Matrix metalloproteinase biology applied to vitreoretinal disorders

Sethi, Charanjit; Bailey, Tracey A.; Luthert, Philip J.; Chong, Victor

doi:10.1136/bjo.84.6.654

Cited by 69 publications

(99 citation statements)

References 135 publications

(109 reference statements)

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“…Another factor that potentially regulates the cleavage of FasL is the presence of tissue inhibitors of MMPs (TIMP), which are expressed within the eye and are the major endogenous regulators of MMP activity (24,32,33). Taken together with the data presented herein, we propose that the cleaving of FasL from the cell surface of tumor cells plays a critical role in the development of metastases.…”

Section: Discussionmentioning

confidence: 52%

Control of Ocular Tumor Growth and Metastatic Spread by Soluble and Membrane Fas Ligand

et al. 2007

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Fas ligand (FasL) can be either membrane bound, or cleaved by metalloproteinases (MMP) to produce a soluble protein.The two different forms of FasL are reported to have opposite functions-membrane-bound FasL (mFasL) is proinflammatory and soluble FasL (sFasL) is antiinflammatory. We previously showed that, within the immune-privileged eye, tumors expressing high levels of mFasL overcame the suppressive ocular environment, triggered an inflammatory response, and were subsequently rejected. By contrast, eye tumors expressing low levels of mFasL grew progressively. To evaluate the effect of sFasL on the tumor growth and metastatic potential of ocular FasL-expressing tumors, we compared tumor cell clones that expressed equal amounts of (low) mFasL in the presence or absence of sFasL. Tumor cells transfected with a modified FasL gene expressed only mFasL (noncleavable), grew progressively within the eye, and induced systemic protective immunity that prevented metastatic spread of tumor cells to the liver. Unexpectedly, tumors transfected with wild-type FasL (wtFasL; cleavable), which could produce both sFasL and mFasL, elicited considerably more inflammation and grew more slowly within the eye. However, the cleavable wtFasL eye tumors failed to trigger protective immunity and gave rise to liver metastases. Interestingly, exposure to the ocular environment was required for the wtFasL tumors to gain metastatic potential. We conclude that the fate of FasL-expressing tumors is determined by a combination of the following: (a) the relative proportion of membrane and sFasL, and (b) the local environment that determines the extent of FasL cleavage.

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Section: Discussionmentioning

confidence: 52%

Control of Ocular Tumor Growth and Metastatic Spread by Soluble and Membrane Fas Ligand

et al. 2007

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“…TIMPs are endogenous inhibitors of MMPs, which have an important role in connective tissue remodelling and in the degradation of the basal lamina and surrounding ECM during angiogenesis (Sethi et al 2000). Matrix remodeling, necessary for sprouting angiogenesis, is dependent on well-coordinated interactions between MMPs and TIMPs.…”

Section: Discussionmentioning

confidence: 99%

Vitreous TIMP-1 levels associate with neovascularization and TGF-β2 levels but not with fibrosis in the clinical course of proliferative diabetic retinopathy

Geest

Klaassen

Lesnik–Oberstein

et al. 2012

J. Cell Commun. Signal.

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In proliferative diabetic retinopathy (PDR), vascular endothelial growth factor (VEGF) and CCN2 (connective tissue growth factor; CTGF) cause blindness by neovascularization and subsequent fibrosis. This angio‐fibrotic switch is associated with a shift in the balance between vitreous levels of CCN2 and VEGF in the eye. Here, we investigated the possible involvement of other important mediators of fibrosis, tissue inhibitor of metalloproteinases (TIMP)‐1 and transforming growth factor (TGF)‐β2, and of the matrix metalloproteinases (MMP)‐2 and MMP‐9, in the natural course of PDR. TIMP‐1, activated TGF‐β2, CCN2 and VEGF levels were measured by ELISA in 78 vitreous samples of patients with PDR (n = 28), diabetic patients without PDR (n = 24), and patients with the diabetes‐unrelated retinal conditions macular hole (n = 10) or macular pucker (n = 16), and were related to MMP‐2 and MMP‐9 activity on zymograms and to clinical data, including degree of intra‐ocular neovascularization and fibrosis. TIMP‐1, CCN2 and VEGF levels, but not activated TGF‐β2 levels, were significantly increased in the vitreous of diabetic patients, with the highest levels in PDR patients. CCN2 and the CCN2/VEGF ratio were the strongest predictors of degree of fibrosis. In diabetic patients with or without PDR, activated TGF‐β2 levels correlated with TIMP‐1 levels, whereas in PDR patients, TIMP‐1 levels, MMP‐2 and proMMP‐9 were associated with degree of neovascularization, like VEGF levels, but not with fibrosis. We confirm here our previous findings that retinal fibrosis in PDR patients is significantly correlated with vitreous CCN2 levels and the CCN2/VEGF ratio. In contrast, TIMP‐1, MMP‐2 and MMP‐9 appear to have a role in the angiogenic phase rather than in the fibrotic phase of PDR.

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“…It is clear that, whatever the stimuli, the process of proteolysis by MMPs is an important step in the final common pathway of angiogenesis. Therefore, inhibition of the process of CNV at this level may be an attractive field of research rather than targeting the inciting stimuli themselves, which include many cytokines and other factors (19). Indeed it has recently been shown that there is reduced CNV in MMP-9 deficient mice (20).…”

Section: Introductionmentioning

confidence: 99%

Preventive Versus Treatment Effect of Ag3340, a Potent Matrix Metalloproteinase Inhibitor in a Rat Model of Choroidal Neovascularization

Bradey

Cheng

Bartsch

et al. 2004

Journal of Ocular Pharmacology and Therapeutics

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Purpose: AG3340 (prinomastat) is a nonpeptidic, small-molecular-weight, synthetic matrix metalloproteinase inhibitor (MMPI) with selective inhibitory action of MMP-2, MMP-9, MMP-3, and MT-MMP1. We evaluated AG3340 injected intravitreally to treat choroidal neovascularization in a laser induced rat CNV model. Methods: In the pretreatment group, the drug was injected the same day after induction of choroidal neovascularization by diode laser. In the treatment group, the drug was injected 2 weeks after induction of choroidal neovascularization (CNV). Fluorescein and indocyanine green angiography were performed to evaluate CNV. ERG recordings and histology were performed to assess toxicity and the CNV lesions. Results: When used at the time of CNV induction, 62.8% of lesions in control versus 22.8% of the laser lesions in treated eyes developed CNV (p < 0.0001). The invading fibrovascular complex was thicker in the control eyes than that in the treated eyes. No signs of toxicity were detected. When used to treat established CNV, the percentage of leakage in treated and control eyes were 54.1% and 58.9% respectively (p > 0.05). Prinomastat was effective when given at the time of induction of CNV in the rat model. Administration of prinomastat 2 weeks after laser induction did not show efficacy. Conclusion: Prinomastat was active in the earliest stages of experimental CNV. It might be best used in combination with photodynamic therapy to inhibit recurrence of CNV from temporarily closed new vessels.

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Matrix metalloproteinase biology applied to vitreoretinal disorders

Cited by 69 publications

References 135 publications

Control of Ocular Tumor Growth and Metastatic Spread by Soluble and Membrane Fas Ligand

Control of Ocular Tumor Growth and Metastatic Spread by Soluble and Membrane Fas Ligand

Vitreous TIMP-1 levels associate with neovascularization and TGF-β2 levels but not with fibrosis in the clinical course of proliferative diabetic retinopathy

Preventive Versus Treatment Effect of Ag3340, a Potent Matrix Metalloproteinase Inhibitor in a Rat Model of Choroidal Neovascularization

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