Fariss R N, Apte S S, Luthert P J, Bird A C, Milam A H
Department of Ophthalmology, University of Washington, Seattle 98195-6485, USA.
Br J Ophthalmol. 1998 Nov;82(11):1329-34. doi: 10.1136/bjo.82.11.1329.
BACKGROUND/AIMS: Tissue inhibitor of metalloproteinases-3 (TIMP-3) is normally synthesised by the retinal pigment epithelium (RPE) and deposited in Bruch's membrane. Mutations in the TIMP3 gene cause Sorsby's fundus dystrophy (SFD), which is characterised by thickening of Bruch's membrane, choroidal neovascularisation, and photoreceptor degeneration. To elucidate the role of TIMP-3 in human retinal degenerative diseases, we immunolocalised TIMP-3 in eyes with SFD caused by the Ser-181-Cys TIMP3 gene mutation or retinitis pigmentosa (RP; not caused by TIMP3 mutations).
Standard light microscopic immunocytochemistry, including antigen retrieval, was used to localise TIMP-3 in paraffin sections of human eyes: two with SFD, three with different genetic forms of RP, and two normal.
In the SFD eyes, the thickened Bruch's membrane was strongly TIMP-3 positive except where RPE cells had degenerated. Similarly, in the RP eyes, Bruch's membrane was TIMP-3 positive except where RPE cells were lost, consistent with ongoing RPE mediated turnover of TIMP-3 in this region. In areas of total photoreceptor loss, migrated RPE cells formed cuffs around blood vessels in the RP retinas. Thick, TIMP-3 positive extracellular matrix (ECM) deposits associated with the migrated RPE cells occluded some vascular lumina, correlating with the observed loss of inner retinal neurons in RP.
TIMP-3 is a component of the increased ECM sequestered in Bruch's membrane in SFD. Further information is needed on normal TIMP-3/ECM interactions in Bruch's membrane and the effect of mutant TIMP-3 on this process. The finding of TIMP-3 accumulations in retinas with RP not caused by TIMP-3 mutations emphasises the importance of ECM remodelling in normal and diseased human eyes.
背景/目的：金属蛋白酶组织抑制剂-3（TIMP-3）通常由视网膜色素上皮（RPE）合成并沉积于Bruch膜。TIMP3基因突变会导致Sorsby眼底营养不良（SFD），其特征为Bruch膜增厚、脉络膜新生血管形成和光感受器变性。为阐明TIMP-3在人类视网膜退行性疾病中的作用，我们对由Ser-181-Cys TIMP3基因突变引起的SFD患者的眼睛以及视网膜色素变性（RP；非由TIMP3突变引起）患者的眼睛进行了TIMP-3免疫定位。
采用标准光镜免疫细胞化学方法（包括抗原修复）对人眼石蜡切片中的TIMP-3进行定位：2例SFD患者的眼睛、3例不同基因形式的RP患者的眼睛以及2例正常眼睛。
在SFD患者的眼睛中，增厚的Bruch膜TIMP-3呈强阳性，但RPE细胞发生变性的部位除外。同样，在RP患者的眼睛中，Bruch膜TIMP-3呈阳性，但RPE细胞缺失的部位除外，这与该区域中RPE介导的TIMP-3持续更新一致。在光感受器完全丧失的区域，迁移的RPE细胞在RP视网膜的血管周围形成袖套。与迁移的RPE细胞相关的厚的、TIMP-3阳性细胞外基质（ECM）沉积物阻塞了一些血管腔，这与RP患者视网膜内层神经元的丧失相关。
TIMP-3是SFD中Bruch膜中隔离的ECM增加的一个组成部分。需要进一步了解Bruch膜中正常的TIMP-3/ECM相互作用以及突变的TIMP-3对该过程的影响。在非由TIMP-3突变引起的RP视网膜中发现TIMP-3积累，强调了ECM重塑在正常和患病人类眼睛中的重要性。
