Inhibition of elastin degradation alleviates joint degeneration in aging mice, dogs, and human models
- Junzhi Yi
- Xiao Xiao
- Hui Zhang
- Xinjie Xu
- Keyu Chen
- Xinqi Cai
- Yutao Zhu
- Xianan Mo
- Shihan Xiong
- Zhichu Chen
- Hairu Sui
- JiaChun Wu
- Jiaqi Xu
- Xuri Chen
- Yan Wu
- Zi Yin
- Youzhi Cai
- Xianzhu Zhang
- Jing Zhou
- Hua Liu
- Hongwei Ouyang
2026-07-08
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.