The arthritis severity locus Cia5d is a novel genetic regulator of the invasive properties of synovial fibroblasts.
The arthritis severity locus Cia5d is a novel genetic regulator of the invasive properties of synovial fibroblasts.
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关节炎严重性基因座CIA5D是滑膜成纤维细胞侵入性特性的新型遗传调节剂。
DOI：
10.1002/art.23610
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发表时间：
2008-08
影响因子：
--
通讯作者：
Gulko, Percio S.
中科院分区：
文献类型：
--
作者：
Laragione, Teresina;Brenner, Max;Mello, Adriana;Symons, Marc;Gulko, Percio S.
滑膜成纤维细胞或成纤维样滑膜细胞 (FLS) 在类风湿性关节炎 (RA) 的血管翳侵袭以及软骨和骨破坏中发挥核心作用。然而，FLS 的监管仍不完全清楚。本研究的目的是确定 FLS 的侵袭特性是否受关节炎严重程度位点的基因调控。研究了 DA 大鼠（关节炎易感）和关节炎保护期同源大鼠品系。原代 FLS 细胞系由每个菌株产生，并通过富含胶原蛋白的屏障用于完善的 FLS 侵袭模型。分析细胞或培养上清液的基因表达、不同基质金属蛋白酶 (MMP) 的活性、细胞骨架完整性和细胞增殖。与DA大鼠侵入FLS的中位数量相比，DA.F344(Cia5d)大鼠侵入富含胶原蛋白屏障的FLS中位数量减少了86.5%。组织学检查显示DA.F344(Cia5d)大鼠保留了正常的关节，没有血管翳、增生或糜烂。与 DA 大鼠的 FLS 相比，DA.F344(Cia5d) 大鼠的 FLS 产生的活性 MMP-2 水平显着降低，但 DA.F344(Cia5d) 大鼠中 proMMP-2 和 MMP-2 信使 RNA 的水平与 DA 大鼠相似。用 MMP-2 抑制剂处理 DA 大鼠的 FLS 将细胞侵袭减少至与 DA.F344(Cia5d) 大鼠相似的水平，证明 MMP-2 活性解释了这 2 个品系的 FLS 之间的差异。 MMP-2 激活途径分析显示，与 DA.F344(Cia5d) 大鼠相比，DA 大鼠中 1 型可溶性膜 (MT1)-MMP 水平升高。这些数据代表了 FLS 入侵调节中遗传成分的第一个证据。位于 Cia5d 间隔内的一个基因负责这种效应，并通过调节可溶性 MT1-MMP 产生和 MMP-2 激活来发挥作用。这些观察结果表明了预测和治疗的新的潜在途径。
The synovial fibroblast, or fibroblast-like synoviocyte (FLS), has a central role in pannus invasion and destruction of cartilage and bone in rheumatoid arthritis (RA). However, regulation of the FLS remains incompletely understood. The aim of this study was to determine whether the invasive properties of FLS are genetically regulated by arthritis severity loci. DA rats (arthritis susceptible) and rat strains congenic for arthritis-protective intervals were studied. Primary FLS cell lines were generated from each strain and used in a well-established FLS invasion model through a collagen-rich barrier. Cells or culture supernatants were analyzed for gene expression, activity of different matrix metalloproteinases (MMPs), cytoskeleton integrity, and cell proliferation. The median number of FLS from DA.F344(Cia5d) rats that invaded through the collagen-rich barrier was reduced 86.5% compared with the median number of invading FLS from DA rats. Histologic examination showed that DA.F344(Cia5d) rats preserved a normal joint without pannus, hyperplasia, or erosions. FLS from DA.F344(Cia5d) rats produced significantly lower levels of active MMP-2 compared with FLS from DA rats, but the levels of proMMP-2 and MMP-2 messenger RNA in DA.F344(Cia5d) rats were similar to those in DA rats. Treatment of FLS from DA rats with an MMP-2 inhibitor reduced cell invasion to a level similar to that in DA.F344(Cia5d) rats, demonstrating that MMP-2 activity accounted for the difference between FLS from these 2 strains. Analysis of MMP-2–activating pathways revealed increased levels of soluble membrane type 1 (MT1)–MMP in DA rats compared with DA.F344(Cia5d) rats. These data represent the first evidence for a genetic component in the regulation of FLS invasion. A gene located within the Cia5d interval accounts for this effect and operates via the regulation of soluble MT1-MMP production and MMP-2 activation. These observations suggest novel potential pathways for prognostication and therapy.
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影响因子：
15.3
作者：
FAVA, RA;OLSEN, NJ;TOWNES, AS
通讯作者：
TOWNES, AS
影响因子：
158.5
作者：
Edwards, JCW;Szczepanski, L;Shaw, T
通讯作者：
Shaw, T
影响因子：
4.8
作者：
Hanemaaijer, R;Sorsa, T;Salo, T
通讯作者：
Salo, T
DOI：
10.1186/ar79
发表时间：
2000
期刊：
Arthritis research
影响因子：
--
作者：
Goldbach-Mansky R;Lee JM;Hoxworth JM;Smith D 2nd;Duray P;Schumacher RH Jr;Yarboro CH;Klippel J;Kleiner D;El-Gabalawy HS
通讯作者：
El-Gabalawy HS
影响因子：
--
作者：
Brenner, M;Meng, HC;Gulko, NS
通讯作者：
Gulko, NS