Inhibition of elastin degradation alleviates joint degeneration in aging mice, dogs, and human models
Abstract
Extracellular matrix degradation is a fundamental pathological feature of osteoarthritis, while the roles of degraded matrix remain largely unknown. We previously showed that serum elastin fragments were a systemic aging driver. Here, we found that elastin fragments were upregulated in synovial fluid in dual-center osteoarthritis patients. Elastin fragments actively impaired joint tissue in mice and human explants. Mechanistically, a specific elastin motif containing Valine-Glycine-Valine-Alanine-Proline-Glycine (VGVAPG) oligopeptide (E-motif) promoted macrophage secretion of inflammatory factors via the neuraminidase-1, a component of the elastin receptor complex. These inflammatory factors, together with the E-motif, upregulated serum amyloid A3 protein in chondrocytes, accelerating cartilage degeneration. Therapeutically, both the myeloid-specific knockout of neutrophil elastase and the pharmacological inhibition using a clinically applied drug (sivelestat) alleviated joint degeneration in naturally aging mice partly by reducing elastin fragments levels. The pharmacological inhibitor exhibited 1-y systemic safety in dogs and alleviated osteoarthritis-like phenotypes in naturally aging dogs and human explants. Finally, several matrix fragments, including the fragments of type II collagen, fibronectin, hyaluronic acid, and aggrecan, were demonstrated to universally induce cartilage degeneration. Conclusively, this study identifies degraded matrix, especially elastin fragments, as one of the drivers of joint degeneration via pathological macrophage–chondrocyte crosstalk, suggesting elastase inhibitors as a potential therapeutic strategy for aging-related osteoarthritis.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (21)
Junzhi Yi
Department of Sports Medicine of the Second Affiliated Hospital, and Liangzhu Laboratory, Zhejiang University School of Medicine
Xiao Xiao
The Education Ministry Key Lab of Resource Chemistry, Shanghai Frontiers Science Center of Biomimetic Catalysis
Hui Zhang
The Fourth Hospital of Hebei Medical University Shijiazhuang China
Xinjie Xu
Li Dak Sum and Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Zhejiang University School of Medicine
Keyu Chen
School of Materials Science and Engineering, State Key Laboratory of Fine Chemicals, Frontiers Science Center for Smart Materials Oriented Chemical Engineering, Technology Innovation Center of High Performance Resin Materials (Liaoning Province)
Xinqi Cai
Department of Sports Medicine of the Second Affiliated Hospital, and Liangzhu Laboratory, Zhejiang University School of Medicine
Yutao Zhu
Department of Sports Medicine of the Second Affiliated Hospital, and Liangzhu Laboratory, Zhejiang University School of Medicine
Xianan Mo
Department of Sports Medicine of the Second Affiliated Hospital, and Liangzhu Laboratory, Zhejiang University School of Medicine
Shihan Xiong
Department of Sports Medicine of the Second Affiliated Hospital, and Liangzhu Laboratory, Zhejiang University School of Medicine
Zhichu Chen
Li Dak Sum and Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Zhejiang University School of Medicine
Hairu Sui
Li Dak Sum and Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Zhejiang University School of Medicine
Jiachun Wu
Department of Chemical and Biomedical Engineering
Jiaqi Xu
Laboratory of Photonics and Interfaces, École Polytechnique Fédérale de Lausanne
Xuri Chen
Department of Sports Medicine of the Second Affiliated Hospital, and Liangzhu Laboratory, Zhejiang University School of Medicine
Yan Wu
Zi Yin
Department of Sports Medicine of the Second Affiliated Hospital, and Liangzhu Laboratory, Zhejiang University School of Medicine
Youzhi Cai
Department of Orthopedics and Center for Sport Medicine, The First Affiliated Hospital, College of Medicine Zhejiang University
Xianzhu Zhang
Department of Sports Medicine of the Second Affiliated Hospital, and Liangzhu Laboratory, Zhejiang University School of Medicine
Jing Zhou
Zhejiang Institute of Photoelectronics
Hua Liu
Hongwei Ouyang
Department of Sports Medicine of the Second Affiliated Hospital, and Liangzhu Laboratory, Zhejiang University School of Medicine