Weiyi Pan1, Wuwei Yin1, Li Yang1, Lili Xue1, Jie Ren1, Wei Wei1, Qiuyu Lu1, Handong Ding1, Zhaohui Liu1, Neel R Nabar2, Min Wang1, Liang Hao1. 1. 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. 2. Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
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.
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.
Authors: Angelica Leticia Reis Pavanelli; Bruna Silva de Menezes; Erica Bianca Barbosa Pereira; Fabio Assuncao de Souza Morais; Joni Augusto Cirelli; Rafael Scaf de Molon Journal: Biomed Res Int Date: 2022-05-02 Impact factor: 3.246
Authors: Carolina Rojas; Michelle P García; Alan F Polanco; Luis González-Osuna; Alfredo Sierra-Cristancho; Samanta Melgar-Rodríguez; Emilio A Cafferata; Rolando Vernal Journal: Front Immunol Date: 2021-06-17 Impact factor: 7.561