Inhibition of Ctsk alleviates periodontitis and comorbid rheumatoid arthritis via downregulation of the TLR9 signalling pathway
Weiyi Pan
The State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Sichuan, China
Authors contributed equally to this manuscriptSearch for more papers by this authorWuwei Yin
The State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Sichuan, China
Authors contributed equally to this manuscriptSearch for more papers by this authorLi Yang
The State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Sichuan, China
Search for more papers by this authorLili Xue
The State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Sichuan, China
Search for more papers by this authorJie Ren
The State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Sichuan, China
Search for more papers by this authorWei Wei
The State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Sichuan, China
Search for more papers by this authorQiuyu Lu
The State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Sichuan, China
Search for more papers by this authorHandong Ding
The State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Sichuan, China
Search for more papers by this authorZhaohui Liu
The State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Sichuan, China
Search for more papers by this authorNeel R. Nabar
Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania
Search for more papers by this authorMin Wang
The State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Sichuan, China
Search for more papers by this authorCorresponding Author
Liang Hao
The State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Sichuan, China
Correspondence
Liang Hao, DDS, PhD, The State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, China.
Email: [email protected]
Search for more papers by this authorWeiyi Pan
The State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Sichuan, China
Authors contributed equally to this manuscriptSearch for more papers by this authorWuwei Yin
The State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Sichuan, China
Authors contributed equally to this manuscriptSearch for more papers by this authorLi Yang
The State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Sichuan, China
Search for more papers by this authorLili Xue
The State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Sichuan, China
Search for more papers by this authorJie Ren
The State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Sichuan, China
Search for more papers by this authorWei Wei
The State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Sichuan, China
Search for more papers by this authorQiuyu Lu
The State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Sichuan, China
Search for more papers by this authorHandong Ding
The State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Sichuan, China
Search for more papers by this authorZhaohui Liu
The State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Sichuan, China
Search for more papers by this authorNeel R. Nabar
Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania
Search for more papers by this authorMin Wang
The State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Sichuan, China
Search for more papers by this authorCorresponding Author
Liang Hao
The State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Sichuan, China
Correspondence
Liang Hao, DDS, PhD, The State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, China.
Email: [email protected]
Search for more papers by this authorFunding information
The funders did not participate in the design or undertaking of this study and preparation of the manuscript. This work was supported by the National Natural Science Foundation of China (grant numbers 81400523, 81570987, 81601909, 81621062 and 81520108009); the Sichuan provincial science and Technology Foundation (grant number 2016RZ0041, 2016FZ0074, 2017FZ0049 and 2018FZ0042).
Abstract
Aim
In this study, we investigate the mechanistic link between rheumatoid arthritis (RA) and periodontitis to identify a novel target (cathepsin K; Ctsk) for the treatment of comorbid periodontitis and RA.
Methods
An experimental model of periodontitis with arthritis was established in DBA/1 mice. We then tested the effect of BML-244, a specific inhibitor of Ctsk, by quantifying several inflammatory markers of TLR9 signalling both in vivo and in vitro.
Results
Our results showed that periodontitis–rheumatoid arthritis comorbidity causes severer periodontal bone and joint cartilage destruction than either disease alone. Inhibition of Ctsk reduced infiltration by dendritic cells and T cells and inflammatory cytokine production; these improvements alleviated the hard-tissue erosion in periodontitis and RA as measured by bone erosion in periodontal lesions and cartilage destruction in knee joints. Inhibition of Ctsk also decreased the expression of TLR4 and TLR9 in vivo, whereas in vitro experiments indicated that Ctsk is involved specifically in the production of cytokines in response to TLR9 engagement.
Conclusion
Our data reveal that periodontitis and RA may have additive pathological effects through dysregulation of the TLR9 pathway and that Ctsk is a critical mediator of this pathway and contributes to the pathogenesis of RA and periodontitis.
CONFLICT OF INTEREST
The authors declare no conflicts of interest.
Supporting Information
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