Significance Of Matrix Metalloproteinases Research Articles

Congenital cleft of the lip and palate in children: pathogenetical significance of matrix metalloproteinases

There are presented data about the prevalence offormation of congenital cleft lip and palate (CCLP) - one of the most common birth defects of the maxillofacial region in children. According to WHO the occurrence of children born with CCLP in the world is 0,6-1,6 cases per 1,000 live births, and varies greatly from the region to region and ethnic group residing there. At the same time, in 63,1% of patients there were established chromosomal abnormalities, and in 36,9% - non-chromosomal syndromes. In Russia, every year there are occurred from 3,5 to 5 thousand children with such defects that requires the development of new methods ofprevention of these malformations. There are reported modern views on the pathogenetical and potent diagnostic significance of the evaluation of the content of tissue matrix metalloproteinases (MMPs) and their inhibitors in mechanisms of the formation of CCLP, shown the probable associations of changes in the expression or activity of MMP and TIMP with various forms of malformations of the palate and upper jaw.

Expression and Significance of MMPs in Synovial Fluid, Serum and PBMC Culture Supernatant Stimulated by LPS in Osteoarthritis Patients With or Without Diabetes.

Patients with Type 2 Diabetes mellitus (T2DM) are prone to osteoarthritis (OA). Matrix metalloproteinases (MMPs), an essential modulator in cartilage matrix homeostasis, increase in T2DM and OA. We aimed to ascertain the expression difference of MMPs and function in mononuclear cells after stimulating by lipopolysaccharide (LPS) in OA patients with or without diabetes. 30 knee OA patients without T2DM (OA group), 20 knee OA patients with T2DM (DM-OA group) and 5 healthy volunteers recruited as control were enrolled from January 2016 to January 2017. The expression levels of MMPs in both serum and synovial fluid were initially detected in three groups by enzyme-linked immunosorbent assay (ELISA). After stimulation of peripheral blood mononuclear cell (PBMC) with LPS, the release of MMPs were determined and evaluated. The expression of MMP-1, -7, -8, -9, -10 and -12 in synovial fluid in DM-OA group were significantly higher than in OA group and healthy control. The expression of MMP-1 and -7 in serum were highest in DM-OA group. LPS significantly promotes the production of MMP-1, -8, -9 and -10 in PBMC of each group after 4 h stimulation. It is worth to note that the LPS-stimulated MMP-8 and -9 elevations were more prominent in DM-OA group compared with their counterparts. High levels of MMP-1, -7, -8, -9, -10, and -12 in the synovial fluid might be one of important reasons that diabetes patients are more frequently suffered from OA. Inflammation-induced malfunction of mononuclear cells would stimulate MMP-8 and -9 secretion to various extents.

The Significance of Matrix Metalloproteinases in Oral Diseases.

Matrix metalloproteinases (MMPs) belong to a family of structurally related zinc-dependent proteolytic enzymes that are known to play a key role in the catabolic turnover of extracellular matrix (ECM) components. Research studies to date have indicated that MMPs regulate the activity of several non-ECM bioactive substrates, including growth factors, cytokines, chemokines and cell receptors, which determine the tissue microenvironment. Disruption of the balance between the concentration of active matalloproteinases and their inhibitors (TIMPs) may lead to pathological changes associated with uncontrolled ECM turnover, tissue remodeling, inflammatory response, cell growth and migration. This brief review presents some information on MMPs' role in inflammatory, metabolic and cancer abnormalities related to the salivary glands, as well as MMP-related aspects that lead to the formation of human dentinal caries lesions. In oral diseases, the most relevant biological fluid commonly used for diagnosing periodontal diseases is saliva. In diseased patients with significantly higher levels of MMPs in their saliva than healthy people, most extracellular matrix components undergo digestion to lower molecular weight forms. Conventional treatment successfully reduces the levels of MMPs inhibits the progressive breakdown of gingival and periodontal ligament collagens. Beside inflammatory abnormalities like Sjögren's syndrome (SS), a large group of disorders is comprised of cancers, most of them involving the parotid gland.

184 FOLLICULOGENESIS AND DONOR AGE INFLUENCE MATRIX METALLOPROTEINASE-2 EXPRESSION IN THE DOMESTIC CAT

Matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) are known to play key roles in the remodelling of extracellular matrix during ovarian folliculogenesis, especially during the final stage of follicle development. To date, little is known about the significance of MMPs and TIMPs during preantral follicle development. This study determined the expression of MMPs and TIMP-1 during various stages of cat folliculogenesis, largely for the purpose of securing information useful to improving in vitro follicle culture. Primordial (~10 follicles/cat), primary (~5 follicles/cat), secondary (~9 follicles/cat), early antral (~9 follicles/cat), and antral (~4 follicles/cat) follicles were physically isolated from ovaries recovered from 15 cats (5 months to 3 years old during follicular stage) undergoing ovariohysterectomy and assessed for expression of MMP-1, -2, -3, -7, -9, and -13 as well as TIMP-1 using real-time quantitative polymerase chain reaction (q-PCR; 2–4 replicates/follicle stage). Additional ovaries were obtained from three prepubertal (6 months old) and three adult (1 year old) cats and ovarian pieces were fixed in Bouin's solution and assessed for MMP-2 and -13 localization using immunohistochemistry. MMP expression data were analysed using the Kruskull-Wallis one-way ANOVA. Follicles from all stages of development expressed MMPs and TIMP-1. Specifically, expression of MMP-2 increased (P < 0.05) as folliculogenesis progressed (10-fold increases from primordial to early-antral and antral stage). There were no differences (P > 0.05) in the expression of other MMPs among follicular classes. For TIMP-1, there was a tendency (P = 0.07) for increased expression after antrum formation (early antral and antral stages). Immunohistochemistry analysis revealed that MMP-2 was expressed in both the oocyte and somatic cells of all follicular stages in prepubertal cats. However, MMP-2 expression was limited to granulosa and theca cells of antral follicles in adult females. MMP-13 was expressed in the granulosa and theca cells of primary, secondary, and antral stage follicles, and there were no differences (P > 0.05) in localization patterns for this protein between prepubertal and adult females. In summary, the study is the first to report the expression of MMPs as well as TIMP-1 in isolated cat follicles. The difference in MMP-2 expression between prepubertal and adult cats suggests that there may be age-specific requirements for in vitro follicle growth. We are keenly interested in this information for underpinning the development of new in vitro microenvironments for growing immature cat follicles. We suspect that such information will be crucial for understanding how to promote the remodelling of the extracellular matrix by creating degradable biomaterials containing MMP-sensitive peptides to allow optimal follicle expansion.

The significance of matrix metalloproteinases in parasitic infections involving the central nervous system.

Matrix metalloproteinases (MMPs) represent a large family of over twenty different secreted or membrane-bound endopeptidases, involved in many physiological (embryogenesis, precursor or stem cell mobilization, tissue remodeling during wound healing, etc.), as well as pathological (inflammation, tumor progression and metastasis in cancer, vascular pathology, etc.) conditions. For a long time, MMPs were considered only for the ability to degrade extracellular matrix (ECM) molecules (e.g., collagen, laminin, fibronectin) and to release hidden epitopes from the ECM. In the last few years, it has been fully elucidated that these molecules have many other functions, mainly related to the immune response, in consideration of their effects on cytokines, hormones and chemokines. Among others, MMP-2 and MMP-9 are endopeptidases of the MMP family produced by neutrophils, macrophages and monocytes. When infection is associated with leukocyte influx into specific organs, immunopathology and collateral tissue damage may occur. In this review, the involvement of MMPs and, in particular, of gelatinases in both protozoan and helminth infections will be described. In cerebral malaria, for example, MMPs play a role in the pathogenesis of such diseases. Also, trypanosomosis and toxoplasmosis will be considered for protozoan infections, as well as neurocysticercosis and angiostrongyloidosis, as regards helminthiases. All these situations have in common the proteolytic action on the blood brain barrier, mediated by MMPs.

Inhibition of estrogen-induced pituitary tumor growth and angiogenesis in Fischer 344 rats by the matrix metalloproteinase inhibitor batimastat

The development of estrogen-induced pituitary prolactinoma in Fischer 344 (F344) rats is associated with enhanced neovascularization. Based on the significance of matrix metalloproteinases (MMPs) for tumor growth and angiogenesis, we have studied the effect of batimastat (BB-94), a synthetic MMPs inhibitor (MMPI) on the progression of prolactin-secreting pituitary adenoma in rats. Pituitary tumors were induced in male F344 rats by s.c. implantation of Silastic tubes containing diethylstilbestrol (DES). The effects of chronic treatment with BB-94 (30 mg/kg b.w.) on pituitary weight, cell proliferation, apoptosis and vascular density were evaluated. We have stated that chronic treatment with batimastat caused a significant reduction in the pituitary weight. Batimastat has been found to decrease cell proliferation evaluated by a number of PCNA-positive stained cell nuclei. A marked increase in the apoptotic index within the pituitary was observed in the study group. Moreover, the density of microvessels identified by CD31 was reduced in the group treated with BB-94. The results of our study provide evidence for an inhibitory effect of batimastat, a synthetic MMPI, on the growth and angiogenesis in an experimental model of human prolactinoma. The ability of BB-94 to suppress established pituitary tumor growth suggests a possible application of MMPIs in the treatment of pituitary adenomas.

Significance of matrix metalloproteinases in the pathophysiology of the ovary and uterus.

Matrix metalloproteinases (MMP) are capable of degrading a variety of extracellular matrix (ECM) proteins and are also involved in the processing of a number of bioactive molecules. Our findings indicate that the functions of MMP in the ovary and uterus are organ-specific and time-dependently vary during the reproductive cycle. Prolactin induces structural luteolysis indicated by loss of luteal weight, protein and DNA within 36h after pretreatment with ergot alkaloid. MMP activation appears crucial for the selective depletion of protein during luteal involution, which entails loss of ECM accompanied by apoptosis. During GnRHagonist-induced luteolysis, this response was also associated with marked increases in MMP-2, which degraded collagen typeIV, and MT1-MMP, which in addition to activating MMP-2 also degrades collagen type I, III and V. We also found that the level of MT1-MMP and MMP-2 expression in the human CL is greater during the late luteal phase than during either the early mid luteal phases or during gestation, respectively. That dehydroepiandrosterone (DHEA) treatment caused the formation of cysts from antral follicles in the ovaries of immature rats while depressing MMP-2 collagenolytic activity and enhancing lysyl oxidase expression highlights the importance of collagen degradation in the process of ovulation and suggests that changes in the activities of these enzymes play a key role in ovarian cystogenesis in polycystic ovary syndrome patients. Furthermore, immunohistochemical analyses showed that MT1-MMP and FasL co-localize with TdT-mediated dUTP-biotin nick end-labeling (TUNEL)-positive apoptotic granulosa cells in rats treated with DHEA, that the Fas/FasL/Caspase-8 (death receptor-dependent) pathway is pivotal for follicular atresia and that increased levels of MT1-MMP likely play an important role in tissue remodeling during follicular atresia. After parturition, the uterus undergoes involution, a conspicuous feature characterized by a rapid reduction in the collagen content mediated by degradation of extracellular collagen bundles. Our findings strongly suggest that MT1-MMP, MMP-2 and MMP-9 are each time-dependently regulated and play important roles in tissue remodeling during postpartum uterine involution. (Reprod Med Biol 2006; 5: 235-243).

Expression and significance of matrix metalloproteinases and their tissue inhibitors in the infiltration and metastasis of lung cancer

To determine the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in lung cancer specimens, and to find out the possible roles of MMPs and TIMPs in the infiltration and metastasis of lung cancer. The expression of MMP-1, MMP-2, MMP-9, MMP-13, TIMP-1, TIMP-2 were detected in 104 lung cancer tissues by immunohistochemical method. The expressions of MMPs and TIMPs were up-regulated in lung cancer tissues. The expression of MMP-2 was related to differentiated degree of tumor cells. MMP-9 correlated with lymph node metastasis of lung cancer. The positive rate of TIMP-1 was related to TNM stage and lymph node metastasis. In lung cancer tissues, there was positive correlation between MMP-2 and TIMP-2, and between MMP-9 and TIMP-2. MMPs and TIMPs may play the important roles in the development of lung cancer. MMP-9 and TIMP-1 might promote the infiltration and metastasis of lung cancer.

129 Significance of matrix metalloproteinases in norepinephrine-induced remodelling of rat hearts

129 Significance of matrix metalloproteinases in norepinephrine-induced remodelling of rat hearts

Significance of matrix metalloproteinases in norepinephrine-induced remodelling of rat hearts.

Norepinephrine (NE) induced hypertrophy and remodelling of the extracellular matrix (ECM) in the left ventricle (LV) of the rat heart with resulting fibrosis. However, there was no increased collagen deposition in the right ventricle (RV). To test the hypothesis that lack of RV fibrosis is the result of elevated cleavage of collagens we inhibited the activity of matrix metalloproteinases (MMP) by doxycycline (Doxy) and then measured function and collagen metabolism in the RV as compared to the LV. Female Sprague-Dawley rats were treated with 30 mg/kg per day doxycycline alone or in combination with i.v. infusion of NE (0.1 mg/kg per h). The activity of MMP-2 was increased both in the LV and RV after 3 days of NE infusion and reduced after concomitant doxycycline treatment which also caused inhibition when given alone. After 14 days of NE infusion in combination with doxycycline there was an additional increase in the NE-induced elevation of collagen accumulation in the LV (interstitial collagen fraction: NE-Doxy 1.797%, P<0.05 versus control and NE; NE 1.113%, P<0.05 versus control) and significant fibrosis in the RV (2.105%, P<0.05 versus control). This correlated with the prevention of the NE-induced elevation of RV systolic pressure (NE: 71.3 mmHg, P<0.05; NE-Doxy: 36.4 mmHg) and RV dP/dt(max) (NE: 5500 mmHg/s, P<0.05; NE-Doxy: 2550 mmHg/s). Also in the NE-stimulated LV, the doxycycline-induced collagen accumulation was associated with reduced LV dP/dt(max) (NE-Doxy: 13169 mmHg/s; NE: 18849 mmHg/s, P<0.05). MMP inhibition leads to myocardial stiffness with negative functional consequences for the RV and LV in NE-treated rat hearts.

Glomerular distribution and gelatinolytic activity of matrix metalloproteinases in human glomerulonephritis.

Matrix metalloproteinases (MMPs) have been implicated in the development of glomerular injury in rat experimental glomerulonephritis (GN). However, the significance of MMPs in human GN remains obscure. In order to evaluate the role of MMPs in human GN, we examined the glomerular distribution and gelatinolytic activities of MMP-2 and MMP-9 in human GN. We performed immunohistochemistry with polyclonal anti-MMP-2 and MMP-9 antibodies, and analysed gelatin zymograms of five isolated glomeruli from various types of human renal disease. The renal specimens investigated were from normal kidneys (n=5), IgA nephritis (n=20), Henoch-Schönlein nephritis (n=4), non-IgA mesangial proliferative GN (n=9), lupus nephritis (n=6), acute poststreptococcal GN (APSGN) (n=4) and diabetic nephropathy (DN) (n=4). MMP-2 immunoreactivity was not detected in normal controls or in any type of GN. MMP-9 staining, which was almost negative in normal glomeruli, was increased mainly in the mesangial region and corresponded to the level of glomerular cell proliferative changes in mesangial proliferative GN (IgA nephritis, Henoch-Schönlein nephritis, non-IgA mesangial proliferative GN and lupus nephritis). Positive but weak staining for MMP-9 was observed in mesangial areas in DN. In addition, double immunostaining showed that MMP-9 is colocalized in scattered neutrophils within diseased glomeruli in APSGN. MMP-9 gelatinolytic activity in five normal glomeruli was weakly detected. Consistent with the levels of immunostaining, MMP-9 glomerular activity was dramatically increased in nephritic glomeruli with IgA nephritis, lupus nephritis and DN. The gelatinolytic activity of MMP-2 was occasionally detectable in nephritic glomeruli. These results strongly suggest that MMP-9 plays an important role in abnormal mesangial proliferative changes in human GN.

Significance of matrix metalloproteinases in cardiovascular diseases

The cardiovascular interstitial space is largely composed of type I and III fibrillar collagens. Tissue structure, form and function are determined not only by the collagen content but also by the ratio of different collagens to each other. Matrix metalloproteinases are members of a family of secreted and membrane-bound enzymes that are capable of degrading highly proteolytic resistant fibrillar type I and III collagens. Collagen tissue content is determined by balanced collagen synthesis and degradation. MMP activity and adverse tissue remodeling have been identified in coronary plaques in unstable angina. It has also been linked with the progression of aortic aneurysms and with left ventricular dilatation in congestive heart failure in patients with ischemic and non-ischemic cardiomyopathy. The role of MMPs in these cardiovascular diseases and possible therapeutic options are the focus of this review.

The significance of matrix metalloproteinases during early stages of tumor progression.

Matrix metalloproteinases (MMPs) orchestrate tissue remodeling and play diverse roles during organ development. They are produced excessively during the course of various pathological conditions, including solid tumors. An important function of MMPs during tumor progression is to provide the proteolytic activity that is necessary both for tumor cells to invade extracellular matrix (ECM) and for neovascularization of tumor tissue by endothelial cells. Recently, independent studies in transgenic animals suggest that MMPs may, in addition, promote very early stages of tumor progression. To investigate this possibility further, we have analyzed the consequences of MMP overexpression in functionally normal and nontumorigenic mouse mammary epithelial cells in culture. Our observations demonstrate that the MMP stromelysin-1 (SL-1) triggers an epigenetic molecular program in mammary epithelial cells that results in a number of phenotypic alterations that eventually culminate in the generation of a malignant tumor-cell phenotype.

Expression of matrix metalloproteinases in human glioma cell lines in the presence of IL-10.

Matrix metalloproteinases have been implicated to play a vital role in glioma invasion as they degrade extracellular matrix to facilitate the subsequent migration of tumor cells into the surrounding brain tissue. The cytokine Interleukin-10 (IL-10) was detected recently in glial tumors in vivo. Expression of specific IL-10 mRNA as well as blood serum levels of IL-10 in glioma patients increased with malignancy suggesting a functional role of IL-10 in glioma progression. Moreover, glioma cell migration in vitro was enhanced in the presence of IL-10. We therefore investigated the expression of the matrix metalloproteinases (MMPs) stromelysin-1 (MMP-3), 72-kDa collagenase (MMP-2), 92-kDa collagenase (MMP-9), matrilysin (MMP-7) and the human macrophage metalloelastase (MMP-12). In addition, a possible relation between exposure of glioma cells to IL-10 and invasiveness of these cells due to MMP expression was analyzed. Experiments with Matrigel coated Boyden chambers revealed a pronounced dose dependent effect of IL-10 on glioma invasiveness. The synthetic MMP-inhibitor Marimastat markedly reduced cell invasion in the Boyden chambers confirming the significance of MMPs in the process of invasion. Subsequently, the expression level of MMPs and the serine protease uPA was investigated in 7 glioma cell lines (U373, GaMG, U251, GHE, SNB19, U138 and D54) by RT-PCR. In all but one cell line no enhancement of MMP expression by IL-10 was detected. Matrilysin in U373 cells was the only protease found to be upregulated in the presence of IL-10 dependent on cell density. The present data suggest that IL-10 related effects on the invasive properties of the cell lines are not directly mediated by an upregulation of matrix metalloproteinase expression.