Giatromanolaki A, Sivridis E, Athanassou N, Zois E, Thorpe P E, Brekken R A, Gatter K C, Harris A L, Koukourakis I M, Koukourakis M I
Department of Pathology, Democritus University of Thrace, P.O. Box 12, Alexandroupolis 68100, Greece.
J Pathol. 2001 May;194(1):101-8. doi: 10.1002/path.842.
Active angiogenesis, together with an up-regulation of angiogenic factors, is evident in the synovium of both rheumatoid arthritis (RA) and osteoarthritis (OA). The present study assessed, by immunohistochemistry, the microvessel density in the synovium of these arthritides and in normal controls, in relation to the expression of the angiogenic factors vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor (PD-ECGF) and the apoptosis-related proteins bcl-2 and p53. More importantly, using the novel 11B5 MAb, the activated "VEGF/flk-1(KDR)-receptor" microvessel density was assessed. VEGF expression in fibroblasts was diffuse in both RA and OA. Diffuse PD-ECGF expression of fibroblasts was noted in all cases of RA, while fibroblast reactivity was focal in the OA material. The standard microvessel density (sMVD), as assessed with the anti-CD31 monoclonal antibody (MAb), was higher in RA (64+/-12) and in OA (65+/-16) than in normal tissues (52+/-8; p=0.008 and 0.0004, respectively). The activated microvessel density (aMVD), assessed with the 11B5 MAb, was significantly higher in RA (29+/-10) than in OA (17+/-4; p<0.0001) and than in normal tissues (14+/-2; p<0.0001). The "activation ratio" (aMVD/sMVD) was statistically higher in RA (0.46+/-0.17) than in OA and normal synovial tissues, the latter two having a similar ratio (0.28+/-0.08 and 0.26+/-0.03, respectively). Cytoplasmic bcl-2 expression was frequent in the synovial cells of OA, but rare in RA. Nuclear p53 protein accumulation was never observed. It is suggested that the angiogenic pathway VEGF/flk-1(KDR) may play an important role in the pathogenesis of RA and OA. Thus, failure of VEGF/flk-1(KDR) activation, in the presence of increased VEGF expression, may indicate a synovium with an impaired capacity to establish a viable vasculature, consistent with the degenerative nature of OA. On the other hand, the activated angiogenesis in RA shows a functional, still pathologically up-regulated VEGF/flk-1(KDR) pathway. Whether restoration of an impaired VEGF/flk-1(KDR) pathway in OA, or inhibition of this in RA, would prove of therapeutic importance requires further investigation.
类风湿关节炎（RA）和骨关节炎（OA）的滑膜中均存在活跃的血管生成，同时血管生成因子上调。本研究通过免疫组织化学评估了这些关节炎滑膜及正常对照滑膜中的微血管密度，以及血管生成因子血管内皮生长因子（VEGF）、血小板衍生内皮细胞生长因子（PD - ECGF）和凋亡相关蛋白bcl - 2及p53的表达。更重要的是，使用新型11B5单克隆抗体评估了活化的“VEGF/flk - 1(KDR)受体”微血管密度。RA和OA中，成纤维细胞的VEGF表达均呈弥漫性。所有RA病例中，成纤维细胞的PD - ECGF表达呈弥漫性，而在OA组织中，成纤维细胞反应呈局灶性。用抗CD31单克隆抗体（MAb）评估的标准微血管密度（sMVD）在RA（64±12）和OA（65±16）中高于正常组织（52±8；p分别为0.008和0.0004）。用11B5单克隆抗体评估的活化微血管密度（aMVD）在RA（29±10）中显著高于OA（17±4；p<0.0001）和正常组织（14±2；p<0.0001）。“活化率”（aMVD/sMVD）在RA（0.46±0.17）中在统计学上高于OA和正常滑膜组织，后两者比率相似（分别为0.28±0.08和0.26±0.03）。OA滑膜细胞中细胞质bcl - 2表达常见，而在RA中少见。未观察到核p53蛋白积累。提示血管生成途径VEGF/flk - 1(KDR)可能在RA和OA的发病机制中起重要作用。因此，在VEGF表达增加的情况下，VEGF/flk - 1(KDR)激活失败可能表明滑膜建立可行脉管系统的能力受损，这与OA的退行性本质一致。另一方面，RA中活化的血管生成显示出功能性但仍在病理上上调的VEGF/flk - 1(KDR)途径。OA中受损的VEGF/flk - 1(KDR)途径是否恢复，或RA中该途径是否被抑制具有治疗重要性，尚需进一步研究。
