Activated NETosis of bone marrow neutrophils up-regulates macrophage osteoclastogenesis via cGAS-STING/AKT2 pathway to promote osteoporosis.

Bone marrow (BM) of postmenopausal osteoporosis has been found highly inflammatory, resulting from dysregulated immune cells induced by both estrogen efficiency and body aging. NETosis of neutrophils has been found aberrantly activated in age-related chronic inflammation, while their role in postmenopausal osteoporosis remains unclear. Here we found NETosis of BM neutrophils of OVX (ovariectomy) mice was significantly activated, and we verified NETs released by neutrophils induced M1 polarization and osteoclastogenesis of RAW264.7 macrophages. Further, we demonstrated effects of NETs on osteoclastogenesis was mediated by cGAS-STING/AKT2 pathway. Finally, we found in vivo NETs-clearance through GSK484 significantly inhibited osteoclastogenesis and attenuated osteoporosis of OVX mice. Our study highlights the role of neutrophil NETosis in activating osteoclastogenesis and bone resorption of postmenopausal osteoporosis, thereby providing novel targets for bone loss treatment.