Role Of Matrix Metalloproteinase-3 Research Articles

Plasma Levels of Metalloproteinase 3 (MMP-3) and Metalloproteinase 7 (MMP-7) as New Candidates for Tumor Biomarkers in Diagnostic of Breast Cancer Patients

Matrix metalloproteinases (MMPs) are a group of enzymes that mediate both physiological and pathological processes such as carcinogenesis. The role of matrix metalloproteinase-3 (MMP-3) and (MMP-7) in the pathogenesis of breast cancer (BC) has been demonstrated, suggesting that they may be considered as potential markers of this condition. The aim of this study was to assess plasma concentrations and diagnostic utility of MMP-3 and MMP-7 in 100 patients with early-stage breast cancer with Luminal A subtype or Luminal B HER-negative subtype, before and after surgical treatment, and in the following control groups: patients with a benign tumor (fibroadenoma) and healthy subjects. The concentrations of MMP-3 and MMP-7 were referenced to the levels of the widely recognized marker for BC diagnosis CA 15-3. MMP-3 and MMP-7 was measured by ELISA method and CA 15-3 by CMIA. Plasma levels of MMP-7 were significantly higher in Luminal A and Luminal B HER2-negative subtype breast cancer patients as compared to the healthy group. MMP-7 demonstrated comparable but mostly higher to CA 15-3 or MMP-3 values of diagnostic sensitivity, specificity, positive and negative predictive values and AUC (0.6888 for Luminal A subtype; 0.7612 for Luminal B HER2-negative; 0.7250 for BC total group, respectively) in the groups tested. The combined use of the tested parameters resulted in a further increase in diagnostic criteria and AUC. These results suggest the usefulness of combining MMP-7 with CA 15-3 in the diagnostics of breast cancer, especially in Luminal B HER2-negative subtypes patients, as a new candidate for tumor markers.

Identification of a novel role for matrix metalloproteinase-3 in the modulation of B cell responses in multiple sclerosis.

There has been a growing interest in the presence and role of B cell aggregates within the central nervous system of multiple sclerosis patients. However, very little is known about the expression profile of molecules associated with these aggregates and how they might be influencing aggregate development or persistence in the brain. The current study focuses on the effect of matrix metalloproteinase-3, which is associated with B cell aggregates in autopsied multiple sclerosis brain tissue, on B cells. Autopsied brain sections from multiple sclerosis cases and controls were screened for the presence of CD20+ B cell aggregates and expression of matrix metalloproteinase-3. Using flow cytometry, enzyme-linked immunosorbent assay and gene array as methods, in vitro studies were conducted using peripheral blood of healthy volunteers to demonstrate the effect of matrix metalloproteinase-3 on B cells. Autopsied brain sections from multiple sclerosis patients containing aggregates of B cells expressed a significantly higher amount of matrix metalloproteinase-3 compared to controls. In vitro experiments demonstrated that matrix metalloproteinase-3 dampened the overall activation status of B cells by downregulating CD69, CD80 and CD86. Furthermore, matrix metalloproteinase-3-treated B cells produced significantly lower amounts of interleukin-6. Gene array data confirmed that matrix metalloproteinase-3 altered the proliferation and survival profiles of B cells. Taken together, out data indicate a role for B cell modulatory properties of matrix metalloproteinase-3.

MMP-3 plays a major role in calcium pantothenate-promoted wound healing after fractional ablative laser treatment

Ablative fractional laser treatment leads to a loss of matrix metalloproteinase-3 (MMP-3) expression; therefore, in the present in vitro study, we addressed the role of MMP-3 and its regulation by calcium pantothenate in wound healing processes at the molecular level. Utilizing confocal laser microscopy, we investigated MMP-3 protein expression in fractional ablative CO2 laser-irradiated skin models. In addition, we established full-thickness 3D skin models using fibroblasts and keratinocytes with a MMP-3 knockdown that were irradiated with a fractional ablative Er:YAG laser to set superficial injuries with standardized dimensions and minimal thermal damage to the surrounding tissue. We revealed an upregulation of MMP-3 protein expression in laser-irradiated skin models receiving aftercare treatment with calcium pantothenate. Skin models with MMP-3 knockdown exhibited a slower wound closure after laser treatment compared to controls. Gene expression profiling detected an MMP-3 knockdown-dependent upregulation of cytokines and chemokines (e.g. IL-36B, CXCL17, IL-37, CXCL5), antimicrobial peptides (e.g., S100A7, S100A12), epidermal crosslinking enzymes (TGM5), and differentiation markers (e.g., LOR, KRT1, FLG2). We also detected a downregulation of cathepsin V and MMP-10, both of which play a prominent role in wound healing processes. After fractional ablative laser injury, an aftercare treatment with calcium pantothenate accelerated wound closure in MMP-3 expressing models faster than in MMP-3 knockdown models. Our data substantiate a major role of MMP-3 in wound healing processes after ablative laser treatments. For the first time, we could show that calcium pantothenate exerts its wound healing-promoting effects at least partly via MMP-3.

A new role for matrix metalloproteinase-3 in the NGF metabolic pathway: Proteolysis of mature NGF and sex-specific differences in the continuum of Alzheimer's pathology

Matrix metalloproteinase-3 (MMP-3) has been associated with risk of Alzheimer's disease (AD). In this study we introduce a novel role for MMP-3 in degrading nerve growth factor (NGF) in vivo and examine its mRNA and protein expression across the continuum of AD pathology. We provide evidence that MMP-3 participates in the degradation of mature NGF in vitro and in vivo and that it is secreted from the rat cerebral cortex in an activity-dependent manner. We show that cortical MMP-3 is upregulated in the McGill-R-Thy1-APP transgenic rat model of AD-like amyloidosis. A similar upregulation was found in AD and MCI brains as well as in cognitively normal individuals with elevated amyloid deposition. We also observed that frontal cortex MMP-3 protein levels are higher in males. MMP-3 protein correlated with more AD neuropathology, markers of NGF metabolism, and lower cognitive scores in males but not in females. These results suggest that MMP-3 upregulation in AD might contribute to NGF dysmetabolism, and therefore to cholinergic atrophy and cognitive deficits, in a sex-specific manner. MMP-3 should be further investigated as a biomarker candidate or as a therapeutic target in AD.

Abstract 544: Increase in Isoflurane-mediated Blood-brain-barrier (bbb) Permeability is Regulated by Mmp3 via the Erk Signal Pathway

Introduction: The blood-brain barrier (BBB) normally maintains the CNS microenvironment. The effect of isoflurane, widely used in clinical anesthesia, on the BBB permeability has not been well studied. Matrix metalloproteinase 3 (MMP3) is implicated in the disruption of BBB. However, the direct role for MMP3 in regulating BBB and the underlying molecular mechanism has not yet been elucidated. We hypothesized that MMP3 plays a critical role in isoflurane mediated increase in BBB permeability. Methods: We used MMP3 deficient (MMP3 -/- ) mice and its littermate, wild-type (MMP3 +/+ ), as a control. Animals were assigned to either vehicle-air or isoflurane in 3 different groups: control, MMP3 -/- and control+MMP3 administration. We evaluated the anesthetic effect of isoflurane by the time of anesthesia induction, emergency time and volume of isoflurane. MMP3 levels were measured in different organs. We monitored the permeability of mouse BBB through in vivo (Evans blue dye extravasation, Sodium-FITC, and brain water content) and an in vitro model of BBB (Electrical cell impedance sensor assay and transwell permeability assay). To determine the mechanism of MMP3 on BBB permeability, we also used an ERK-inhibitor. Expression of the endothelial tight junctional protein was detected by both western blot and immunofluorescence staining. Results: The use of MMP3 increased the anesthetic sensitivity of isoflurane compared with the control group. In contrast, MMP3 KO mice displayed significantly longer induction time, higher isoflurane usage volume, and lower emergency time. Data showed that MMP3 increased BBB permeability in both in vivo and in vitro experiments, which is associated with a reduction in occluding, ZO-1 and claudin-5. We found mmp3 levels had negative correlations with tight junctional proteins and positive associations with p-ERK. Moreover, the use of an ERK-inhibitor abolished the effect of MMP3 on the junctional protein and in vitro BBB permeability. Conclusion: Our data suggest that MMP3 is required for modulation of isoflurane mediated BBB permeability by the reduction of tight junctional protein expression via the ERK pathway. Thus, mmp3 enhances the anesthetic effect of isoflurane, while the deletion of MMP3 protects against BBB disruption.

Serum level of matrix metalloproteinase 3 (stromelysin 1) in patients with systemic lupus erythematosus: relation to clinical nephritis and neuropsychiatric manifestations

Aim The aim of this study was to assess serum matrix metalloproteinase 3 (MMP-3) level in patients of systemic lupus erythematosus (SLE) and its relation to various clinical and laboratory findings. Patients and methods The study involved 40 female patients with SLE as a study group and 20 sex-matched and age-matched healthy individuals as a control group. All patients were subjected to thorough clinical examinations and laboratory investigations. Disease activity was assessed using SLE Disease Activity Index, as well as Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index. Serum level of MMP-3 was assessed using enzyme-linked immunosorbent assay technique. Patients who showed clinical manifestations of neuropsychiatric lupus were subjected to brain MRI. Results The mean serum MMP-3 was significantly higher in patients with SLE than controls (24.93 ± 21.67 vs. 6.98 ± 1.85,P Conclusion MMP-3 was reported to be higher in patients with SLE than controls and patients who presented with either nephritis or neuropsychiatric symptoms showed elevated level of MMP-3 than patients presented with other clinical manifestations. In addition to its proven role in development of lupus nephritis, this study highlighted the possible role of MMP-3 in neuropsychiatric disease.

The Role of Matrix Metalloproteinase-3 in the Doxycycline Attenuation of Intracranial Venous Hypertension-Induced Angiogenesis.

The molecular mechanism of brain arteriovenous malformation (BAVM) is largely unknown. Intracranial venous hypertension (VH) may enhance focal angiogenesis and promote BAVM development and progression. A rat VH model effectively simulates the hemodynamic microenvironment of this disease. To explore the effect of doxycycline in VH-related angiogenesis, as well as the role of matrix metalloproteinase-3 (MMP-3) and other molecular factors. A rat VH model was generated by common carotid artery and distal external jugular vein anastomosis. Microvessel density (MVD) in the perisinus area and expression of MMP-3/2/9, VEGF, TIMP-1, TGF-β, and HIF-1α were examined, with and without daily doxycycline treatment for 4 wk. The effects of doxycycline were verified in Vitro using human brain microvascular endothelial cells (HBMECs). MMP-3 overexpression or knockdown in HBMECs was used to confirm the role of MMP-3 in cell functions. MVD in the perisinus cortex was greatly increased after VH. Doxycycline decreased MVD, suppressed MMP-3 overexpression, and reduced VEGF, TGF-β, and TIMP-1 levels compared with the controls (P < .05). In Vitro, doxycycline decreased HBMEC migration, tube formation, and the mRNA, protein, and enzymatic activity levels of MMP-3. MMP-3 overexpression in HBMECs promoted migration, while knockdown of MMP-3 significantly attenuated proliferation, migration, and tube formation (P < .05). Our findings indicate that MMP-3 plays an important role in VH-related angiogenesis and the promotion of vascular remodeling. Suppression of MMP-3 overexpression by doxycycline may provide a potential strategy for inhibiting BAVM development.

MMP-3 Deficiency Alleviates Endotoxin-Induced Acute Inflammation in the Posterior Eye Segment.

Matrix metalloproteinase-3 (MMP-3) is known to mediate neuroinflammatory processes by activating microglia, disrupting blood–central nervous system barriers and supporting neutrophil influx into the brain. In addition, the posterior part of the eye, more specifically the retina, the retinal pigment epithelium (RPE) and the blood–retinal barrier, is affected upon neuroinflammation, but a role for MMP-3 during ocular inflammation remains elusive. We investigated whether MMP-3 contributes to acute inflammation in the eye using the endotoxin-induced uveitis (EIU) model. Systemic administration of lipopolysaccharide induced an increase in MMP-3 mRNA and protein expression level in the posterior part of the eye. MMP-3 deficiency or knockdown suppressed retinal leukocyte adhesion and leukocyte infiltration into the vitreous cavity in mice subjected to EIU. Moreover, retinal and RPE mRNA levels of intercellular adhesion molecule 1 (Icam1), interleukin 6 (Il6), cytokine-inducible nitrogen oxide synthase (Nos2) and tumor necrosis factor α (Tnfα), which are key molecules involved in EIU, were clearly reduced in MMP-3 deficient mice. In addition, loss of MMP-3 repressed the upregulation of the chemokines monocyte chemoattractant protein (MCP)-1 and (C-X-C motif) ligand 1 (CXCL1). These findings suggest a contribution of MMP-3 during EIU, and its potential use as a therapeutic drug target in reducing ocular inflammation.

Lack of matrix metalloproteinase 3 in mouse models of lung injury ameliorates the pulmonary inflammatory response in female but not in male mice

ABSTRACTBackground: The acute respiratory distress syndrome (ARDS) is a complex pulmonary disorder in which the local release of cytokines and chemokines appears central to the pathophysiology. Objective: Based on the known role of matrix metalloproteinase-3 (MMP3) in inflammatory processes, the objective was to examine the role of MMP3 in the pathogenesis of ARDS through the modulation of pulmonary inflammation. Materials and Methods: Female and male, wild type (MMP3+/+) and knock out (MMP3−/−) mice were exposed to two, clinically relevant models of ARDS including (i) lipopolysaccharide (LPS)-induced lung injury, and (ii) hydrochloric acid-induced lung injury. Parameters of lung injury and inflammation were assessed through measurements in lung lavage including total protein content, inflammatory cell influx, and concentrations of mediators such as TNF-α, IL-6, G-CSF, CXCL1, CXCL2, and CCL2. Lung histology and compliance were also evaluated in the LPS model of injury. Results: Following intra-tracheal LPS instillation, all mice developed lung injury, as measured by an increase in lavage neutrophils, and decrease in lung compliance, with no overall effect of genotype observed. Increased concentrations of lavage inflammatory cytokines and chemokines were also observed following LPS injury, however, LPS-instilled female MMP3−/− mice had lower levels of inflammatory mediators compared to LPS-instilled female MMP3+/+ mice. This effect of the genotype was not observed in male mice. Similar findings, including the MMP3-related sex differences, were also observed after acid-induced lung injury. Conclusion: MMP3 contributes to the pathogenesis of ARDS, by affecting the pulmonary inflammatory response in female mice in relevant models of lung injury.

Distinct effects of SIRT1 in cancer and stromal cells on tumor promotion.

The lysyl deacetylase SIRT1 acts as a metabolic sensor in adjusting metabolic imbalance. To explore the role of SIRT1 in tumor-stroma interplay, we designed an in vivo tumor model using SIRT1-transgenic mice. B16F10 mouse melanoma grew more quickly in SIRT1-transgenic mice than in wild-type mice, whereas SIRT1-overexpressing one grew slowly in both mice. Of human tumors, SIRT1 expression in stromal fibroblasts was found to correlate with poor prognosis in ovarian cancer. B16F10 and human ovarian cancer (SKOV3 and SNU840) cells were more proliferative in co-culture with SIRT1-overexpressiong fibroblasts. In contrast, SIRT1 within cancer cells has a negative effect on cell proliferation. In conditioned media from SIRT1-overexpressing fibroblasts, matrix metalloproteinase-3 (MMP3) was identified in cytokine arrays to be secreted from fibroblasts SIRT1-dependently. Fibroblast-derived MMP3 stimulated cancer cell proliferation, and such a role of MMP3 was also demonstrated in cancer/fibroblast co-grafts. In conclusion, SIRT1 plays differential roles in cancer and stromal cells. SIRT1 in stromal cells promotes cancer growth by producing MMP3, whereas SIRT1 in cancer cells inhibits growth via an intracellular event. The present study provides a basis for setting new anticancer strategies targeting SIRT1.

Matrix Metalloprotease 3 Exacerbates Hemorrhagic Transformation and Worsens Functional Outcomes in Hyperglycemic Stroke.

Acute hyperglycemia worsens the clinical outcomes and exacerbates cerebral hemorrhage after stroke. The mediators of hemorrhagic transformation (HT) in hyperglycemic stroke are not fully understood. Matrix metalloproteinase 3 (MMP3) plays a critical role in the tissue-type plasminogen activator-induced HT. However, the role of MMP3 in exacerbating the HT and worsening the functional outcomes in hyperglycemic stroke remains unknown. Control/normoglycemic and hyperglycemic (blood glucose, 140-200 mg/dL) male Wistar rats were subjected to middle cerebral artery occlusion for 90 minutes and either 24 hours or 7 days reperfusion. MMP3 was inhibited pharmacologically (UK 356618, 15 mg/kg IV at reperfusion) or knocked down in the brain by shRNA lentiviral particles (injected intracerebroventricular). Neurovascular injury was assessed at 24 hours, and functional outcomes were assessed at 24 hours, day 3, and day 7. MMP3 activity was measured in brain homogenate and cerebral macrovessels. Localization of MMP3 within the neurovascular unit after hyperglycemic stroke was demonstrated by immunohistochemistry. Hyperglycemia significantly increased MMP3 activity in the brain after stroke, and this was associated with exacerbated HT and worsened functional outcomes. MMP3 inhibition significantly reduced HT and improved functional outcomes. MMP3 plays a critical role in mediating cerebrovascular injury in hyperglycemic stroke. Our findings point out MMP3 as a potential therapeutic target in hyperglycemic stroke.

Stromelysin‐1(MMP3) Worsens the Neurovascular Injury in Hyperglycemic Stroke.

IntroductionAcute hyperglycemia (HG) worsens stroke outcomes and increases the risk of cerebral hemorrhage especially with the co‐administration of tissue plasminogen activator (tPA). Matrix metalloproteinase 3 (MMP3) mediates tPA‐induced hemorrhagic transformation (HT) after stroke. However, the role of MMP3 in hyperglycemic stroke is unknown. The goals of the study were to evaluate the impact of the severity of HG 1) on stroke outcomes and 2) on MMP3 activity and expression.MethodsMild and severe HG were induced by glucose injections in rats that were subjected to 90 min middle cerebral artery occlusion and 22.5 h reperfusion. Stroke outcome and cerebrovascular MMP3 activity were assessed. Brain microvascular endothelial cells (BVEC) are subjected to oxygen glucose deprivation (OGD) followed by HG and MMP3 expression was measured.ResultsSevere HG significantly increased the infarct size. Mild elevation in blood glucose has significantly increased HT and MMP3 activity in cerebral vasculature. HG increased MMP3 expression in BVEC and hypoxia potentiated this effect.ConclusionMild elevation in blood glucose worsens the vascular injury without increasing the infarct size. Up‐regulation of MMP3 in the cerebrovasculature and endothelial cells suggests that MMP3 highly contributes to the HG induced vascular injury.

Matrix Metalloproteinase 3 Is a Mediator of Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) may be triggered by epithelial injury that results in aberrant production of growth factors, cytokines, and proteinases, leading to proliferation of myofibroblasts, excess deposition of collagen, and destruction of the lung architecture. The precise mechanisms and key signaling mediators responsible for this aberrant repair process remain unclear. We assessed the importance of matrix metalloproteinase-3 (MMP-3) in the pathogenesis of IPF through i) determination of MMP-3 expression in patients with IPF, ii) in vivo experiments examining the relevance of MMP-3 in experimental models of fibrosis, and iii) in vitro experiments to elucidate possible mechanisms of action. Gene expression analysis, quantitative RT-PCR, and Western blot analysis of explanted human lungs revealed enhanced expression of MMP-3 in IPF, compared with control. Transient adenoviral vector-mediated expression of recombinant MMP-3 in rat lung resulted in accumulation of myofibroblasts and pulmonary fibrosis. Conversely, MMP-3-null mice were protected against bleomycin-induced pulmonary fibrosis. In vitro treatment of cultured lung epithelial cells with purified MMP-3 resulted in activation of the β-catenin signaling pathway, via cleavage of E-cadherin, and induction of epithelial-mesenchymal transition. These processes were inhibited in bleomycin-treated MMP-3-null mice, as assessed by cytosolic translocation of β-catenin and cyclin D1 expression. These observations support a novel role for MMP-3 in the pathogenesis of IPF, through activation of β-catenin signaling and induction of epithelial-mesenchymal transition.

Role of matrix metalloproteinase-3 (MMP-3) and magnetic resonance imaging of sacroiliitis in assessing disease activity in ankylosing spondylitis

The objective of this study is to evaluate the role of MMP-3 and MRI in assessing disease activity in sacroiliac joints of AS patients in comparison to the conventional measures Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Serum MMP-3 was measured in 30 patients who fulfilled the modified New York criteria for AS and in ten healthy volunteers. AS patients were categorized into those having high or low MMP-3 according to a cut-off value=7.1ng/ml. MRI of the sacroiliac joints (SIJs) was performed on all patients. SIJs were evaluated for enhancement and subchondral bone marrow edema. Results of MMP-3 and findings on MRI were correlated with multiple clinical parameters including BASDAI, ESR and CRP. Serum MMP-3 was significantly elevated in AS patients with active disease. Elevated MMP-3 levels were significantly associated with high BASDAI (P=0.046), but not with ESR or CRP. MRI showed bone marrow edema and enhancement of SIJs in 19/30 patients with one patient showing enhancement only. These MRI findings were not correlated with MMP-3, BASDAI, CRP or ESR. In conclusion, serum MMP-3 is an objective measure reflecting clinical disease activity in AS. Bone marrow edema and enhancement detected by MRI of SIJs is another objective measure of disease activity, but are not correlated with MMP-3 or the conventional parameters as BASDAI, ESR, or CRP. Although both MMP-3 and MRI can reflect disease activity in AS they seem to be unrelated, perhaps each is reflecting a different aspect of disease activity. MMP-3 and MRI should be considered together with BASDAI in assessing disease activity and in guiding the available recommendations for initiation of biologics in AS.

Role of matrix metalloproteinase-3 in neurodegeneration

Matrix metalloproteinase-3 (MMP-3) is a member of the class of zinc-dependent proteases known to degrade the extracellular matrix. MMP-3 activity is regulated at three different levels: gene expression, proteolytic activation of the zymogen, and inhibition by the endogenous tissue inhibitors of metalloproteinase. A line of evidence indicates a role of MMP-3 in neurodegeneration. In neuronal cells, MMP-3 expression is increased in response to cell stress, and the cleaved, active MMP-3 participates in apoptotic signaling. In the extracellular space, MMP-3 triggers microglia to produce proinflammatory and cytotoxic molecules as well as MMP-3, which in turn contribute to neuronal damage. MMP-3 is increased in various experimental models of Parkinson's disease that are produced by selective toxins and by inflammagen, and the neuronal death is attenuated by various ways that inhibit MMP-3. α-Synuclein, whose gene mutations are associated with familial forms of Parkinson's disease, is proteolyzed by MMP-3. Contribution of MMP-3 toward the pathogenesis of Alzheimer's disease and other neurodegenerative diseases has also been suggested. Thus, modulation of MMP-3 expression and/or activity could be of therapeutic value for neurodegenerative diseases.

Matrix metalloproteinase-2 is involved in the migration and network formation of enteric neural crest-derived cells

The enteric nervous system is derived from neural crest cells that emigrate from the hindbrain, enter the foregut and colonise the entire length of the gastrointestinal tract. Previous studies have shown that although enteric neural crest-derived cells migrate in chains, they have the ability to detach from their existing chain in order to join or form a new chain. In this study, the possible role of matrix metalloproteinase-3, -8 and -2/-9 on the migration of enteric neural crest-derived cells and the formation of the neural network within the developing gut were examined using specific pharmacological inhibitors. Blocking MMP-2/MMP-9 activity significantly decreased the distance that enteric neural crest-derived cells migrated through the developing gut. Morevover, the reticulated network formed by these cells was less complex. MMP-3 and MMP-8 inhibitors had no effect on neural crest migration. Expression studies showed that MMP-2, but not MMP-9, was expressed within the developing mouse gut. Collectively, the data suggest that MMP-2 activity is important for enteric neural crest-derived cell migration and the formation of the neural crest network.

Peptidomics of bronchoalveolar lavage fluid (BALF) from preterm infants with bronchopulmonary dysplasia: Role of matrix metalloproteinase-3 (MMP-3)

Peptidomics of bronchoalveolar lavage fluid (BALF) from preterm infants with bronchopulmonary dysplasia: Role of matrix metalloproteinase-3 (MMP-3)

Interaction of MMP-3 and sex hormones in the control of energy balance.

Matrix metalloproteinase-3 (MMP-3) is an endopeptidase important for regulating cell-to-cell interactions and remodeling the extracellular matrix, including the development of adipose tissue. We hypothesized that MMP-3 is also active in the central nervous system, specifically acting to cleave synedecan-3 and thereby regulate AgRP signaling. Because previous studies have shown sex difference in syndecan-3-mediated regulation of food intake, we also tested the hypothesis that CNS MMP-3 might mediate the sex-differences underlying syndecan-3 regulation of energy balance. We first observed that MMP-3 deficient mice are hyperphagic and gain significantly more weight on high-fat diet compared to wild-type controls. Second, MMP-3 null mice exhibit a delayed and prolonged orexigenic response to ICV NPY and AgRP, compared to wild-type controls. These findings are consistent with our hypothesis that MMP-3 regulates cleavage of cell-surface syndecan-3. To test the role of sex hormones in mice lacking MMP-3, we assessed food intake following ovariectomy (OVX). WT-ovariectomized mice exhibit hyperphagia and increased food intake and body weight compared to sham-controls. A separate cohort of MMP-3 null or WT female mice was randomized to receive OVX or sham surgery, after which we recorded daily food intake and body weights. While MMP-3 null and WT OVX mice exhibited similar amounts of hyperphagia, MMP-3 KO mice gained more weight than WT controls. Collectively, these data suggest an important role for MMP-3 in the regulation of food intake and the mediation of sex-hormones on energy balance, consistent with a potential role to regulate cleavage of hypothalamic syndecans.

Role of matrix metalloproteinase-3 in joint destruction in rheumatoid arthritis

Matrix metalloproteinase-3 (MMP-3) , which is induced by inflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) in rheumatoid synovium, degrades a number of extracellular matrix components of cartilage, and plays central roles in rheumatoid joint destruction. In addition, serum MMP-3 level is a clinically useful maker for predicting joint destruction and for disease activity in rheumatoid arthritis (RA) . In this review, I summarized the role of MMP-3 in rheumatoid joint destruction, and clinical usefulness of serum MMP-3 level as a laboratory marker in RA.

Role of Matrix Metalloproteinase-3 in Degenerative Lumbar Scoliosis

Purpose: This study was performed to investigate the differences in the expression of matrix metalloproteinase-3 in degenerative scoliosis compared with other degenerative disc disease of the spine. Materials and Methods: The intervertebral disc materials were obtained during discectomies. Six, 13 and 12 cases of herniated nucleus pulposus, spinal stenosis and degenerative lumbar scoliosis, respectively, were included in the experimental group. The expression of MMP-3 was evaluated three times that of the means, in the immunohistochemical staining, western blotting using anti human MMP-3 antibody and RT-PCR with MMP-3 primer, respectively Results: On the immunohistochemical stains, extensive and strong staining was noted in the discs of degenerative lumbar scoliosis compared to those with spinal stenosis and HNP. In the western blotting, greater expression of MMP-3 was noted in the discs of degenerative lumbar scoliosis (mean optical density: 20.68) than in other degenerative disc diseases (SS: 6.24, HNP: 2.0). In the RT-PCR, a similar result was shown (DLS: 62.1, SS: 27.4 & HNP: 10.4). There were statistically significant differences between degenerative lumbar scoliosis and degenerative disc disease (p<0.05). C o n c l u s i o n: Rapid degeneration of the intervertebral disc might be an important factor in the pathogenesis of degenerative lumbar scoliosis. MMP-3 could be a key enzyme for the rapid degeneration of the intervertebral discs, especially in degenerative lumbar scoliosis.