Upregulated hypoxia inducible factor-1α and -2α pathway in rheumatoid arthritis and osteoarthritis
Upregulated hypoxia inducible factor-1α and -2α pathway in rheumatoid arthritis and osteoarthritis
复制标题
DOI：
10.1186/ar756
复制
发表时间：
2003-01-01
影响因子：
4.9
通讯作者：
Koukourakis, MI
中科院分区：
文献类型：
--
作者：
Giatromanolaki, A;Sivridis, E;Koukourakis, MI
类风湿性关节炎（RA）和骨关节炎（OA）的发病机制仍然不清楚，虽然血管生成似乎发挥了重要作用。我们最近证实了过度表达的两种血管生成因子，即血管内皮生长因子（VEGF）和血小板衍生的内皮细胞生长因子（PD-ECGF），由衬里和基质细胞的滑膜在这两种条件。由于缺氧诱导因子（HIF）-1 α和HIF-2 α在调节VEGF基因转录中是必不可少的，因此可以预期HIF-α分子在这些关节炎的发病机制中的积极参与。我们研究了HIF-1 α和HIF-2 α在22例RA患者、34例OA患者和22例“正常”非关节炎个体滑膜中的免疫组化表达，与VEGF、VEGF/KDR（激酶插入域蛋白受体）血管活化、PD-ECGF和bcl-2的关系。与正常相比，两种疾病的滑膜衬里和基质细胞中HIF-1 α和HIF-2 α的细胞质和细胞核显著过表达。HIF-α的过表达与高微血管密度、高PD-ECGF表达和高VEGF/KDR受体活化相关，表明OA中存在HIF-α依赖性滑膜血管生成。相比之下，血管生成VEGF/KDR途径的激活在RA中持续增加，微血管密度和PD-ECGF的表达也确实增加，而与HIF-α表达的程度无关，表明了精氨酸依赖性血管生成。在所有情况下，OA中的VEGF/KDR血管活化显著低于RA，表明HIF-α途径相对未能有效产生OA的可行血管系统，这与疾病的退行性性质一致。HIF-α通路的激活发生在RA和OA中，尽管原因不相关。
The pathogenesis of rheumatoid arthritis (RA) and osteoarthritis (OA) remains obscure, although angiogenesis appears to play an important role. We recently confirmed an overexpression of two angiogenic factors, namely vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor (PD-ECGF), by the lining and stromal cells of the synovium in both conditions. Because hypoxia inducible factor (HIF)-1alpha and HIF-2alpha are essential in regulating transcription of the VEGF gene, active participation of HIF-alpha molecules in the pathogenesis of these arthritides is anticipated. We investigated the immunohistochemical expression of HIF-1alpha and HIF-2alpha in the synovium of 22 patients with RA, 34 patients with OA and 22 'normal' nonarthritic individuals, in relation to VEGF, VEGF/KDR (kinase insert domain protein receptor) vascular activation, PD-ECGF and bcl-2. A significant cytoplasmic and nuclear overexpression of HIF-1alpha and HIF-2alpha was noted in the synovial lining and stromal cells of both diseases relative to normal. Overexpression of HIF-alphas was related to high microvessel density, high PD-ECGF expression and high VEGF/KDR receptor activation, suggesting HIF-alpha-dependent synovial angiogenesis in OA. By contrast, the activation of the angiogenic VEGF/KDR pathway was persistently increased in RA, as indeed was microvessel density and the expression of PD-ECGF, irrespective of the extent of HIF-alpha expression, indicating a cytokine-dependent angiogenesis. In all cases, the VEGF/KDR vascular activation was significantly lower in OA than in RA, suggesting a relative failure of the HIF-alpha pathway to effectively produce a viable vasculature for OA, which is consistent with the degenerative nature of the disease. The activation of the HIF-alpha pathway occurs in both RA and OA, although for unrelated reasons.