ProMMP-9 (92 kDa gelatinase) in vitreous fluid of patients with proliferative diabetic retinopathy

doi:10.1016/S0024-3205(99)00184-8

Life Sciences

Volume 64, Issue 25, 14 May 1999, Pages 2307-2315

https://doi.org/10.1016/S0024-3205(99)00184-8 Get rights and content

Abstract

Matrix metalloproteinases (MMPs) are implicated in tissue destruction during various pathophysiologic conditions. The vitreous body is a gel-like extracellular matrix that undergoes liquefaction during aging and pathological processes. To investigate the pathogenic role of MMPs in proliferative diabetic retinopathy (PDR), we studied 73 eyes from PDR patients and 25 eyes from patients with non-diabetic ocular diseases. Vitreous MMPs were measured by zymography. Retinopathy was assessed by ophthalmoscopy and PDR was classified into 3 stages, ‘naked’, ‘active’ and ‘quiescent’. Although proMMP-9 was expressed in only 8% (2/25) of non-diabetic patients, it was expressed in more than 80% (38/47) of ‘active’ PDR patients and still expressed in 60% (9/15) of those with ‘quiescent’ PDR. Vascular endothelial growth factor (VEGF) in vitreous fluids was undetectable (<0.16 ng/ml) in most of the non-diabetic patients, and was maximally elevated in the ‘active’ PDR patients (mean = 2.20 ng/ml, range; 0.16–7.61), declining in patients with ‘quiescent’ PDR (1.04 ng/ml, 0.16–3.77). These results suggest that MMP-9 is one of the noteworthy factors in relation to the progress of PDR, as well as angiogenic cytokines such as VEGF.

Reference (31)

AdamisA.P. et al.
Am. J. Ophthalmol.
(1994)
HeussenC. et al.
Anal. Biochem.
(1980)
FolkmanJ. et al.
J. Biol. Chem.
(1992)
TanakaY. et al.
Lancet
(1997)
SaloT. et al.
J. Biol. Chem.
(1991)
SivallinghamA. et al.
Arch. Ophthalmol.
(1990)
AielloL.P. et al.
N. Eng. J. Med.
(1994)
BoultonM. et al.
Br. J. Ophthalmol.
(1997)
BrownD. et al.
Curr. Eye Res.
(1994)
PepperM.S. et al.
Cell Different. Dev.
(1990)

MatrisianL.M.

Bioassays

(1992)

ApteB.A. et al.

Invest. Ophthalmol. Vis. Sci.

(1997)

KondapakaS.B. et al.

Int. J. Cancer

(1997)

AndersonS.S. et al.

Cell. Adhes. Commun.

(1996)

KosnoskyW. et al.

Invest. Ophthalmol. Vis. Sci.

(1994)

Cited by (44)

Association of functional SNP-1562C > T in MMP9 promoter with proliferative diabetic retinopathy in north Indian type 2 diabetes mellitus patients
2017, Journal of Diabetes and its Complications
Citation Excerpt :
Prior to the present study, only one report is available where association of -1306C > T SNP of MMP-2 gene and SNP-1562C > T of MMP-9 gene with PDR has been assessed in Caucasian population and found no significant association but the MMP-2 and MMP-9 plasma levels showed statistically significant differences among the studied groups with highest levels in the PDR group.14 Several previous studies have reported elevated levels of MMP-9 in neovascular membranes as well as serum and vitrous of PDR patients.15,16 Moreover, inhibition of MMPs is shown to reduce the retinal neovasularization.17
Retinal angiogenesis is a hallmark of diabetic retinopathy. Matrix Metalloproteinases (MMPs) are involved in degradation of extracellular matrix (ECM). Functional SNP-1562C > T in the promoter of the MMP-9 gene results increase in transcriptional activity. The present work was designed to evaluate the contribution of functional SNP-1562C > T of MMP-9 gene to the risk of proliferative diabetic retinopathy (PDR) in type 2 diabetes mellitus (T2DM) patients in north Indian Population.
This Case control study comprised of a total of 645 individuals in which 320 were T2DM patients out of which 73 had PDR, 98 had non- proliferative diabetic retinopathy (NPDR), 149 T2DM cases without any eye related disease (DM) and 325 non diabetic healthy individuals as controls (non DM controls). Genotyping for SNP-1562C > T of MMP-9 was done by polymerase chain reactions followed by restriction analyses with specific endonucleases (PCR-RFLP). DNA sequencing was used to ascertain PCR-RFLP results.
T allele frequency in PDR patients was 32.1%, 20.4% in NPDR, 15.4% in DM and 13.7% in controls. Statistically significant difference was observed in both allele and genotype distribution between the PDR versus non-DM control group (p < 0.0001 by T allele; p = 0.002 by TT and p < 0.0001 by CT genotype).
The present study suggests that the functional SNP-1562C > T in the promoter of the MMP-9 gene could be regarded as a major risk factor for PDR as increased MMP-9 production from high expressing T allele may promote retinal angiogenesis.
Sprouty gain of function disrupts lens cellular processes and growth by restricting RTK signaling
2015, Developmental Biology
Citation Excerpt :
Using lens culture, gelatin zymography and immunofluorescence, we were not able to detect any significant differences in MMP-2 or MMP-9 between the WT lens and the transgenic lens epithelial cells overexpressing Spry1 or Spry2 (data not shown). Aqueous and vitreous humors also contain MMPs (Brown et al., 1994; De La Paz et al., 1998; Huang et al., 1996), with MMP-9 increasing dramatically in the humor (Huang et al., 1996; Brown et al., 1994; Kosano et al., 1999) of patients with proliferative diabetic retinopathy, or following cataract surgery. As noted earlier, given that Rac1 GTPase activity has been shown to play an essential role in lens ECM turnover (Maddala et al., 2011) and Spry2 can limit Rac1 activation (Poppleton et al., 2004), this may be the contributing mechanism to the lens capsule rupture.
Sprouty proteins function as negative regulators of the receptor tyrosine kinase (RTK)-mediated Ras/Raf/MAPK pathway in many varied physiological and developmental processes, inhibiting growth factor-induced cellular proliferation, migration and differentiation. Like other negative regulators, Sprouty proteins are expressed in various organs during development, including the eye; ubiquitously expressed in the optic vesicle, lens pit, optic cup and lens vesicle. Given the synexpression of different antagonists (e.g, Sprouty, Sef, Spred) in the developing lens, to gain a better understanding of their specific role, in particular, their ability to regulate ocular growth factor signaling in lens cells, we characterized transgenic mice overexpressing Sprouty1 or Sprouty2 in the eye. Overexpression of Sprouty in the lens resulted in reduced lens and eye size during ocular morphogenesis, influenced by changes to the lens epithelium, aberrant fiber cell differentiation and compromised de novo maintenance of the lens capsule. Here we demonstrate an important inhibitory role for Sprouty in the regulation of lens cell proliferation and fiber differentiation in situ, potentially through its ability to modulate FGF- (and even EGF-) mediated MAPK/ERK1/2 signaling in lens cells. Whilst growth factor regulation of lens cell proliferation and fiber differentiation are required for orchestrating lens morphogenesis and growth, in turn, antagonists such as Sprouty are just as important for regulating the intracellular signaling pathways driving lens cellular processes.
Functional links between gelatinase B/matrix metalloproteinase-9 and prominin-1/CD133 in diabetic retinal vasculopathy and neuropathy
2014, Progress in Retinal and Eye Research
Citation Excerpt :
A further corroboration was the analysis by zymography in 25 controls and 73 patients with various degrees of PDR. Again, increased levels of MMP-9 were observed in PDR versus non-diabetic controls (Kosano et al., 1999). No activity was assessed, because with zymography tests, it is impossible to draw any conclusions about the activities of MMPs in biological samples (Vandooren et al., 2013a).
Retinopathy, a common cause of blindness, is a hallmark of diabetes and depends on two pathological mechanisms: vasculopathy and neuropathy. Whereas vasculopathy is well understood and has been associated with changes in gelatinase B/matrix metalloproteinase-9 (MMP-9) and other vasculotropic factors, specific markers for diabetes-induced retinal neuropathy are not yet described. Neuropathy may result from damages to the blood-retinal barrier (BRB) and from loss of neuroprotective factors. We studied diabetes-induced changes in vascular, inflammatory and regenerative markers and demonstrated that MMP-9 was increased, whereas prominin-1/CD133 was decreased in retinal extracts. In vitro, MMP-9 specifically destroyed prominin-1/CD133. Streptozotocin-induced diabetes resulted in BRB breakdown as a sign of vasculopathy and in prominin-1/CD133 destruction in photoreceptors as an in situ parameter of diabetic neuropathy. Both in vivo phenotypes were completely reversed in single MMP-9 gene knockout mice, demonstrating that MMP-9 mediates both diabetes-induced retinal vasculopathy and neuropathy, with prominin-1/CD133 being a critical and specific substrate of MMP-9. This functional link between gelatinase B/MMP-9 and prominin-1/CD133 explains mechanistically both the vasculopathy and neuropathy of diabetic retinopathy and suggests that specific MMP-9 inhibition is an interesting therapeutic avenue to investigate.
Interleukin-6 in the pathogenesis of posterior capsule opacification and the potential role for interleukin-6 inhibition in the future of cataract surgery
2013, Medical Hypotheses
Citation Excerpt :
However, ocular quantities of these MMPs are increased with culture [59] and following trauma or infection [56], with particular increases in the levels of MMP-9 [63]. For example, Kosano et al. demonstrated constitutive presence of MMP-2 in normal vitreous humor with no detectable MMP-9 expression, while levels of MMP-9 were elevated in the vitreous of patients with diabetic retinopathy [63]. Another study showed increased amounts of MMP-9 in human cataractous lenses (including posterior subcapsular cataract or PCO tissue) and also revealed elevation in these levels with advancing age [64].
Posterior capsule opacification (PCO) is a debilitating and relatively common complication of cataract surgery despite modern medical and surgical advances. The pathophysiology of this condition has largely been attributed to peptide mediators, such as transforming growth factor-beta (TGFβ), epidermal growth factor (EGF) and matrix metalloproteinases (MMPs), with the inhibition of these and other related molecules showing promising results. Studies have also shown that the levels of interleukin-6 are elevated in the eyes following cataract surgery and in various ocular inflammatory disorders that predispose to PCO development. This review proposes, utilizing ocular and extra-ocular disease models, several potential pathways through which IL-6 may modulate the activity of TGFβ, EGF, MMP-2/-9 and immune cells to promote PCO. Among the IL-6-mediated pathways discussed are the transactivation of EGF receptor, the up-regulation of TGFβ and MMP-2/-9, and the loss of ocular immune privilege through trans-signaling, down-regulation of T-regulatory cells (Tregs) and up-regulation of Th17 cells. After establishing both the potential role of ocular IL-6 in the development of PCO and the apparent upstream activity of IL-6 in relation to the known mediators of PCO, the author hypothesizes that intraoperative anti-IL-6 therapy may be of great benefit in reducing all parameters of PCO pathogenesis. This review also provides a strong basis for carrying out multiple experimental studies with IL-6 inhibitors to further elucidate the specific pathways by which IL-6 may promote PCO as well as to better determine what role inflammation may play in this disease process.
Genetic variation in the matrix metalloproteinase genes and diabetic nephropathy in type 1 diabetes
2011, Molecular Genetics and Metabolism
Citation Excerpt :
Contrary to studies of cardiovascular disease, the remaining polymorphisms were not statistically different between case and control subjects from GoKinD. There is mounting evidence to support the role of MMPs in the development and progression of diabetic complications, including diabetic retinopathy [23,24], diabetic foot ulcers [25,26], and DN [27]. In the kidney, MMPs produced by mesangial cells account for up to 70% of ECM degradation and turnover during normal matrix remodeling [17].
Genetic data support the notion that polymorphisms in members of the matrix metalloproteinase (MMP) family of genes play an important role in extracellular matrix remodeling and contribute to the pathogenesis of vascular disease. To identify novel genetic markers for diabetic nephropathy (DN), we examined the relationship between MMP gene polymorphisms and DN in the Genetics of Kidneys in Diabetes (GoKinD) population. Genotypic data from the Genetic Association Information Network (GAIN) type 1 DN project were analyzed for associations across 21 MMP genes in 1705 individual with type 1 diabetes, including 885 normoalbuminuric control subjects and 820 advanced DN case subjects. In total, we investigated the role of 1283 SNPs (198 genotyped SNPs and 1085 imputed SNPs) mapping to the MMP genes. We identified associations at several correlated SNPs across a 29.2 kb interval on chromosome 11q at the MMP-3/MMP-12 locus. The strongest associations occurred at 2 highly-correlated SNPs, rs610950 (OR = 0.50, P = 1.6 × 10⁻⁵) and rs1277718 (OR = 0.50, P = 2.1 × 10⁻⁵). Further examination of this locus identified 17 SNPs (2 genotyped SNPs and 15 imputed SNPs) in complete linkage disequilibrium associated with DN (P-values < 2.5 × 10⁻⁴), including a non-synonymous SNP (rs652438, Asn357Ser) located in exon 8 of MMP-12 that significantly reduced the risk of DN among carriers of the serine substitution relative to homozygous carriers of asparagine (OR = 0.51; 95% CI = 0.37–0.71, P = 6.2 × 10⁻⁵). Taken together, our study suggests that genetic variations within the MMP-3/MMP-12 locus influence susceptibility of DN in type 1 diabetes.
Effect of retinal laser photocoagulation on the activity of metalloproteinases and the α<inf>2</inf>-Macroglobulin proteolytic state in the vitreous of eyes with proliferative diabetic retinopathy
2007, Experimental Eye Research
Panretinal photocoagulation (PRP) reduces the incidence of severe visual loss in proliferative diabetic retinopathy (PDR). The aim of the study was to determine the effect of PRP on the activity of matrix metalloproteinase-2 (MMP-2) and MMP-9, and also on the α₂-Macroglobulin (α₂M) proteolytic state in the vitreous of eyes with PDR. Vitreous samples were obtained from patients undergoing vitrectomy for the treatment of retinal diseases: 17 with PDR and eight with idiopathic macular hole (MH). Qualitative evaluation of the MMP-2 and MMP-9 activation status was performed by gelatin zymography and quantitative assay was carried out for vitreous total protein content and α₂M. The proteolytic state of α₂M was evaluated by Western blotting. Although all vitreous samples contained proMMP-2, increased proMMP-9 and active MMP-9 were detected in PDR samples without PRP. In addition, after PRP the proMMP-9 activity was significantly decreased, whereas the proMMP-2 activity was not affected. Enhanced total protein and α₂M concentrations were observed in all vitreous samples from PDR patients with and without previous PRP compared with samples from patients with MH. However, a differential proteolytic state of α₂M, expressed as 180/85–90 kDa ratio, was detected among PDR patients with and without PRP treatment. Whereas a low 180/85–90 kDa ratio of α₂M in vitreous of PDR patients without PRP was observed, a high proportion of 180 kDa subunit was principally detected in PDR with PRP. These results demonstrate that PDR occurs with an enhanced activity of MMP-9 and activation of α₂M by proteinases, which is reversed after PRP. In addition, we suggest that α₂M plays a key role in the control and regulation of the ocular neovascularization involved in the pathogenesis of ischemic retinal diseases such as PDR.

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ProMMP-9 (92 kDa gelatinase) in vitreous fluid of patients with proliferative diabetic retinopathy

Abstract

Am. J. Ophthalmol.

Anal. Biochem.

J. Biol. Chem.

Lancet

J. Biol. Chem.

Arch. Ophthalmol.

N. Eng. J. Med.

Br. J. Ophthalmol.

Curr. Eye Res.

Cell Different. Dev.

Bioassays

Invest. Ophthalmol. Vis. Sci.

Int. J. Cancer

Cell. Adhes. Commun.

Invest. Ophthalmol. Vis. Sci.