Therapeutic promise of proteinase-activated receptor-2 antagonism in joint inflammation
Therapeutic promise of proteinase-activated receptor-2 antagonism in joint inflammation
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DOI：
10.1124/jpet.105.093807
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发表时间：
2006-03-01
影响因子：
3.5
通讯作者：
Ferrell, WR
中科院分区：
文献类型：
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作者：
Kelso, EB;Lockhart, JC;Ferrell, WR
生物疗法，如肿瘤坏死因子- α抑制剂，促进了类风湿性关节炎的治疗，但三分之一的患者对这种疗法没有反应。此外，这些抑制剂现在通常与传统的改善疾病的抗风湿药物联合使用，这表明它们尚未实现其早期的承诺。本研究探讨了一个新的治疗靶点，蛋白酶激活受体(PAR)-2，在关节炎症。小鼠关节内注射卡拉胶/高岭土（C/K）导致关节肿胀，与滑膜PAR 2上调有关。免疫印迹证实，使用小干扰RNA技术抑制受体上调可显著降低关节炎症反应。丝氨酸蛋白酶诱导的关节肿胀主要通过PAR 2激活介导，因为在PAR 2敲除小鼠中对外源性胰蛋白酶和胰蛋白酶的应用没有反应。此外，丝氨酸蛋白酶抑制剂是有效的抗炎药。使用靶向受体裂解/激活位点的抗血清（B5）破坏PAR 2的蛋白水解激活也能减轻C/ k诱导的炎症，同样靶向PAR 2单克隆抗体SAM-11也能减轻炎症。最后，我们报道了一种新型的小分子PAR 2拮抗剂n -1-3-甲基丁基- n -4-6-氨基己基哌嗪（ENMD-1068）的活性，它可以剂量依赖性地减轻关节炎症。我们的研究结果在共同确定par2作为未来关节炎治疗的新靶点方面取得了重大进展。
Biological therapies such as tumor necrosis factor-alpha inhibitors have advanced the treatment of rheumatoid arthritis, but one-third of patients do not respond to such therapy. Furthermore, these inhibitors are now usually administered in combination with conventional disease-modifying antirheumatic drugs, suggesting they have not achieved their early promise. This study investigates a novel therapeutic target, proteinase-activated receptor ( PAR)-2, in joint inflammation. Intra-articular carrageenan/kaolin ( C/K) injection in mice resulted in joint swelling that was associated with synovial PAR 2 up-regulation. Inhibiting receptor up-regulation using small interfering RNA technology, as confirmed by immunoblotting, substantially reduced the inflammatory response in the joint. Serine proteinase-induced joint swelling was mediated primarily via PAR 2 activation, since the response to exogenous application of trypsin and tryptase was absent in PAR 2 knockout mice. Furthermore, serine proteinase inhibitors were effective anti-inflammatory agents in this model. Disrupting proteolytic activation of PAR 2 using antiserum ( B5) directed to the receptor cleavage/activation site also attenuated C/K-induced inflammation, as did the similarly targeted PAR 2 monoclonal antibody SAM-11. Finally, we report the activity of a novel small molecule PAR 2 antagonist, N-1-3-methylbutyryl-N-4-6-aminohexanoyl-piperazine ( ENMD-1068), that dose dependently attenuated joint inflammation. Our findings represent a major advance in collectively identifying PAR 2 as a novel target for the future treatment of arthritis.