Combination therapy of a TRPV2 agonist with a TNF inhibitor achieves sustained suppression of disease severity and reduced joint damage.
Combination therapy of a TRPV2 agonist with a TNF inhibitor achieves sustained suppression of disease severity and reduced joint damage.
复制标题
DOI：
10.1093/cei/uxac124
复制
发表时间：
2023-03-24
影响因子：
4.6
通讯作者：
中科院分区：
文献类型：
--
作者：
我们的目标是比较瞬时受体潜力香草素2(TRPV2)激动剂和肿瘤坏死因子抑制剂，并测试它们联合治疗胶原诱导性关节炎(CIA)作为未来治疗类风湿关节炎(RA)的潜在策略的可能性。在CIA DBA1/j小鼠发病后，开始使用依那西普(8 mg/kg，每周三次)、TRPV2激动剂O1821(20-30 mg/kg/天)或两者的组合进行治疗。对小鼠进行了61天的评分。取滑膜组织进行RNA测序。单独使用O1821或依那西普治疗的小鼠出现较轻微的临床疾病。与依那西普组相比，观察到O1821保护作用的时间点更早。联合治疗组在疾病严重性方面比任何一种单一治疗组都实现了更强劲和更持续的降低。与对照组相比，所有治疗组在滑膜炎症、滑膜增生和侵蚀性改变方面的评分都有所降低，其中联合组获得了最显著的保护。滑膜组织的RNA测序和通路分析确定了受TRPV2激动剂调控的途径和过程，如趋化和细胞因子受体信号转导，包括IL6R。联合治疗影响了单一治疗组中未见的其他途径。总而言之，TRPV2激动剂在关节炎严重程度和组织学评分方面实现了与依那西普相似的总体降低，但联合疗法实现了更持久的疾病控制和更显著的关节损伤减少，这表明未来有可能改善类风湿关节炎的疾病控制。RNA测序分析发现了受TRPV2调控的新途径，也受到联合处理的影响。我们比较了TRPV2激动剂和依那西普。两者在抑制关节炎和减少关节损伤方面取得了相似的效果。两种药物联合用药优于单一用药。
We aimed to compare a transient receptor potential vanilloid 2 (TRPV2) agonist with a TNF inhibitor, and to test the potential of their combination in collagen-induced arthritis (CIA) as a potential future strategy for rheumatoid arthritis (RA). Following the onset of CIA DBA1/j mice were started on treatment with either vehicle, etanercept (8 mg/kg three times a week), the TRPV2 agonist O1821 (20–30 mg/kg/day), or a combination of both. Mice were scored over a 61-day period. Synovial tissues were obtained for RNA sequencing. Mice on monotherapy with either O1821 or etanercept developed milder clinical disease. The O1821 protection was observed at an earlier time-point than in the etanercept group. The combination therapy group achieved a more robust and sustained reduction in disease severity than either monotherapy group. All treatment groups had reduced scores for synovial inflammation, synovial hyperplasia, and erosive changes, compared with controls, with the combination group achieving the most significant protection. RNA sequencing and pathway analyses of synovial tissues identified pathways and processes regulated by the TRPV2 agonist, such as chemotaxis and cytokine receptor signaling, including IL6R. The combination therapy affected additional pathways not seen in the monotherapy groups. In conclusion, the TRPV2 agonist achieved an overall similar reduction in arthritis severity and histology scores as etanercept, but the combination therapy achieved a more sustained disease control and more pronounced reduction in joint damage, suggesting a potential future option for improving disease control in RA. RNA sequencing analyses identified new pathways regulated by TRPV2, and also by the combination treatment. We compared a TRPV2 agonist with etanercept. Both achieved similar effects in suppressing arthritis and reducing joint damage. The combination of both agents was superior than the monotherapies.
登录
查看更多内容
DOI：
10.1523/jneurosci.1384-09.2011
发表时间：
2011-08-10
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Park U;Vastani N;Guan Y;Raja SN;Koltzenburg M;Caterina MJ
通讯作者：
Caterina MJ
影响因子：
5.5
作者：
Larsson, E;Harris, HE;Klareskog, L
通讯作者：
Klareskog, L
依那西普通过调节 BAFFR 表达与脾记忆 B 细胞生成之间的关联来减轻胶原诱导的关节炎。
影响因子：
9.3
作者：
Wang, Qing-tong;Wu, Yu-jing;Wei, Wei
通讯作者：
Wei, Wei
关节炎严重性基因座CIA5D是滑膜成纤维细胞侵入性特性的新型遗传调节剂。
影响因子：
--
作者：
Laragione, Teresina;Brenner, Max;Mello, Adriana;Symons, Marc;Gulko, Percio S.
通讯作者：
Gulko, Percio S.
DOI：
10.1016/j.clim.2015.04.001
发表时间：
2015-06
期刊：
Clinical immunology (Orlando, Fla.)
影响因子：
--
作者：
Laragione T;Cheng KF;Tanner MR;He M;Beeton C;Al-Abed Y;Gulko PS
通讯作者：
Gulko PS