Increased expression of the WNT antagonist sFRP-1 in glaucoma elevates intraocular pressure.
Increased expression of the WNT antagonist sFRP-1 in glaucoma elevates intraocular pressure.
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DOI：
10.1172/jci33871
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发表时间：
2008-03
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影响因子：
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通讯作者：
Wan-heng Wang;L. Mcnatt;I. Pang;J. Millar;P. Hellberg;Mark Hellberg;H. T. Steely;J. Rubin;J. Fingert;V. Sheffield;V. Sheffield;E. Stone;E. Stone;A. Clark
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作者：
Wan-heng Wang;L. Mcnatt;I. Pang;J. Millar;P. Hellberg;Mark Hellberg;H. T. Steely;J. Rubin;J. Fingert;V. Sheffield;V. Sheffield;E. Stone;E. Stone;A. Clark
升高的眼内压（IOP）是青光眼的主要危险因素，并且是由从眼睛流出的流体的过度阻抗引起的。这种异常可能起源于流出道组织，如小梁网（TM），但相关的分子病因学知之甚少。我们发现了分泌型卷曲相关蛋白-1（sFRP-1）在调节IOP中的新作用，sFRP-1是Wnt信号的拮抗剂。sFRP 1在人结肠癌TM细胞中过表达。参与Wnt信号通路的基因在培养的TM细胞和人TM组织中表达。向离体灌注培养的人眼中添加重组sFRP-1降低了流出设施，伴随着TM中Wnt信号传导介质β-连环蛋白水平的降低。在小鼠中玻璃体内注射编码sFRP 1的腺病毒载体产生IOP的滴度依赖性增加。载体注射后5天，IOP增加2倍，这通过局部眼部施用Wnt信号传导的下游抑制剂的抑制剂而显著降低。因此，这些数据表明TM中sFRP 1表达增加似乎是青光眼IOP升高的原因，恢复TM中的Wnt信号传导可能是治疗青光眼的新疾病干预策略。
Elevated intraocular pressure (IOP) is the principal risk factor for glaucoma and results from excessive impedance of the fluid outflow from the eye. This abnormality likely originates from outflow pathway tissues such as the trabecular meshwork (TM), but the associated molecular etiology is poorly understood. We discovered what we believe to be a novel role for secreted frizzled-related protein-1 (sFRP-1), an antagonist of Wnt signaling, in regulating IOP. sFRP1 was overexpressed in human glaucomatous TM cells. Genes involved in the Wnt signaling pathway were expressed in cultured TM cells and human TM tissues. Addition of recombinant sFRP-1 to ex vivo perfusion-cultured human eyes decreased outflow facility, concomitant with reduced levels of beta-catenin, the Wnt signaling mediator, in the TM. Intravitreal injection of an adenoviral vector encoding sFRP1 in mice produced a titer-dependent increase in IOP. Five days after vector injection, IOP increased 2 fold, which was significantly reduced by topical ocular administration of an inhibitor of a downstream suppressor of Wnt signaling. Thus, these data indicate that increased expression of sFRP1 in the TM appears to be responsible for elevated IOP in glaucoma and restoring Wnt signaling in the TM may be a novel disease intervention strategy for treating glaucoma.