A selective c-Fos/AP-1 inhibitor prevents cartilage destruction and subsequent osteophyte formation
A selective c-Fos/AP-1 inhibitor prevents cartilage destruction and subsequent osteophyte formation
复制标题
DOI：
10.1016/j.bbrc.2018.02.147
复制
发表时间：
2018-03-04
影响因子：
3.1
通讯作者：
Kimura, Tomoatsu
中科院分区：
文献类型：
--
作者：
Motomura, Hiraku;Seki, Shoji;Kimura, Tomoatsu
本研究的目的是证明一种新开发的选择性c-Fos/激活蛋白（AP）-1抑制剂，T-5224，抑制基质金属蛋白酶（MMPs）在人关节软骨细胞的表达，并防止骨关节炎（OA）诱导的小鼠模型中的软骨破坏。首先，我们通过实时聚合酶链反应检测了T-5224对人关节软骨细胞MMP和炎性细胞因子表达的影响。我们通过破坏小鼠内侧半月板（DMM）的稳定性建立了OA模型。T-5224每日一次口服给药，通过组织学、免疫组织化学和显微计算机断层扫描（CT）分析评估OA病理学。T-5224抑制IL-1刺激的人软骨细胞中MMP-1、3和13以及白细胞介素（IL）-1 β、肿瘤坏死因子（TNF）-α和IL-6的mRNA表达水平。对OA诱导的小鼠口服T-5224可防止软骨破坏。T-5224给药组的OA组织学评分显著优于溶剂给药组。免疫组织化学染色显示，T-5224治疗组的X型胶原和MMP-13没有增加。Micro-CT分析显示，溶媒给药组股骨髁和胫骨前内侧出现轻度但明显的骨赘生长，但T-5224给药组未出现。总之，c-Fos/AP-1的特异性抑制和由此产生的对广谱下游MMP的反式激活的抑制，沿着炎性细胞因子，有效地防止了软骨破坏和骨赘形成。(C)2018爱思唯尔公司All rights reserved.
The objective of the present study is to demonstrate that a newly developed selective c-Fos/activator protein (AP)-1 inhibitor, T-5224, inhibits the expression of matrix metalloproteinases (MMPs) in human articular chondrocytes, and prevents cartilage destruction in an osteoarthritis (OA)-induced mouse model. First, we examined the effect of T-5224 on MMP and inflammatory cytokine expression by real-time polymerase chain reaction in human articular chondrocytes. We created an OA model by destabilization of the medial meniscus (DMM) in mice. T-5224 was orally administered once a day and the OA pathology was assessed by histological, immunohistochemical, and micro-computed tomography (CT) analyses. T-5224 inhibited the mRNA expression levels of MMP-1, 3, and 13, and interleukin (IL)-1 beta, tumor necrosis factor (TNF)-alpha and IL-6 in IL-1-stimulated human chondrocytes. Oral administration of T-5224 to OA -induced mice prevented cartilage destruction. The histological scores for OA were significantly better in the T-5224-treated group than the vehicle-treated group. Type X collagen and MMP-13 were not increased in the T-5224-treated group by immunohistochemical staining. Micro-CT analysis showed mild but apparent osteophyte development in the femoral condyle and antero-medial aspect of the tibia in the vehicle-treated group but not in the T-5224-treated group. Taken together, specific inhibition of c-Fos/AP-1 and the resulting inhibition of the transactivation of a broad spectrum of downstream MMPs, along with inflammatory cytokines, effectively prevented cartilage destruction and osteophyte formation. (C) 2018 Elsevier Inc. All rights reserved.