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ResearchIn-Press PreviewAgingImmunology Open Access | 10.1172/jci.insight.182418

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

Yoshio Nishida,1 M. Alaa Terkawi,1 Gen Matsumae,1 Shunichi Yokota,1 Taiki Tokuhiro,1 Yuki Ogawa,1 Hotaka Ishizu,1 Junki Shiota,1 Tsutomu Endo,1 Hend Alhasan,1 Taku Ebata,1 Keita Kitahara,1 Tomohiro Shimizu,1 Daisuke Takahashi,1 Masahiko Takahata,1 Ken Kadoya,1 and Norimasa Iwasaki1

1Department of Orthopedic Surgery, Faculty of Medicine and Graduate School o, Hokkaido University, Sapporo, Japan

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1Department of Orthopedic Surgery, Faculty of Medicine and Graduate School o, Hokkaido University, Sapporo, Japan

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1Department of Orthopedic Surgery, Faculty of Medicine and Graduate School o, Hokkaido University, Sapporo, Japan

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1Department of Orthopedic Surgery, Faculty of Medicine and Graduate School o, Hokkaido University, Sapporo, Japan

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1Department of Orthopedic Surgery, Faculty of Medicine and Graduate School o, Hokkaido University, Sapporo, Japan

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1Department of Orthopedic Surgery, Faculty of Medicine and Graduate School o, Hokkaido University, Sapporo, Japan

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1Department of Orthopedic Surgery, Faculty of Medicine and Graduate School o, Hokkaido University, Sapporo, Japan

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1Department of Orthopedic Surgery, Faculty of Medicine and Graduate School o, Hokkaido University, Sapporo, Japan

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1Department of Orthopedic Surgery, Faculty of Medicine and Graduate School o, Hokkaido University, Sapporo, Japan

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1Department of Orthopedic Surgery, Faculty of Medicine and Graduate School o, Hokkaido University, Sapporo, Japan

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1Department of Orthopedic Surgery, Faculty of Medicine and Graduate School o, Hokkaido University, Sapporo, Japan

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1Department of Orthopedic Surgery, Faculty of Medicine and Graduate School o, Hokkaido University, Sapporo, Japan

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1Department of Orthopedic Surgery, Faculty of Medicine and Graduate School o, Hokkaido University, Sapporo, Japan

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1Department of Orthopedic Surgery, Faculty of Medicine and Graduate School o, Hokkaido University, Sapporo, Japan

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1Department of Orthopedic Surgery, Faculty of Medicine and Graduate School o, Hokkaido University, Sapporo, Japan

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1Department of Orthopedic Surgery, Faculty of Medicine and Graduate School o, Hokkaido University, Sapporo, Japan

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1Department of Orthopedic Surgery, Faculty of Medicine and Graduate School o, Hokkaido University, Sapporo, Japan

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Published October 31, 2024 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.182418.
Copyright © 2024, Nishida et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published October 31, 2024 - Version history
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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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