Neutrophil extracellular traps promote bone loss in type 1 diabetes via suppression of the FN1–PI3K/Akt signaling axis

IF 4.7 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2025-10-06 DOI:10.1016/j.intimp.2025.115629

Xin Liu , Donglun Xiao , Dongliang Zhang , Yujun Pan , Jie Guo , Ying Zhang , Shanshan Li , Qiong Tang , Xin Jin , Tianwei Sun

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引用次数: 0

Abstract

Diabetes-induced osteoporosis (DOP) is a severe complication of type 1 diabetes mellitus (T1D), characterized by impaired bone formation. However, the underlying mechanisms remain poorly understood. Using a streptozotocin (STZ)-induced T1D mouse model, we observed pronounced trabecular bone loss, demonstrated by micro-CT and histological analyses. Concurrently, diabetic bone marrow showed a marked accumulation of neutrophil extracellular traps (NETs), as confirmed by immunofluorescence and Western blot for MPO and citrullinated histone H3 (CitH3). Therapeutic degradation of NETs with DNase I significantly restored trabecular bone microarchitecture and enhanced osteoblast activity, evidenced by increased osteocalcin (OCN) and RUNX2 expression. In vitro, NETs impaired osteogenic differentiation of MC3T3-E1 cells, suppressing ALP activity and downregulating osteogenic markers OPN and RUNX2—effects that were reversed by DNase I. Transcriptomic profiling revealed that NETs downregulated fibronectin 1 (FN1), disrupting PI3K/Akt signaling and ECM-receptor interaction pathways. Restoration of FN1 expression, either in vivo via DNase I or in vitro via exogenous supplementation, rescued osteogenic capacity. Furthermore, inhibition of PI3K signaling with LY294002 abrogated the osteoprotective effects of FN1, confirming that the FN1–PI3K/Akt axis mediates NETs-induced osteogenic suppression. These findings identify NETs as critical mediators of diabetic bone loss through FN1 downregulation and suppression of PI3K/Akt signaling. Targeting NETs or restoring FN1–PI3K/Akt signaling may therefore represent promising therapeutic strategies for diabetes-associated osteoporosis.

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中性粒细胞胞外陷阱通过抑制FN1-PI3K/Akt信号轴促进1型糖尿病的骨质流失。

糖尿病性骨质疏松症（DOP）是1型糖尿病（T1D）的严重并发症，以骨形成受损为特征。然而，潜在的机制仍然知之甚少。使用链脲佐菌素（STZ）诱导的T1D小鼠模型，我们通过显微ct和组织学分析观察到明显的小梁骨丢失。同时，通过免疫荧光和Western blot检测MPO和瓜氨酸组蛋白H3 (CitH3)，证实糖尿病骨髓中中性粒细胞胞外陷阱（NETs）明显积累。通过骨钙素（OCN）和RUNX2表达的增加，DNase I治疗性降解NETs可显著恢复小梁骨微结构并增强成骨细胞活性。在体外，NETs破坏了MC3T3-E1细胞的成骨分化，抑制了ALP活性，下调了成骨标志物OPN和runx2的作用，这些作用被DNase i逆转。转录组学分析显示，NETs下调了纤维连接蛋白1 (FN1)，破坏了PI3K/Akt信号通路和ecm受体相互作用途径。无论是在体内通过DNase I还是在体外通过外源补充恢复FN1的表达，都能恢复成骨能力。此外，LY294002抑制PI3K信号通路可消除FN1的骨保护作用，证实FN1-PI3K/Akt轴介导nets诱导的成骨抑制。这些发现表明，NETs是通过FN1下调和PI3K/Akt信号传导抑制糖尿病骨质流失的关键介质。因此，靶向NETs或恢复FN1-PI3K/Akt信号通路可能是治疗糖尿病相关性骨质疏松症的有希望的治疗策略。

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来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.