Nagy Zsolt B, Gergely Péter, Donáth Judit, Borgulya Gábor, Csanád Mónika, Poór Gyula
National Institute of Rheumatology and Physiotherapy, Budapest, Hungary.
J Bone Miner Res. 2008 Feb;23(2):253-9. doi: 10.1359/jbmr.071021.
We examined the gene expression profile of genes involved in bone metabolism in 23 patients with PD compared with 23 healthy controls. We found a significant overexpression of the genes of the IFN pathway along with a downregulation of tnf-alpha. Our result suggest that IFN-mediated signaling may play important roles in aberrant osteoclastogenesis of PD.
Paget's disease of bone (PD) is characterized by focal regions of highly exaggerated bone remodeling and aberrant osteoclastogenesis. Under physiological conditions, circulating monocytes may serve as early progenitors of osteoclasts and along with peripheral blood lymphocytes produce a wide variety of factors important in bone metabolism. Nevertheless, little is known about the roles of circulating monocytes and lymphocytes in relation to the pathological bone turnover in PD.
In this study, we aimed at investigating the gene expression pattern of PD using quantitative real-time PCR in monocytes and lymphocytes isolated from peripheral blood mononuclear cells (PBMCs). Fifteen genes known to be involved in osteoclastogenesis were studied in cells from 23 patients with PD and in cells from 23 healthy controls. Eight human genes including ifn-alpha (3.48-fold, p < 0.001), ifn-beta (2.68-fold, p < 0.001), ifn-gamma (1.98-fold, p = 0.002), p38 beta2 mapk (2.47-fold, p = 0.002), ifn-gammar1 (2.03-fold, p = 0.01), ifn-gammar2 (1.81-fold, p = 0.02), stat1 (1.57-fold, p = 0.037), and tnf-alpha (-2.34, p < 0.001) were found to be significantly altered in pagetic monocytes compared with monocytes of healthy controls.
In pagetic lymphocytes, significant changes in the expression of ifn-alpha (2.17-fold, p < 0.001), ifn-beta (2.13-fold, p = 0.005), ifn-gamma (1.89-fold, p < 0.001), ifn-gammar1 (1.02-fold, p = 0.04), ifn-gammar2 (1.01-fold, p = 0.031), stat2 (1.79-fold, p < 0.001), and tnf-alpha (-1.49, p < 0.001) were found compared with lymphocytes of healthy controls. Furthermore, IFN-gamma protein was significantly elevated in the sera of PD patients (18.7 +/- 6.69 pg/ml) compared with healthy controls (3.87 +/- 6.48 pg/ml, p = 0.042).
In conclusion, our data suggest that novel pathways mainly related to the IFN-mediated signaling may play important roles in the aberrant osteoclastogenesis of PD.
我们研究了23例帕金森病（PD）患者与23名健康对照者中参与骨代谢的基因表达谱。我们发现IFN途径的基因显著过表达，同时肿瘤坏死因子-α（TNF-α）下调。我们的结果表明，IFN介导的信号传导可能在PD异常破骨细胞生成中起重要作用。
骨Paget病（PD）的特征是骨重塑高度夸张的局部区域和异常的破骨细胞生成。在生理条件下，循环单核细胞可能作为破骨细胞的早期祖细胞，并与外周血淋巴细胞一起产生多种对骨代谢重要的因子。然而，关于循环单核细胞和淋巴细胞在PD病理性骨转换中的作用知之甚少。
在本研究中，我们旨在使用定量实时PCR研究从外周血单核细胞（PBMC）分离的单核细胞和淋巴细胞中PD的基因表达模式。在23例PD患者的细胞和23名健康对照者的细胞中研究了15个已知参与破骨细胞生成的基因。发现8个人类基因，包括干扰素-α（IFN-α，3.48倍，p<0.001）、干扰素-β（IFN-β，2.68倍，p<0.001）、干扰素-γ（IFN-γ，1.98倍，p = 0.002）、p38β2丝裂原活化蛋白激酶（p38β2 MAPK，2.47倍，p = 0.002）、干扰素-γ受体1（IFN-γR1，2.03倍，p = 0.01）、干扰素-γ受体2（IFN-γR2，1.81倍，p = 0.02）、信号转导子和转录激活子1（STAT1，1.57倍，p = 0.037）以及肿瘤坏死因子-α（-2.34，p<0.001）与健康对照者的单核细胞相比在Paget病单核细胞中显著改变。
在Paget病淋巴细胞中，发现与健康对照者的淋巴细胞相比，IFN-α（2.17倍，p<0.001）、IFN-β（2.13倍，p = 0.005）、IFN-γ（1.89倍，p<0.001）、IFN-γR1（1.02倍，p = 0.04）、IFN-γR2（1.01倍，p = 0.031）、信号转导子和转录激活子2（STAT2，1.79倍，p<0.001）以及肿瘤坏死因子-α（-1.49，p<0.001）的表达有显著变化。此外，与健康对照者（3.87±6.48 pg/ml，p = 0.042）相比，PD患者血清中IFN-γ蛋白显著升高（18.7±6.69 pg/ml）。
总之，我们的数据表明主要与IFN介导的信号传导相关的新途径可能在PD异常破骨细胞生成中起重要作用。
