Inflammation produced by senescent osteocytes mediates age-related bone loss

Zixuan Wang; Xiaofei Zhang; Xing Cheng; Tianxing Ren; Weihua Xu; Jin Li; Hui Wang; Jinxiang Zhang

doi:10.3389/fimmu.2023.1114006

Inflammation produced by senescent osteocytes mediates age-related bone loss

Front Immunol. 2023 Feb 6:14:1114006. doi: 10.3389/fimmu.2023.1114006. eCollection 2023.

Authors

Zixuan Wang¹, Xiaofei Zhang², Xing Cheng³, Tianxing Ren¹, Weihua Xu⁴, Jin Li⁴, Hui Wang⁵, Jinxiang Zhang¹

Affiliations

¹ Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
² Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
³ Health Care Management Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁴ Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁵ Department of Medical Genetics, Basic School of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Abstract

Purpose: The molecular mechanisms of age-related bone loss are unclear and without valid drugs yet. The aims of this study were to explore the molecular changes that occur in bone tissue during age-related bone loss, to further clarify the changes in function, and to predict potential therapeutic drugs.

Methods: We collected bone tissues from children, middle-aged individuals, and elderly people for protein sequencing and compared the three groups of proteins pairwise, and the differentially expressed proteins (DEPs) in each group were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). K-means cluster analysis was then used to screen out proteins that continuously increased/decreased with age. Canonical signaling pathways that were activated or inhibited in bone tissue along with increasing age were identified by Ingenuity Pathway Analysis (IPA). Prediction of potential drugs was performed using the Connectivity Map (CMap). Finally, DEPs from sequencing were verified by Western blot, and the drug treatment effect was verified by quantitative real-time PCR.

Results: The GO and KEGG analyses show that the DEPs were associated with inflammation and bone formation with aging, and the IPA analysis shows that pathways such as IL-8 signaling and acute-phase response signaling were activated, while glycolysis I and EIF2 signaling were inhibited. A total of nine potential drugs were predicted, with rapamycin ranking the highest. In cellular experiments, rapamycin reduced the senescence phenotype produced by the H₂O₂-stimulated osteocyte-like cell MLO-Y4.

Conclusion: With age, inflammatory pathways are activated in bone tissue, and signals that promote bone formation are inhibited. This study contributes to the understanding of the molecular changes that occur in bone tissue during age-related bone loss and provides evidence that rapamycin is a drug of potential clinical value for this disease. The therapeutic effects of the drug are to be further studied in animals.

Keywords: age-related bone loss; inflammation; osteocyte; proteomics; rapamycin; senescence.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Hydrogen Peroxide / metabolism
Inflammation / metabolism
Osteocytes* / metabolism
Osteoporosis* / metabolism
Sirolimus / pharmacology

Substances

Hydrogen Peroxide
Sirolimus

Grants and funding

This research was supported by the National Natural Science Foundation of China (NFSC) (Nos. 82170642, 82100673, 82100662, and 81801923) and the Pre-Research Fund for Free Innovation of Union Hospital, Huazhong University of Science and Technology (Nos. 02.03.2017-312, 02.03.2017-59, and 02.03.2018-126).