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

IF 3.5 3区生物学 Q3 CELL BIOLOGY Experimental cell research Pub Date : 2025-02-21 DOI:10.1016/j.yexcr.2025.114477

Yutong Guo , Hanzhang Zhou , Yixiang Wang , Yan Gu

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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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活化的骨髓中性粒细胞NETosis通过cGAS-STING/AKT2途径上调巨噬细胞破骨生成，促进骨质疏松。

绝经后骨质疏松症的骨髓（BM）被发现高度炎症，这是由雌激素效率和身体衰老引起的免疫细胞失调引起的。中性粒细胞的NETosis在年龄相关的慢性炎症中被发现异常激活，而它们在绝经后骨质疏松症中的作用尚不清楚。我们发现OVX（卵巢切除）小鼠BM中性粒细胞的NETosis被显著激活，我们证实了中性粒细胞释放的NETs诱导了M1极化和RAW264.7巨噬细胞的破骨生成。此外，我们证明了NETs对破骨细胞形成的影响是通过cGAS-STING/AKT2途径介导的。最后，我们发现通过GSK484清除体内nets可显著抑制OVX小鼠的破骨细胞生成并减轻骨质疏松症。我们的研究强调了中性粒细胞NETosis在激活绝经后骨质疏松症的破骨细胞生成和骨吸收中的作用，从而为骨质流失治疗提供了新的靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Experimental cell research 医学-细胞生物学

CiteScore

7.20

自引率

0.00%

发文量

295

审稿时长

30 days

期刊介绍： Our scope includes but is not limited to areas such as: Chromosome biology; Chromatin and epigenetics; DNA repair; Gene regulation; Nuclear import-export; RNA processing; Non-coding RNAs; Organelle biology; The cytoskeleton; Intracellular trafficking; Cell-cell and cell-matrix interactions; Cell motility and migration; Cell proliferation; Cellular differentiation; Signal transduction; Programmed cell death.