Bone morphogenetic protein-7 is an antagonist of transforming growth factor-β2 in human trabecular meshwork cells
Bone morphogenetic protein-7 is an antagonist of transforming growth factor-β2 in human trabecular meshwork cells
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DOI：
10.1167/iovs.06-0226
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发表时间：
2007-02-01
影响因子：
4.4
通讯作者：
Tamm, Ernst R.
中科院分区：
文献类型：
--
作者：
Fuchshofer, Rudolf;Yu, Alice H. L.;Tamm, Ernst R.
目的。原发性开角型青光眼(POAG)眼压升高可能与转化生长因子-β2信号转导有关，因为POAG患者房水中的转化生长因子-β2含量高于正常。在体外，转化生长因子-β2导致小梁网(TM)细胞外基质(ECM)的积聚和TM流出阻力的增加。本研究旨在探讨骨形态发生蛋白(BMP)-7信号通路是否拮抗转化生长因子-β2对TM细胞的作用。方法取9例供者的TM细胞，分别用BMP-7、转化生长因子-β2或两者联合作用24或72小时。免疫组织化学、实时定量RT-PCR、Western和Northern印迹分析及酶谱(MMP2)检测结缔组织生长因子(CTGF)、凝血酶敏感蛋白(TSP)-1、纤维连接蛋白(FN)、I型、III型和IV型胶原、纤溶酶原激活物抑制物(PAI)-1和基质金属蛋白酶(MMP2)-2的表达。转化生长因子-β2与骨形态发生蛋白-7联合应用时，上述作用均被抑制，而骨形态发生蛋白-7单独作用不明显。转化生长因子-β2、骨形态发生蛋白-7或两者联合作用对I型和III型胶原的表达无影响。结论：在体外，骨形态发生蛋白-7强烈拮抗转化生长因子-β诱导的一系列分子的表达，从而导致TMECM的原位积聚。由于BMP-7在成人TM中原位表达，似乎有理由认为它在体内类似地调节和拮抗转化生长因子-β2信号对流出通路组织的影响。在TM中对BMP-7信号的药理调节可能是治疗POAG的一种有前途的策略。
PURPOSE. The increase in intraocular pressure in primary open-angle glaucoma ( POAG) may involve transforming growth factor (TGF)-beta 2 signaling, as TGF-beta 2 is found in higher amounts than normal in the aqueous humor of patients with POAG. In vitro, TGF-beta 2 causes an accumulation of extracellular matrix (ECM) in the trabecular meshwork (TM) and an increase in TM outflow resistance. The present study was undertaken to determine whether bone morphogenetic protein (BMP)-7 signaling antagonizes the effects of TGF-beta 2 on TM cells.METHODS. Cultured TM cells from nine human donors were treated with BMP-7, TGF-beta 2, or a combination of both for 24 or 72 hours. The expression of connective tissue growth factor (CTGF); thrombospondin (TSP)-1; fibronectin; collagen types I, III, and IV; plasminogen activator inhibitor (PAI)-1; and matrix metalloproteinase (MMP)-2 were analyzed by immunohistochemistry, real time RT-PCR, Western and Northern blot analysis, and zymography (MMP-2).RESULTS. Treatment with TGF-beta 2 induced the expression of CTGF, TSP-1, fibronectin, collagen types IV and VI, and PAI-1. All these effects were inhibited when TGF-beta 2 was added in combination with BMP- 7, whereas BMP- 7 alone had no effects. Treatment with TGF-beta 2, BMP- 7, or the combination of both had no effect on the expression of collagen types I and III.CONCLUSIONS. BMP-7 strongly antagonizes in vitro the TGF-beta-induced expression of a broad panel of molecules, which would result in an accumulation of TM ECM in situ. As BMP-7 is expressed in the adult human TM in situ, it seems reasonable to assume that it similarly modulates and antagonizes the effects of TGF-beta 2 signaling on the tissues of the outflow pathways in vivo. The pharmacological modulation of BMP- 7 signaling in the TM might be a promising strategy to treat POAG.