The Rheumatoid Arthritis Risk Gene LBH Regulates Growth in Fibroblast-like Synoviocytes.
The Rheumatoid Arthritis Risk Gene LBH Regulates Growth in Fibroblast-like Synoviocytes.
复制标题
DOI：
10.1002/art.39060
复制
发表时间：
2015-05
影响因子：
13.3
通讯作者：
Firestein, Gary S.
中科院分区：
文献类型：
--
作者：
Ekwall, Anna-Karin H.;Whitaker, John W.;Hammaker, Deepa;Bugbee, William D.;Wang, Wei;Firestein, Gary S.
成纤维细胞样滑膜细胞（FLS）是类风湿关节炎（RA）滑膜病理学的关键参与者。目前，还没有专门针对这些侵袭性细胞的治疗方法。通过结合3个不同的“组学”数据集，即，1)2）RA与骨关节炎（OA）FLS的差异表达基因，3）RA与OA FLS的差异DNA甲基化，我们确定LBH（肢芽和心脏发育）为RA的候选基因。本研究旨在确定该基因在FLS中的作用。关节置换术时采集RA和OA患者的滑膜组织标本。在原代FLS中使用小干扰RNA沉默LBH表达或使用LBH表达载体过表达LBH表达。通过微阵列测定基因表达谱，并使用免疫途径分析进行评估。在功能测定中研究了修饰的LBH表达的影响。类风湿关节炎患者滑膜衬里层表达LBH。转化生长因子β1显著增加了原发性FLS中LBH的表达，而血小板衍生生长因子BB降低了LBH的表达。与对照FLS相比，LBH缺陷型FLS的转录组的通路分析确定“细胞生长和增殖”是最显著富集的通路。在生长测定中，LBH缺乏增加FLS增殖。相反，LBH过表达显著抑制细胞生长。细胞周期分析表明，与对照组相比，LBH缺陷型FLS中进入细胞周期的细胞显著增加。LBH不改变细胞凋亡。LBH是RA滑膜病理的候选基因。它受生长因子调节，并调节原发性FLS中的细胞生长。我们的数据提示RA滑膜内膜增生和关节损伤的新机制。
Fibroblast-like synoviocytes (FLS) are key players in the synovial pathology of rheumatoid arthritis (RA). Currently, there is no treatment that specifically targets these aggressive cells. By combining 3 different “omics” data sets, i.e., 1) risk genes in RA, 2) differentially expressed genes, and 3) differential DNA methylation in RA versus osteoarthritis (OA) FLS, we identified LBH (limb bud and heart development) as a candidate gene in RA. The present study was undertaken to define the role of this gene in FLS. Synovial tissue specimens from RA and OA patients were collected at the time of joint replacement surgery. LBH expression was silenced using small interfering RNA or overexpressed using an LBH expression vector in primary FLS. Gene expression profiles were determined by microarray and assessed using Ingenuity Pathway Analysis. Effects of modified LBH expression were investigated in functional assays. LBH was expressed in the synovial lining layer in patients with RA. Transforming growth factor β1 significantly increased LBH expression in primary FLS, and platelet-derived growth factor BB decreased it. Pathway analysis of the transcriptome of LBH-deficient FLS compared to control FLS identified “cellular growth and proliferation” as the most significantly enriched pathway. In growth assays, LBH deficiency increased FLS proliferation. Conversely, LBH overexpression significantly inhibited cell growth. Cell cycle analysis demonstrated a marked increase in cells entering the cell cycle in LBH-deficient FLS compared to controls. LBH did not alter apoptosis. LBH is a candidate gene for synovial pathology in RA. It is regulated by growth factors and modulates cell growth in primary FLS. Our data suggest a novel mechanism for synovial intimal hyperplasia and joint damage in RA.
登录
查看更多内容
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
2.8
作者：
Ai, Jianping;Wang, Yuequn;Wu, Xiushan
通讯作者：
Wu, Xiushan
影响因子：
27.4
作者：
Del Rey, Manuel J.;Usategui, Alicia;Pablos, Jose L.
通讯作者：
Pablos, Jose L.
影响因子：
4.4
作者：
Bartok, Beatrix;Hammaker, Deepa;Firestein, Gary S.
通讯作者：
Firestein, Gary S.
DOI：
10.1073/pnas.0903103106
发表时间：
2009-06-09
影响因子：
11.1
作者：
Hindorff, Lucia A.;Sethupathy, Praveen;Manolio, Teri A.
通讯作者：
Manolio, Teri A.