Iyengar Laxmi, Patkunanathan Bramilla, McAvoy John W, Lovicu Frank J
Save Sight Institute, University of Sydney, NSW, Australia.
Growth Factors. 2009 Feb;27(1):50-62. doi: 10.1080/08977190802610916.
Lens epithelial cell proliferation is regulated by growth factors in the aqueous humour of the eye. Although the lens fibre cell-differentiating factors are well defined, the factors in aqueous that promote lens cell proliferation are not. Mitogens present in aqueous primarily signal through the MAPK/ERK and PI3-K/Akt pathways. By characterising the signalling pathways involved in lens cell proliferation, we aim to identify the factors in aqueous that regulate this process in vivo. Using rat lens epithelial explants, 5'-2'-bromo-deoxyuridine and H(3)-thymidine incorporation were used to compare the effects of aqueous, insulin-like growth factor (IGF-1), platelet-derived growth factor (PDGF-A), epidermal growth factor (EGF) and fibroblast growth factor (FGF-2) on lens cell proliferation. Western blotting was employed to characterise ERK1/2 and Akt signalling induced by these mitogens. The above assays were also repeated in the presence of selective receptor inhibitors. Similar to aqueous, FGF induced a sustained ERK1/2 signalling profile (up to 6 h), unlike IGF, PDGF and EGF that induced a transient activation of ERK1/2. In the presence of a FGF receptor (FGFR) inhibitor, the sustained aqueous-induced ERK1/2 signalling profile was perturbed, resembling the transient IGF-, PDGF- or EGF-induced profile. In the presence of other growth factor receptor inhibitors, aqueous maintained its sustained, 6 h, ERK1/2 signalling profile, although ERK1/2 phosphorylation at earlier time periods was reduced. No one-specific receptor inhibitor could block aqueous-induced lens cell proliferation; however, combinations of inhibitors could, providing FGFR signalling was blocked. Multiple growth factors are likely to regulate lens cell proliferation in vivo, with a key role for FGF in aqueous-induced signalling and lens cell proliferation.
晶状体上皮细胞的增殖受眼房水中生长因子的调节。虽然晶状体纤维细胞分化因子已明确，但房水中促进晶状体细胞增殖的因子尚不明确。房水中存在的促有丝分裂原主要通过MAPK/ERK和PI3-K/Akt信号通路发挥作用。通过对晶状体细胞增殖所涉及的信号通路进行表征，我们旨在确定房水中在体内调节这一过程的因子。使用大鼠晶状体上皮外植体，通过5'-2'-溴脱氧尿苷和H(3)-胸苷掺入来比较房水、胰岛素样生长因子（IGF-1）、血小板衍生生长因子（PDGF-A）、表皮生长因子（EGF）和成纤维细胞生长因子（FGF-2）对晶状体细胞增殖的影响。采用蛋白质免疫印迹法来表征这些促有丝分裂原诱导的ERK1/2和Akt信号传导。上述实验也在存在选择性受体抑制剂的情况下重复进行。与房水相似，FGF诱导持续的ERK1/2信号传导模式（长达6小时），而IGF、PDGF和EGF则诱导ERK1/2的瞬时激活。在存在FGF受体（FGFR）抑制剂的情况下，房水诱导的持续ERK1/2信号传导模式受到干扰，类似于IGF、PDGF或EGF诱导的瞬时模式。在存在其他生长因子受体抑制剂的情况下，房水保持其持续6小时的ERK1/2信号传导模式，尽管早期ERK1/2的磷酸化有所减少。没有一种特异性受体抑制剂能够阻断房水诱导的晶状体细胞增殖；然而，抑制剂组合可以做到，前提是FGFR信号传导被阻断。多种生长因子可能在体内调节晶状体细胞增殖，其中FGF在房水诱导的信号传导和晶状体细胞增殖中起关键作用。
