosis.