Dynamic transcriptome analysis of osteal macrophages identifies distinct subset with senescence features in experimental osteoporosis.

IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL JCI insight Pub Date : 2024-10-31 DOI:10.1172/jci.insight.182418
Yoshio Nishida, M Alaa Terkawi, Gen Matsumae, Shunichi Yokota, Taiki Tokuhiro, Yuki Ogawa, Hotaka Ishizu, Junki Shiota, Tsutomu Endo, Hend Alhasan, Taku Ebata, Keita Kitahara, Tomohiro Shimizu, Daisuke Takahashi, Masahiko Takahata, Ken Kadoya, Norimasa Iwasaki
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Abstract

Given the potential fundamental function of osteal macrophages in bone pathophysiology, we study here their precise function in experimental osteoporosis. Gene profiling of osteal macrophages from ovariectomized mice demonstrated the upregulation of genes that were involved in oxidative stress, cell senescence and apoptotic process. A scRNA-seq analysis revealed that osteal macrophages were heterogenously clustered into 6 subsets that expressed proliferative, inflammatory, anti-inflammatory and efferocytosis gene signatures. Importantly, postmenopausal mice exhibited a 20-fold increase in subset-3 that showed a typical gene signature of cell senescence and inflammation. These findings suggest that the decreased production of estrogen due to postmenopause altered the osteal macrophages subsets, resulting in a shift toward cell senescence and inflammatory conditions in the bone microenvironment. Furthermore, adoptive macrophage transfer onto calvarial bone was performed and mice that received oxidative-stressed macrophages exhibited greater osteolytic lesions than control macrophages, suggesting the role of these cells in development of inflammaging in bone microenvironment. Consistently, depletion of senescent cells and oxidative-stressed macrophages subset alleviated the excessive bone loss in postmenopausal mice. Our data provided a new insight into the pathogenesis of osteoporosis and sheds light on a new therapeutic approach for the treatment/prevention of postmenopausal osteoporosis.

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骨膜巨噬细胞的动态转录组分析确定了实验性骨质疏松症中具有衰老特征的独特亚群。
鉴于骨膜巨噬细胞在骨病理生理学中的潜在基本功能,我们在此研究了它们在实验性骨质疏松症中的确切功能。对卵巢切除小鼠的骨膜巨噬细胞进行的基因谱分析显示,参与氧化应激、细胞衰老和凋亡过程的基因上调。scRNA-seq分析表明,骨膜巨噬细胞异质性地聚集成6个亚群,分别表达增殖、炎症、抗炎和排泄基因特征。重要的是,绝经后小鼠的子集-3 增加了 20 倍,显示出细胞衰老和炎症的典型基因特征。这些发现表明,绝经后雌激素分泌减少改变了骨膜巨噬细胞亚群,导致骨微环境向细胞衰老和炎症状态转变。此外,在小鼠钙骨上进行了巨噬细胞收养转移,与对照组巨噬细胞相比,接受氧化应激巨噬细胞的小鼠表现出更大的溶骨病变,这表明这些细胞在骨微环境炎症发展中的作用。同样,清除衰老细胞和氧化应激巨噬细胞亚群可减轻绝经后小鼠骨质过度流失的情况。我们的数据为骨质疏松症的发病机制提供了新的见解,并为治疗/预防绝经后骨质疏松症提供了新的治疗方法。
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来源期刊
JCI insight
JCI insight Medicine-General Medicine
CiteScore
13.70
自引率
1.20%
发文量
543
审稿时长
6 weeks
期刊介绍: JCI Insight is a Gold Open Access journal with a 2022 Impact Factor of 8.0. It publishes high-quality studies in various biomedical specialties, such as autoimmunity, gastroenterology, immunology, metabolism, nephrology, neuroscience, oncology, pulmonology, and vascular biology. The journal focuses on clinically relevant basic and translational research that contributes to the understanding of disease biology and treatment. JCI Insight is self-published by the American Society for Clinical Investigation (ASCI), a nonprofit honor organization of physician-scientists founded in 1908, and it helps fulfill the ASCI's mission to advance medical science through the publication of clinically relevant research reports.
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