Anti-rheumatic activities of histone deacetylase (HDAC) inhibitors in vivo in collagen-induced arthritis in rodents
Anti-rheumatic activities of histone deacetylase (HDAC) inhibitors in vivo in collagen-induced arthritis in rodents
复制标题
DOI：
10.1038/sj.bjp.0707165
复制
发表时间：
2007-04-01
影响因子：
7.3
通讯作者：
Clement-Lacroix, P.
中科院分区：
文献类型：
--
作者：
Lin, H-S;Hu, C-Y;Clement-Lacroix, P.
背景与目的：类风湿性关节炎（RA）是一种慢性炎症性疾病。组蛋白去乙酰化酶抑制剂（HDACi）是一类新型的抗肿瘤药物，具有较强的抗炎活性。用辛二酰苯胺异羟肟酸（SAHA）和MS-275进行了概念验证研究，这两种HDACi目前正在进行各种肿瘤学indication.Experimental approach的临床研究：在小鼠和大鼠胶原诱导的关节炎（CIA）模型中评估SAHA和MS-275的抗风湿作用。它减弱了由于炎症引起的足肿胀，减少了小鼠和大鼠的骨侵蚀，并轻微减少了RA诱导的大鼠骨吸收。然而，SAHA不能抑制关节炎的发作。相比之下，MS-275显示出显著的抗风湿活性。在预防性干预中，高剂量的MS-275可预防骨侵蚀并显著延迟关节炎的发作;在低剂量下，MS-275可强烈减弱与RA相关的爪肿胀、骨侵蚀和骨吸收。此外，还记录了MS-275的疗效。在关节炎发作后，它可以阻止疾病的进展和关节破坏。MS-275的抗炎作用也通过其在CIA诱导的小鼠模型中降低血清IL-6和IL-1b水平的能力得到证实。MS-275的抗风湿活性也通过组织学观察得到证实。没有滑膜增生，血管翳形成，软骨或骨破坏，观察在高剂量的预防性干预在mice.Conclusion和含义：这项研究强烈支持HDACi作为一种创新的治疗策略，RA。
Background and purpose: Rheumatoid arthritis (RA) is a chronic inflammatory disease. Histone deacetylase inhibitors (HDACi), a new class of anti-cancer agents, have recently been reported to exhibit potent anti-inflammatory activities. A proof of concept study was carried out with suberoylanilide hydroxamic acid (SAHA) and MS-275, two HDACi currently undergoing clinical investigations for various oncological indications.Experimental approach: The anti-rheumatic effects of SAHA and MS-275 were assessed in both mouse and rat collagen induced arthritis (CIA) models.Key results: SAHA exhibited moderate prophylactic efficacy. It attenuated paw swelling due to inflammation, decreased bone erosion in both mice and rats and reduced slightly the RA-induced bone resorption in rats. However, SAHA could not inhibit the onset of arthritis. In contrast, MS-275 displayed dramatic anti-rheumatic activities. In prophylactic intervention, high doses of MS-275 prevented bone erosion and markedly delayed the onset of arthritis; at low doses, MS-275 strongly attenuated paw swelling, bone erosion, and bone resorption associated with RA. Furthermore, the therapeutic efficacy of MS-275 was also documented. After the onset of arthritis, it could stop the disease progression and joint destruction.. An anti inflammatory effect of MS-275 was also confirmed through its capacity to decrease serum IL-6 and IL-1b levels in the CIA induced mouse model. The anti-rheumatic activity of MS-275 was also confirmed through histological observation. No synovial hyperplasia, pannus formation, cartilage or bone destruction were observed in the high dose prophylactic intervention in mice.Conclusion and implication: This study strongly supported HDACi as an innovative therapeutic strategy for RA.