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

Yutong Guo, Hanzhang Zhou, Yixiang Wang, Yan Gu

Department of Orthodontics, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices& Beijing Key Laboratory of Digital Stomatology & NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory for Dental Materials, No.22, Zhongguancun South Avenue, Haidian District, Beijing, 100081, PR China. · pubmed

Paper

Abstract

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.

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Research summary

The paper claims that activated NETosis of bone marrow neutrophils promotes osteoclastogenesis via the cGAS-STING/AKT2 pathway, contributing to osteoporosis. This research addresses the inflammatory mechanisms underlying osteoporosis, which is a significant age-related condition, and suggests potential therapeutic targets that could mitigate bone loss associated with aging.

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