scholarly journals 265.Matrix metalloproteinases in the mouse model of menstruation: effect of doxycycline inhibition

2004 ◽  
Vol 16 (9) ◽  
pp. 265
Author(s):  
J. Shen ◽  
J. Zhang ◽  
T. J. Kaitu'u ◽  
M. Brasted ◽  
L. A. Salamonsen
Keyword(s):  
Matrix Metalloproteinases ◽  
Mouse Model ◽  
Functional Significance ◽  
Human Endometrium ◽  
Tissue Destruction ◽  
Apparent Effect ◽  
Gelatinase Activity ◽  
Old World ◽  
Uterine Lumen ◽  
Mmp Inhibitor

Strong correlative evidence supports a role for matrix metalloproteinases (MMP) in the tissue breakdown at menstruation. Because menstruation occurs only in women and a few old-world primates, it has not been possible to examine the functional significance of potentially key mediators of this process. To this end, we developed a mouse model for menstruation (1), in which ovariectomised mice are subjected to a decidualising stimulus: injection of oil into the uterine lumen following appropriate hormone-priming. During the 24 h following withdrawal of progesterone (P), the decidualised tissue progressively breaks down, in a manner that morphologically resembles that of human endometrium at menstruation. The aims of the present study were to examine the pattern of MMP expression during the time from progesterone withdrawal until complete tissue breakdown, and to determine whether administration of doxycycline, (a known MMP modulator), 3 h prior to P withdrawal, affected the expression or activity of the MMPs or restrained the tissue destruction. MMP-3 was present at foci in the decidual zone: these were initially associated with the restructuring at decidualisation and subsequently with the tissue destruction. MMP-7 was detected both in epithelium and in leukocytes, predominantly neutrophils. These were first apparent in the basal zone during the earliest stages of tissue instability, and dramatically increased in numbers as breakdown progressed. MMP-9 was found only in leukocytes, predominantly neutrophils and some macrophages, with greatly increased numbers with time. Zymography revealed a dramatic increase in both latent and active MMP-9 as tissue breakdown proceeded. Doxycycline reduced immunoreactive MMP-3 but not MMP-7 or MMP-9 in the tissue, and also decreased gelatinase activity. However, no apparent effect on tissue breakdown was observed. Further studies with a more potent MMP inhibitor are required to fully establish the importance of MMPs in these processes. (1) Brasted et al. (2003) Biol. Reprod. 69, 1273.

244. Effect of batimastat, a specific inhibitor of matrix metalloproteinases, on endometrial breakdown and repair in a mouse model

2005 ◽  
Vol 17 (9) ◽  
pp. 97
Author(s):  
T. J. Kaitu'u ◽  
N. B. Morison ◽  
L. A. Salamonsen
Keyword(s):  
Matrix Metalloproteinases ◽  
Mouse Model ◽  
Expression Patterns ◽  
Specific Inhibitor ◽  
Apparent Difference ◽  
Cross Sectional ◽  
Gelatinase Activity ◽  
Expected Time ◽  
Mmp Inhibitor

Strong correlative evidence supports a role for matrix metalloproteinases (MMPs) in the tissue breakdown at menstruation. As menstruation occurs in very few species besides women, there is a lack of suitable and easily accessible animal models available to examine the functional significance of potential key mediators of this process. A mouse model of endometrial breakdown and repair has been developed,1 which morphologically resembles that of human endometrium at menstruation. Previous studies in our laboratory showed that the expression patterns of various MMPs in the mouse model closely resembled those seen in the human.2 Administration of doxycycline, a broad spectrum MMP inhibitor, decreased gelatinase activity, but had no effect on tissue breakdown in this model. The aim of the present study was to further examine the importance of MMPs in endometrial breakdown and repair via administration of batimistat, a highly potent and specific MMP inhibitor. Batimistat was administered I.P to mice 24 h prior to the expected time of endometrial breakdown. The efficacy of batimistat within the uterus was proven using in situ zymography, which identifies MMP activity (rather than latent forms). This demonstrated that batimistat was reaching its target organ and effectively inhibiting MMP activities (both gelatinase and collagenase). Examination of gross uterine morphology revealed no apparent difference between groups, with batimistat treated uteri displaying a similar extent of tissue breakdown and repair to their control counterparts. Measurement of the breaking down area compared to total endometrial area revealed no difference between control and batimistat treatment, with the breaking down areas being 69 ±13% and 72 ± 9.8% of total endometrial cross-sectional area respectively. There was likewise no effect on endometrial repair. The results of this study together with our previous study using doxycycline, indicate that MMPs are not the key mediators of endometrial breakdown in this model. (1)Shen et al. (2004) Reprod. Fert. Dev. 16(Suppl), A265, p. 97.(2)Brasted et al. (2003) Biol. Reprod. 69, 1273.

scholarly journals Inhibition of matrix metalloproteinases in Siberian hamsters impedes photostimulated recrudescence of ovaries

Reproduction ◽  
2010 ◽  
Vol 140 (6) ◽  
pp. 875-883 ◽  
Author(s):  
Julie Whited ◽  
Asha Shahed ◽  
Carling F McMichael ◽  
Kelly A Young
Keyword(s):  
Matrix Metalloproteinases ◽  
Ovarian Function ◽  
Corpora Lutea ◽  
Gelatinase Activity ◽  
Antral Follicles ◽  
Mmp Inhibitor ◽  
Siberian Hamsters ◽  
First Time ◽  
Long Photoperiod

Exposure of Siberian hamsters to short photoperiod for 14 weeks induces ovarian regression. Subsequent transfer to long photoperiod restores ovarian function, and 2 weeks of photostimulation increases plasma estradiol (E2), antral follicles, and corpora lutea (CL). Because tissue remodeling involved with photostimulated ovarian recrudescence is associated with differential expression of matrix metalloproteinases (MMPs), we hypothesized that inhibiting MMP activity using a broad-spectrumin vivoMMP inhibitor, GM6001, would curtail recrudescence. One group of hamsters was placed in long days (LD; 16 h light:8 h darkness) for 16 weeks. Another group was placed in inhibitory short days (SD; 8 h light:16 h darkness) for 14 weeks. A third group was placed in SD for 14 weeks and transferred to LD for 2 weeks to stimulate recrudescence. During weeks 14–16, animals were either not treated or treated daily with i.p. injections of GM6001 (20 mg/kg) or vehicle (DMSO). GM6001 reduced gelatinase activity and decreased immunohistochemical staining for MMP1, MMP2, and MMP3 compared with vehicle. No differences between controls, vehicle, or GM6001 treatment were observed among LD animals, despite a trend toward reduction in CL and E2with GM6001. Although SD reduced ovarian function, photostimulation of transferred controls increased uterine mass, plasma E2, appearance of antral follicles, and CL. With GM6001 treatment, photostimulation failed to increase uterine mass, plasma E2, antral follicles, or CL. These data show, for the first time, thatin vivoGM6001 administration inhibits MMP activity in hamster ovaries during photostimulation, and indicate that this inhibition may impede photostimulated recrudescence of ovaries. This study suggests an intriguing link between MMP activity and return to ovarian function during photostimulated recrudescence.

scholarly journals Suppression of matrix metalloproteinases inhibits establishment of ectopic lesions by human endometrium in nude mice.

1997 ◽  
Vol 99 (12) ◽  
pp. 2851-2857 ◽  
Author(s):  
K L Bruner ◽  
L M Matrisian ◽  
W H Rodgers ◽  
F Gorstein ◽  
K G Osteen
Keyword(s):  
Matrix Metalloproteinases ◽  
Nude Mice ◽  
Human Endometrium

The functional significance of glycosylation of proopiomelanocortin in melanotrophs of the mouse pituitary gland

1985 ◽  
Vol 107 (3) ◽  
pp. 365-374 ◽  
Author(s):  
B. G. Jenks ◽  
A. G. H. Ederveen ◽  
J. H. M. Feyen ◽  
A. P. van Overbeeke
Keyword(s):  
Pituitary Gland ◽  
Functional Significance ◽  
Peptide Hormones ◽  
Terminal Region ◽  
Pars Intermedia ◽  
Apparent Effect ◽  
Glycoprotein Precursor ◽  
Tunicamycin Treatment ◽  
Mouse Pituitary

ABSTRACT Pro-opiomelanocortin (POMC) is a glycoprotein precursor for a number of neuropeptides and peptide hormones. The functional significance of the glycosylation of POMC has never been established. Using the antibiotic tunicamycin to block glycosylation of the prohormone in the mouse pars intermedia, we have compared processing of non-glycosylated prohormone with that of glycosylated prohormone in pulse-chase experiments. The peptides produced from non-glycosylated prohormone were shown to be correct cleavage products. Therefore it was concluded that, with the possible exception of peptides from the N-terminal region of the prohormone, the carbohydrate on POMC plays no role in directing cleavage or in protecting the prohormone from random proteolysis. Tunicamycin treatment retarded N-terminal acetylation of melanotrophin but had no apparent effect on acetylation of β-endorphin. The mouse pars intermedia synthesizes two forms of POMC which differ in their degree of glycosylation. Our results indicated that, during secretion, the melanotrophs make no distinction between peptides derived from the two prohormones. J. Endocr. (1985) 107, 365–374

Abstract 476: Shear Stress-induced Atherosclerotic Plaque Regression is Reversed by Regulation of Macrophage Mobility via Matrix Metalloproteinase Inhibition

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Stefania Simeone ◽  
Talin Ebrahimian ◽  
Veronique Michaud ◽  
Stephanie Lehoux
Keyword(s):  
Shear Stress ◽  
High Fat Diet ◽  
Fold Increase ◽  
Atherosclerotic Plaques ◽  
High Shear ◽  
High Fat ◽  
Gelatinase Activity ◽  
Mmp Inhibitor ◽  
Post Surgery ◽  
Plaque Regression

Atherosclerotic plaques form in regions of low blood flow, whereas vessels exposed to high shear stress remain lesion-free. We hypothesized that exposing established atherosclerotic plaques to elevated shear stress leads to lesion regression by facilitating inflammatory cell movement within the plaque. We developed a model of arteriovenous fistula (AVF) in mice, where the right carotid artery is anastomosed into the jugular vein. LDLR-/- mice were placed on a high-fat diet. Control mice were sacrificed at week 12, which coincided with sham and AVF surgery. Sham and AVF mice were kept on a high-fat diet for a further 4 weeks. This procedure increases the shear stress in the brachiocephalic artery (BCA) and leads to a 51% plaque regression in AVF. All groups had comparable lipid levels. However, BCA plaque macrophage, smooth muscle cell and collagen content was halved in AVF. We observed greater gelatinase activity in plaques of AVF mice, suggesting a role for matrix metalloproteinases (MMPs) in plaque regression. MMP-9 and MMP-3 expression was increased in AVF plaques whereas MMP-2 and MMP-14 expression was decreased (p<0.05). A separate group of mice was therefore treated post-surgery with an MMP inhibitor, doxycycline, or with a TIMP-1 over-expressing plasmid. Both prevented the reduction in plaque size in the AVF group. To better define the mechanism of plaque regression in the AVF, we devised an endothelial cell (EC)-macrophage co-culture system where the ECs were exposed to high, low or no shear stress, and macrophages exposed to the EC effluent. There was a 2.5 fold increase in the migration of macrophages exposed to high shear effluent vs. low shear (p<0.05). This coincided with a 3-fold increase in the number of macrophages expressing activated β1 integrin in the high shear conditions. Uptake of apoptotic cells by macrophages was also 25% higher in the high shear vs. static (p<0.05). When repeated using the MMP inhibitor, GM6001, the high shear increase in migration was blocked in the presence of MMP inhibition; however, it had no effect on cell phagocytosis. Our findings suggest that shear stress acting on ECs may influence the cells within the plaque by increasing MMP activity allowing for better macrophage motility, an important feature of regressing plaques.

MP21-20 DEVELOPMENT OF THE ORTHOTROPIC MOUSE MODEL OF BLADDER CANCER METASTASIS: THE FUNCTIONAL SIGNIFICANCE OF MICRORNA-218

2014 ◽  
Vol 191 (4S) ◽  
Author(s):  
Shuichi Tatarano ◽  
Takeshi Chiyomaru ◽  
Tomoaki Ishihara ◽  
Satoru Inoguchi ◽  
Hideki Enokida ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Mouse Model ◽  
Functional Significance ◽  
Cancer Metastasis

scholarly journals Lung volumes and respiratory mechanics in elastase-induced emphysema in mice

2008 ◽  
Vol 105 (6) ◽  
pp. 1864-1872 ◽  
Author(s):  
Z. Hantos ◽  
Á. Adamicza ◽  
T. Z. Jánosi ◽  
M. V. Szabari ◽  
J. Tolnai ◽  
...  
Keyword(s):  
Mouse Model ◽  
Low Frequency ◽  
Forced Oscillations ◽  
Mechanical Parameters ◽  
Tissue Destruction ◽  
Lung Volumes ◽  
Lung Capacity ◽  
Thoracic Gas Volume ◽  
Residual Capacity ◽  
Gas Volume

Absolute lung volumes such as functional residual capacity, residual volume (RV), and total lung capacity (TLC) are used to characterize emphysema in patients, whereas in animal models of emphysema, the mechanical parameters are invariably obtained as a function of transrespiratory pressure (Prs). The aim of the present study was to establish a link between the mechanical parameters including tissue elastance (H) and airway resistance (Raw), and thoracic gas volume (TGV) in addition to Prs in a mouse model of emphysema. Using low-frequency forced oscillations during slow deep inflation, we tracked H and Raw as functions of TGV and Prs in normal mice and mice treated with porcine pancreatic elastase. The presence of emphysema was confirmed by morphometric analysis of histological slices. The treatment resulted in an increase in TGV by 51 and 44% and a decrease in H by 57 and 27%, respectively, at 0 and 20 cmH2O of Prs. The Raw did not differ between the groups at any value of Prs, but it was significantly higher in the treated mice at comparable TGV values. In further groups of mice, tracheal sounds were recorded during inflations from RV to TLC. All lung volumes but RV were significantly elevated in the treated mice, whereas the numbers and size distributions of inspiratory crackles were not different, suggesting that the airways were not affected by the elastase treatment. These findings emphasize the importance of absolute lung volumes and indicate that tissue destruction was not associated with airway dysfunction in this mouse model of emphysema.

scholarly journals Matrix Metalloproteinases Contribute to Brain Damage in Experimental Pneumococcal Meningitis

2000 ◽  
Vol 68 (2) ◽  
pp. 615-620 ◽  
Author(s):  
Stephen L. Leib ◽  
David Leppert ◽  
John Clements ◽  
Martin G. Täuber
Keyword(s):  
Matrix Metalloproteinases ◽  
Bacterial Meningitis ◽  
Brain Damage ◽  
Neuronal Injury ◽  
Housekeeping Gene ◽  
Close Correlation ◽  
Necrosis Factor Alpha ◽  
Mmp Inhibitor ◽  
Tnf Α ◽  
Cytokine Tumor Necrosis Factor

ABSTRACT The present study was performed to evaluate the role of matrix metalloproteinases (MMP) in the pathogenesis of the inflammatory reaction and the development of neuronal injury in a rat model of bacterial meningitis. mRNA encoding specific MMPs (MMP-3, MMP-7, MMP-8, and MMP-9) and the inflammatory cytokine tumor necrosis factor alpha (TNF-α) were significantly (P< 0.04) upregulated, compared to the β-actin housekeeping gene, in cortical homogenates at 20 h after infection. In parallel, concentrations of MMP-9 and TNF-α in cerebrospinal fluid (CSF) were significantly increased in rats with bacterial meningitis compared to uninfected animals (P = 0.002) and showed a close correlation (r = 0.76; P < 0.001). Treatment with a hydroxamic acid-type MMP inhibitor (GM6001; 65 mg/kg intraperitoneally every 12 h) beginning at the time of infection significantly lowered the MMP-9 (P< 0.02) and TNF-α (P < 0.02) levels in CSF. Histopathology at 25.5 ± 5.7 h after infection showed neuronal injury (median [range], 3.5% [0 to 17.5%] of the cortex), which was significantly (P < 0.01) reduced to 0% (0 to 10.8%) by GM6001. This is the first report to demonstrate that MMPs contribute to the development of neuronal injury in bacterial meningitis and that inhibition of MMPs may be an effective approach to prevent brain damage as a consequence of the disease.

scholarly journals The Role of Matrix Metalloproteinases in Periodontal Disease

2020 ◽  
Vol 17 (14) ◽  
pp. 4923 ◽  
Author(s):  
Vittorio Checchi ◽  
Tatjana Maravic ◽  
Pierantonio Bellini ◽  
Luigi Generali ◽  
Ugo Consolo ◽  
...  
Keyword(s):  
Matrix Metalloproteinases ◽  
Periodontal Disease ◽  
Anaerobic Bacteria ◽  
Therapeutic Strategies ◽  
Oral Diseases ◽  
Tissue Destruction ◽  
Proinflammatory Mediators ◽  
Disease Therapy ◽  
Important Pathway

This review provides a detailed description of matrix metalloproteinases (MMPs), focusing on those that are known to have critical roles in bone and periodontal disease. Periodontal disease is an inflammatory process initiated by anaerobic bacteria, which promote the host immune response in the form of a complex network of molecular pathways involving proinflammatory mediators such as cytokines, growth factors, and MMPs. MMPs are a family of 23 endopeptidases, collectively capable of degrading virtually all extracellular matrix (ECM) components. This study critically discusses the available research concerning the involvement of the MMPs in periodontal disease development and progression and presents possible therapeutic strategies. MMPs participate in morphogenesis, physiological tissue turnover, and pathological tissue destruction. Alterations in the regulation of MMP activity are implicated in the manifestation of oral diseases, and MMPs comprise the most important pathway in tissue destruction associated with periodontal disease. MMPs can be considered a risk factor for periodontal disease, and measurements of MMP levels may be useful markers for early detection of periodontitis and as a tool to assess prognostic follow-ups. Detection and inhibition of MMPs could, therefore, be useful in periodontal disease prevention or be an essential part of periodontal disease therapy, which, considering the huge incidence of the disease, may greatly improve oral health globally.

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