Liu X, Mashour G A, Webster H F, Kurtz A
Laboratory of Experimental Neuropathology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
Glia. 1998 Dec;24(4):390-7. doi: 10.1002/(sici)1098-1136(199812)24:4<390::aid-glia4>3.0.co;2-1.
Heparin-binding growth factors have been implicated in central nervous system development, regeneration and pathology. To assess the expression pattern and possible function in multiple sclerosis, the heparin-binding growth factors pleiotrophin (PTN), midkine (MK), basic fibroblast growth factor (FGF-2) and one of its receptors (FGFR1/flg) mRNA and protein levels were examined in an experimental autoimmune encephalomyelitis (EAE) model in the Lewis rat. We assessed the time course of expression of PTN, MK and FGF-2 during EAE and determined the cellular origin of FGF-2 and FGFR1 in normal spinal cord and during inflammatory demyelination. Basal expression of PTN and MK mRNAs in normal spinal cords was significantly upregulated after induction of EAE. MK expression was upregulated two to threefold correlating with disease progression, whereas PTN expression reached peak levels threefold above basal levels during the clinical recovery period. FGF-2 mRNA expression was low in normal spinal cord and dramatically increased in correlation with progressive demyelination. FGF-2 was confined to neurons in normal tissue and shifted dramatically to microglia, paralleling their activation during EAE. Double immunohistochemistry revealed colocalization of FGF-2 to activated microglia/macrophages with strongest expression in the macrophage-rich perivascular core area and microglial expression at the edges of white and gray matter perivascular regions. FGFR1, like its ligand, was induced in activated macrophages/microglia. Growth factor expression in demyelinating diseases could serve several functions, e.g., to modulate the activity of microglia/macrophage in an autocrine fashion, to induce the expression of other factors like insulin-like growth factor 1 or plasminogen activator, which can effect regeneration or degeneration, respectively, and finally to stimulate directly localized proliferation and/or regeneration of oligodendrocytes within the lesion area.
肝素结合生长因子与中枢神经系统的发育、再生及病理过程有关。为评估其在多发性硬化症中的表达模式及可能的功能，我们检测了Lewis大鼠实验性自身免疫性脑脊髓炎（EAE）模型中肝素结合生长因子多效生长因子（PTN）、中期因子（MK）、碱性成纤维细胞生长因子（FGF-2）及其一种受体（FGFR1/flg）的mRNA和蛋白水平。我们评估了EAE过程中PTN、MK和FGF-2的表达时间进程，并确定了正常脊髓及炎性脱髓鞘过程中FGF-2和FGFR1的细胞来源。EAE诱导后，正常脊髓中PTN和MK mRNA的基础表达显著上调。MK表达上调两到三倍，与疾病进展相关，而PTN表达在临床恢复期达到高于基础水平三倍的峰值。FGF-2 mRNA在正常脊髓中表达较低，与进行性脱髓鞘相关而显著增加。FGF-2在正常组织中局限于神经元，在EAE期间随着小胶质细胞的激活而显著转移至小胶质细胞。双重免疫组化显示FGF-2与活化的小胶质细胞/巨噬细胞共定位，在富含巨噬细胞的血管周围核心区域表达最强，在白质和灰质血管周围区域边缘有小胶质细胞表达。FGFR1与其配体一样，在活化的巨噬细胞/小胶质细胞中被诱导表达。脱髓鞘疾病中的生长因子表达可能具有多种功能，例如以自分泌方式调节小胶质细胞/巨噬细胞的活性，诱导其他因子如胰岛素样生长因子1或纤溶酶原激活剂的表达，它们可分别影响再生或退变，最终直接刺激病变区域内少突胶质细胞的局部增殖和/或再生。
