Lin H-S, Hu C-Y, Chan H-Y, Liew Y-Y, Huang H-P, Lepescheux L, Bastianelli E, Baron R, Rawadi G, Clément-Lacroix P
Proskelia a Galapagos Company, Romainville, France.
Br J Pharmacol. 2007 Apr;150(7):862-72. doi: 10.1038/sj.bjp.0707165. Epub 2007 Feb 26.
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.
The anti-rheumatic effects of SAHA and MS-275 were assessed in both mouse and rat collagen induced arthritis (CIA) models.
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-1beta 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.
This study strongly supported HDACi as an innovative therapeutic strategy for RA.
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）是一类新型抗癌药物，最近有报道称其具有强大的抗炎活性。本研究以辛二酰苯胺异羟肟酸（SAHA）和MS - 275进行了概念验证，这两种HDACi目前正针对各种肿瘤适应症进行临床研究。
在小鼠和大鼠胶原诱导性关节炎（CIA）模型中评估了SAHA和MS - 275的抗风湿作用。
SAHA表现出中等的预防效果。它减轻了炎症引起的爪肿胀，减少了小鼠和大鼠的骨侵蚀，并略微降低了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表现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；在低剂量时，MS - 275可强烈减轻与RA相关的爪肿胀、骨侵蚀和骨吸收。此外，还记录了MS - 275的治疗效果。关节炎发作后，它可以阻止疾病进展和关节破坏。通过降低CIA诱导的小鼠模型中的血清IL - 6和IL - 1β水平，也证实了MS - 275的抗炎作用。通过组织学观察也证实了MS - 275的抗风湿活性。在小鼠高剂量预防性干预中未观察到滑膜增生、血管翳形成、软骨或骨破坏。
本研究有力地支持了HDACi作为RA的一种创新治疗策略。
