Schopf Lisa, Savinainen Anneli, Anderson Karen, Kujawa Julie, DuPont Michelle, Silva Matthew, Siebert Elizabeth, Chandra Sudeep, Morgan Jennifer, Gangurde Pranoti, Wen Danyi, Lane Joan, Xu Yajun, Hepperle Michael, Harriman Geraldine, Ocain Timothy, Jaffee Bruce
Millennium Pharmaceuticals, Cambridge, Massachusetts, USA.
Arthritis Rheum. 2006 Oct;54(10):3163-73. doi: 10.1002/art.22081.
The IKK complex regulates NF-kappaB activation, an important pathway implicated in the rheumatoid arthritis (RA) disease process. This study was undertaken to assess the efficacy of N-(6-chloro-7-methoxy-9H-beta-carbolin-8-yl)-2-methylnicotinamide (ML120B), a potent and selective small molecule inhibitor of IKKbeta.
Polyarthritis was induced in rats by injection of Freund's complete adjuvant into the hind footpad. ML120B was administered orally twice daily, either prophylactically or therapeutically. Paw volumes and body weights were measured every 2-3 days throughout the study. We assessed bone erosions by several methods: histologic evaluation, quantitative micro-computed tomography (micro-CT) imaging analysis, and measurement of type I collagen fragments in the serum. Quantitative polymerase chain reaction was used to evaluate expression of messenger RNA for genes related to inflammation and to bone and cartilage integrity.
Oral administration of ML120B inhibited paw swelling in a dose-dependent manner (median effective dosage 12 mg/kg twice daily) and offered significant protection against arthritis-induced weight loss as well as cartilage and bone erosion. We were able to directly demonstrate that NF-kappaB activity in arthritic joints was reduced after ML120B administration. Also, we observed that down-regulation of the NF-kappaB pathway via IKKbeta inhibition dampened the chronic inflammatory process associated with rat adjuvant-induced arthritis.
The results of the present study suggest that IKKbeta inhibition is an effective therapeutic approach to treat both the inflammation and the bone/cartilage destruction observed in RA. Methods for the determination of serum markers for bone and cartilage destruction, as well as micro-CT analysis, may aid in predicting and evaluating the therapeutic efficacy of IKKbeta inhibition therapy in humans.
IKK复合物调节核因子κB（NF-κB）的激活，这是类风湿关节炎（RA）疾病进程中一条重要的信号通路。本研究旨在评估N-（6-氯-7-甲氧基-9H-β-咔啉-8-基）-2-甲基烟酰胺（ML120B）的疗效，它是一种强效且具有选择性的IKKβ小分子抑制剂。
通过将弗氏完全佐剂注射到大鼠后足垫诱导多关节炎。ML120B每日口服两次，分别进行预防性给药或治疗性给药。在整个研究过程中，每2-3天测量一次爪体积和体重。我们通过几种方法评估骨侵蚀：组织学评估、定量微计算机断层扫描（micro-CT）成像分析以及血清中I型胶原片段的测量。采用定量聚合酶链反应来评估与炎症以及骨和软骨完整性相关基因的信使核糖核酸（mRNA）表达。
口服ML120B以剂量依赖性方式抑制爪肿胀（中位有效剂量为每日两次12mg/kg），并对关节炎引起的体重减轻以及软骨和骨侵蚀提供显著保护。我们能够直接证明给药后关节炎关节中的NF-κB活性降低。此外，我们观察到通过抑制IKKβ下调NF-κB信号通路可减轻与大鼠佐剂诱导性关节炎相关的慢性炎症过程。
本研究结果表明，抑制IKKβ是治疗RA中观察到的炎症以及骨/软骨破坏的一种有效治疗方法。用于测定骨和软骨破坏血清标志物的方法以及micro-CT分析，可能有助于预测和评估IKKβ抑制疗法在人类中的治疗效果。
