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In this study, we found that there was some expression of MMP9 mRNA in retina of C57BL/6J mouse during the early period after laser photocoagulation. Then the expression increased along with the time until to the CNV development at 1 week after laser treatment. As a follow, it would stabilize at a high level. According to these findings, combinating with references showed above, we presume that MMP9 may play a role in the pathogenesis of retinal neovasculization and CNV by degrading of ECM.
TIMPs are a family of MMP inhibitors thought to act as local regulators of matrix degradation by the MMPs. Recent histological studies have examined the location and expression of the TIMPs in retinal and choroidal tissue. While TIMP1 could not be found, TIMP2 was shown to be present in Bruchs membrane and choroid, and TIMP3 mRNA expression was localized to the RPE and choroidal endothelial cells, and there is general consensus that TIMP3 in Bruchs membrane is synthesized and secreted by the RPE. TIMP3 is unique in having a strong affinity for ECM, while the other two are found predominantly in the media from cultured cells [6]. It is suggested that TIMP3 normally functions for maintenance of the ECM in Bruchs membrane [7].
One role of TIMP3 in Bruchs membrane may be as a potent local inhibitor of MMP activity, regulating the rate of Bruch's membrane turnover, as well as limiting choroidal neovascularization. In 2000, Takahashi et al[8] injected hemagglutinating virus of Japan liposomes containing hemagglutin epitopetagged TIMP3 gene into the subretinal space in rat eyes. Three days after transfection of TIMP3 gene into retinal pigment epithelium cells, intense laser photocoagulation was performed and the incidence of CNV was assessed by FFA. They found that exogenous TIMP3 mRNA expression in the choroid and retina was detected on day 3. The efficiency of TIMP3 gene transfection into retinal pigment epithelium cells was greatest on day 7 and decreased gradually thereafter. The incidence of CNV in TIMP3 genetransfected eyes was markedly decreased compared with controls (15% vs 75%). This study shows that TIMP3 gene can be transferred into rat retinal pigment epithelium and that TIMP3 gene overexpression can inhibit development of experimental CNV. This method may represent a future treatment modality for human macular degeneration associated with CNV. Murata also confirmed the possibility of gene therapy (coding for TIMP) for the treatment of CNV [9].
In this study, we found that, although the expression of TIMP3 mRNA increased after laser photocoagulation, CNV still developed. This may be due to the imbalance between MMPs and TIMPs: a few expressions for both MMP9 and TIMP3 mRNA could be detected at 1 day after laser photocoagulation. The expressions increased significantly, especially for the TIMP3 at 3 days after laser. Along the time, although expression of TIMP3 mRNA stabilized in a higher level, the expression of MMP9 mRNA was not inhibited completely, and moreover it still increased. The imbalance between MMP9 and TIMP3 breakdown the acceleration inhibition balance of degradation of ECM, and the predominant former may activate the "angiogenic switch" [10]. As a result, the CNV was induced at 1 week after laser photocoagulation. Studies have indicated that an imbalance of MMPs and their inhibitors may be involves in the pathogenesis of ocular diseases such as glaucoma [11, 12], corneal diseases [13, 14] and proliferative retinopathy [1517]. Then the new balance rebuilt between MMP9 and TIMP3 made the CNV exist for a longer period. In our previous studies [18], we have confirmed that CNV may be induced at 1 week after laser photocoagulation, and the incidence of CNV at 1 week, 2 weeks and 4 weeks were similar.
The mechanisms that trigger release of MMPs and TIMPs during CNV induced by laser photocoagulation are unclear. It is suggested by observations that cytokines such as tumor necrosis factor α (TNFα) and interleukin1 (IL1) may induce production of MMPs and TIMPs by vascular endothelial cells, fibroblasts, and retinal pigment epithelial cells [19]. Majka et al[20] also found that TNFα and VEGF had a role in the regulation of extracelluar proteinase expression during retinal neovascularization. The stimulation of TNFα could enhance the production of MMPs in retinal microvascular endothelial cell. VEGF also played a role in this process through its regulation of TNFαconverting enzyme (TACE).
In summary, both MMP9 and TIMP3 play a role during the development of CNV in the murine model. It is the imbalance between the changes of MMP9 and TIMP3 that accelerates the degradation of ECM, and then is involved in the pathogenesis of CNV.
【参考文献】
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