Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0851184 (thinning)
 11,252 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The thinning of the cornea that occurs in keratoconus has been well described; however, the mechanism of tissue degradation remains unknown. Elevated proteinase activity is one possibility and approximately 20 publications over the last 20 years have addressed this hypothesis. Early studies reported increased collagenase and gelatinase activities in the medium of keratoconus corneal cultures. After the characterization of the matrix metalloproteinase (MMP) enzymes, studies focused on the expression of specific MMPs, in particular the gelatinases, MMP-2 and MMP-9. Matrix metalloproteinase-2 was found to be the major MMP of the cornea and was constitutively produced in normal tissue, whereas MMP-9 expression was induced by various stimuli, including phorbol esters and even tissue culturing. These studies suggested that there were no differences in the amounts or states of activation of MMP between normal and keratoconus corneas, although the amounts of some proteinase inhibitors, including tissue inhibitors of metalloproteinases, alpha-1-proteinase inhibitor and alpha-2-macroglobulin, were decreased in keratoconus. Most recently, the lysosomal proteinases, cathepsin B and cathepsin G were reported to be elevated in keratoconus corneas, and it is possible that it was cathepsin activity, not MMP activity, that was measured in some early studies. Nevertheless, there are now about 20 human MMPs identified and it is possible that some of these, other than the well known collagenase (MMP-1) and gelatinases (MMP-2 and MMP-9), could be implicated in the pathology of keratoconus. Studies have begun to address more recently described MMPs and it has been reported that the membrane-bound MT1-MMP (MMP-14), which activates latent MMP-2, was found to have increased expression in keratoconus corneas, whereas the stromelysins, MMP-3 and MMP-10, were not.
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PMID:Is the corneal degradation in keratoconus caused by matrix-metalloproteinases? 1177

In order to understand the effect of mechanical strain on scleral extracellular matrix remodeling, human scleral fibroblasts were subjected to equibiaxial stretch in vitro and the expression of proteoglycans, metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase-2 (TIMP-2) were evaluated. Isolated human scleral fibroblasts were seeded onto flexible bottom culture plates, and subjected to a cyclic stretch regimen of 15% equibiaxial stretch for 45 s followed by 15s of rest for 6-48 h in the presence of 35SO4. Newly synthesized proteoglycans were measured in the medium by CPC precipitation of radiolabelled glycosaminoglycans. MMP-2 activity and expression levels were measured in the medium by, Western blot, gel zymography and real-time PCR. Steady state levels of TIMP-2 mRNA and membrane-type MMP, MT1-MMP (MMP-14) mRNA were measured in the cell layer using real-time PCR. The predominant gelatinolytic enzyme secreted by scleral fibroblasts was the pro-enzyme form of MMP-2 (ProMMP-2). Mechanical stretch resulted in a significant increase of ProMMP-2 after 12 and 48 h (+76.28%, p<0.05; +19.56%, p<0.01, respectively). Mechanical stretch significantly increased the production of the active form of MMP-2 (ActiveMMP-2) after 48 h (+59.72%, p<0.05) and decreased levels of TIMP-2 mRNA (-22%, p<0.05). The rate of scleral proteoglycan synthesis and the steady state levels of MMP-2 and MMP-14 mRNA were not significantly affected by mechanical stretch. These results suggest that mechanical strain stimulates the activation of MMP-2 by scleral fibroblasts, possibly through increased levels of ProMMP-2 and reduced levels of TIMP-2. Increased levels of ActiveMMP-2 in the sclera would be expected to contribute to scleral extracellular matrix degradation, scleral thinning and possible ocular ectasia.
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PMID:Effects of cyclic mechanical stretch on extracellular matrix synthesis by human scleral fibroblasts. 1712 15

To investigate if increased activation of matrix metalloproteinases (MMPs) may contribute to the large cardiovascular risk associated with obesity-related insulin resistance, we examined the effects of physiologically elevated levels of insulin and free fatty acid (FFA) on three MMPs and their physiologic inhibitors (tissue inhibitors of MMP ) in aortic tissue of male rats during euglycemic-hyperinsulinemic clamping. Hyperinsulinemia increased the active forms of MMP-2 (approximately sixfold), MMP-9 (approximately 13-fold), and membrane type 1-MMP (MT1-MMP; approximately eightfold) (all Western blots), and the gelatinolytic activity (zymography) of MMP-2 (twofold); it did not affect TIMP-1 and TIMP-2. FFA augmented the insulin-mediated increases in MMP-2 (from approximately six- to approximately 11-fold), MMP-9 (from approximately 13- to approximately 23-fold), MT1-MMP (from approximately eight- to approximately 20-fold), and MMP-2 gelatinolytic activity (from two- to threefold). FFA also increased JNK and p38 mitogen-activated protein kinase activities. The insulin- and FFA-induced hyperactivity of three proatherogenic MMPs in vascular tissues may promote degradation of extracellular matrix over time, leading to thinning of atherosclerotic capsules and acute vascular problems.
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PMID:Effects of insulin and free fatty acids on matrix metalloproteinases. 1862 23