Hypoxia upregulates angiogenesis and synovial cell migration in rheumatoid arthritis.
Hypoxia upregulates angiogenesis and synovial cell migration in rheumatoid arthritis.
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DOI：
10.1186/ar2689
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发表时间：
2009
影响因子：
4.9
通讯作者：
Paleolog EM
中科院分区：
文献类型：
--
作者：
Akhavani MA;Madden L;Buysschaert I;Sivakumar B;Kang N;Paleolog EM
类风湿性关节炎（RA）的特征是软骨、骨和肌腱受到滑膜炎症的侵袭。我们实验室以前的研究表明缺氧是类风湿性关节炎滑膜炎的一个特征。在本研究中，我们研究了缺氧对RA血管生成和滑膜成纤维细胞迁移的影响。从RA患者身上采集滑膜组织，在缺氧（1%氧气）或常氧（21%氧气）条件下培养滑膜细胞。测定基质金属蛋白酶（MMPs）和血管生成因子的蛋白水平，提取RNA用于PCR定量MMPs/ MMP组织抑制剂（TIMPs）和血管生成因子。RA滑膜成纤维细胞通过胶原的迁移，以及RA滑膜细胞上清液在体外血管生成实验中的作用，被用来确定mRNA/蛋白变化的功能相关性。我们观察到在缺氧条件下，负责胶原分解的MMPs，特别是胶原酶MMP-8，明胶酶MMP-2和MMP-9的mRNA和蛋白水平均上调。MT1-MMP mRNA升高，但对TIMP-1和TIMP-2无影响。在缺氧条件下，RA成纤维细胞跨胶原迁移显著增加，并依赖于MMP活性。此外，血管生成刺激因子，如血管内皮生长因子（VEGF）和VEGF/胎盘生长因子异源二聚体的表达也增加。至关重要的是，我们首次表明缺氧增加了RA细胞的血管生成驱动，正如在体外血管生成实验中增强血管形成所证明的那样。缺氧可能导致RA滑膜内膜促血管生成和促侵入，从而导致RA的衰弱特征。
Rheumatoid arthritis (RA) is characterised by invasion of cartilage, bone and tendon by inflamed synovium. Previous studies in our laboratory have shown that hypoxia is a feature of RA synovitis. In the present study, we investigated the consequences of hypoxia on angiogenesis and synovial fibroblast migration in RA. Synovial tissue was harvested from RA patients, and synovial membrane cells were cultured under conditions either of hypoxia (1% oxygen) or normoxia (21% oxygen). Protein levels of matrix metalloproteinases (MMPs) and angiogenic factors were measured, while RNA was extracted for PCR quantification of MMPs/tissue inhibitors of MMP (TIMPs) and angiogenic factors. Migration of RA synovial fibroblasts through collagen, and the effect of RA synovial cell supernatants in an in vitro angiogenesis assay, were utilised to determine the functional relevance of changes in mRNA/protein. We observed upregulation under hypoxic conditions of MMPs responsible for collagen breakdown, specifically collagenase MMP-8, and the gelatinases MMP-2 and MMP-9, at both mRNA and protein levels. Increased MT1-MMP mRNA was also observed, but no effect on TIMP-1 or TIMP-2 was detected. RA fibroblast migration across collagen was significantly increased under hypoxic conditions, and was dependent on MMP activity. Furthermore, expression of angiogenic stimuli, such as vascular endothelial growth factor (VEGF), and VEGF/placental growth factor heterodimer, was also increased. Crucially, we show for the first time that hypoxia increased the angiogenic drive of RA cells, as demonstrated by enhanced blood vessel formation in an in vitro angiogenesis assay. Hypoxia may be responsible for rendering RA synovial lining proangiogenic and proinvasive, thus leading to the debilitating features characteristic of RA.
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影响因子：
1.9
作者：
BROWN, FE;BROWN, ML
通讯作者：
BROWN, ML
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Zhang, Yufeng
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Giatromanolaki, A;Sivridis, E;Koukourakis, MI
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Persico, MG
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作者：
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THOMAS, KA