Disease relevance of Mmp9

• Mice deficient in either GB or neutrophil elastase (NE) are resistant to blister formation in response to these antibodies in a mouse model of the autoimmune disease bullous pemphigoid [1].
• Bone marrow transplantation from wild-type mice prevented the aneurysm-resistant phenotype in MMP-9-deficient animals, and wild-type mice acquired aneurysm resistance after transplantation from MMP-9-deficient donors [2].
• Targeted gene disruption of matrix metalloproteinase-9 (gelatinase B) suppresses development of experimental abdominal aortic aneurysms [2].
• Matrix metalloproteinase-9 (MMP-9) is prominently overexpressed after myocardial infarction (MI) [3].
• Synergy between a plasminogen cascade and MMP-9 in autoimmune disease [4].

Psychiatry related information on Mmp9

• Activated MMP-9 (1 microg g(-1)) significantly prolonged the latency period of inducing platelet plug formation in mesenteric venules [5].
• This study provides evidence that MMP-9 plays a key role in abnormal vascular permeability and inflammation within the first 3 d after spinal cord injury, and that blockade of MMPs during this critical period attenuates these vascular events and leads to improved locomotor recovery [6].

High impact information on Mmp9

• BM ablation induces SDF-1, which upregulates MMP-9 expression, and causes shedding of sKitL and recruitment of c-Kit+ stem/progenitors [7].
• Matrix metalloproteinase-9 (MMP-9), induced in BM cells, releases soluble Kit-ligand (sKitL), permitting the transfer of endothelial and hematopoietic stem cells (HSCs) from the quiescent to proliferative niche [7].
• Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand [7].
• Release of sKitL by MMP-9 enables BM repopulating cells to translocate to a permissive vascular niche favoring differentiation and reconstitution of the stem/progenitor cell pool [7].
• In MMP-9-/- mice, release of sKitL and HSC motility are impaired, resulting in failure of hematopoietic recovery and increased mortality, while exogenous sKitL restores hematopoiesis and survival after BM ablation [7].

Chemical compound and disease context of Mmp9

• Finally, Ang II-induced abdominal aortic aneurysm formation in ApoE-/-OPN-/- mice was reduced and associated with decreased MMP-2 and MMP-9 activity [8].
• In vivo activation of gelatinase B/MMP-9 by trypsin in acute pancreatitis is a permissive factor in streptozotocin-induced diabetes [9].
• These findings suggest that endogenous tPA, through the enhancement of MMP 9 expression and proteolytic activation, plays an essential role in the pathogenesis of heparin-produced cerebral hemorrhage [10].
• Reduced peribronchial fibrosis in allergen-challenged MMP-9-deficient mice [11].
• Polymorphonuclear leukocytes (PMNs) contain MMP-9, and in the presence of both PMN-derived serine protease and membrane type 1 (MT1)-MMP, are able to activate pro-MMP-2 following hindlimb ischemia [12].

Biological context of Mmp9

• Genetic mapping studies showed that Mmp9 maps to the distal end of chromosome 2 near the proximal boundary of a region affected by genomic imprinting [13].
• Assignment of matrix metalloproteinase 9 (Mmp9) to mouse chromosome 2 bands H1-H2 [14].
• Defects in extraembryonic tissue gene expression and function include deficient expression of matrix metalloproteinase-9 (MMP-9, gelatinase B), persistent extracellular matrix, and failure of ectoplacental cone proliferation [15].
• In MMP-3+/+ and MMP-3-/- macrophages, comparable levels of 94 kD proMMP-9 were detected, and plasmin(ogen)-mediated conversion to 83 kD MMP-9 was obtained in both genotypes [16].
• Finally, the effect of MMP-9 on apoptosis was measured using TUNEL and caspase expression [17].

Anatomical context of Mmp9

• Considering our results together with those of previous reports of reduced fertility in Mmp9-deficient female mice, we speculate that neutrophil infiltration participates in the extracellular matrix degradation needed to support pregnancy [18].
• At 4 days after injury, TIMP-1, gelatinase B, and TNF-alpha mRNAs were localized to infiltrating macrophages and Schwann cells in the regions of nerve infiltrated by elicited macrophages [19].
• Gelatinase B-deficient mice were resistant to the blistering effect of intracutaneous anti-mBP180 antibodies, although these mice showed deposition of autoantibodies at the basement membrane zone and neutrophil recruitment to the skin comparable to that observed in the control mice [20].
• Double immunostaining showed colocalization of MMP-9 with macrophages in the adventitia, whereas MMP-2 was also detected mainly in the adventitia but failed to colocalize with smooth muscle cells [16].
• We have previously reported that tumor necrosis factor-alpha (TNF-alpha) stimulation of CCKS1, a cell line established from cholangiocarcinoma with i.p. dissemination, dramatically increased matrix metalloproteinase-9 (MMP-9) production and tumor invasion [21].

Associations of Mmp9 with chemical compounds

• They also demonstrate that this activation is mediated by a plasmin/serine protease- and MMP-9-dependent and CD44-independent mechanism(s) and that the fibrogenic effects of IL-13 are mediated, in great extent, by this TGF-beta pathway [22].
• Elastase-induced aneurysmal degeneration was suppressed by treatment with a nonselective MMP inhibitor (doxycycline) and by targeted gene disruption of MMP-9, but not by isolated deficiency of MMP-12 [2].
• However, gelatinase B-deficient mice had a normal rate of resolution of acute inflammation elicited by cutaneous phenol [23].
• Allergen exposure induced an increase of MMP-9-related gelatinolytic activity in WT lung extracts [24].
• Proving the specificity of the effect, transient transfection of alphaT3-1 cells with ribozymes directed against MMP2 or MMP9 specifically blocked EGFR tyrosine phosphorylation in response to GnRH stimulation [25].
• Overexpression of a dominant negative inhibitor of NF-kappaB or AP-1 blocked the TNF-alpha-induced expression of MMP-9 in myotubes [26].
• M. avium-induced MMP-9 gene induction requires the histone acetyltransferase p300 and chromatin modifications involving phosphorylation of p65 at serine 276 and its acetylation at lysines 221 and 310 [27].

Physical interactions of Mmp9

• Transcription Factors Pax6 and AP-2alpha Interact To Coordinate Corneal Epithelial Repair by Controlling Expression of Matrix Metalloproteinase Gelatinase B [28].
• Site directed mutagenesis of the prohormone convertase PC2 was used to define the effect of certain residues on the zymogen activation of proPC2 and on its binding to the neuroendocrine protein 7B2 [29].

Enzymatic interactions of Mmp9

• HGF is secreted as an inactive zymogen and must be cleaved by a serine protease to initiate Met signaling [30].
• The increase of mRNA levels and of both the zymogen and the cleaved forms of caspase-3 was observed in in vivo stimulated Ag-specific effector, but not memory T cells, correlating with the enhanced susceptibility of effector T cells to AICD [31].
• Gelatinase B is present in the cerebrospinal fluid during experimental autoimmune encephalomyelitis and cleaves myelin basic protein [32].

Regulatory relationships of Mmp9

• Instead, GB acts upstream to regulates NE activity by inactivating alpha1-proteinase inhibitor (alpha1-PI) [1].
• Gelatinase B secretion by LuM1 cells was enhanced by the addition of TGF-beta1 to the culture medium, but that by NM11 cells was not seriously affected, although the latter bound more of the factor [33].
• This study investigated the mechanism by which tPA induces MMP-9 gene expression [34].
• However, the molecular mechanism(s) by which OPN regulates promatrix metalloproteinase-9 (pro-MMP-9) activation, MMP-9-dependent cell motility, and tumor growth and the involvement of upstream kinases in regulation of these processes in murine melanoma cells are not well defined [35].
• Mmp-9 deficiency enhances collagenase-induced intracerebral hemorrhage and brain injury in mutant mice [36].
• MMP-9 was up-regulated by tumor necrosis factor alpha (TNFalpha) and produced primarily by vascular smooth muscle cells [37].

Other interactions of Mmp9

• Excess NE produces lesions in GB -/- mice without cleaving alpha1-PI [1].
• Instead, deficiency of urokinase-type plasminogen activator (u-PA-/-) completely protected against rupture, whereas lack of gelatinase-B partially protected against rupture [38].
• TIMP-1 protected basement membrane type IV collagen from degradation by exogenous gelatinase B in cryostat sections of nerve in vitro [19].
• A marked decrease in matrix metalloproteinase-9 (MMP-9) induction was found in the obstructed kidneys of tPA(-/-) mice, which led to a dramatic preservation of the structural and functional integrity of tubular basement membrane (TBM) [39].
• Brachiocephalic artery plaques were significantly larger in apoE/MMP-3 and apoE/MMP-9 double knockouts than in controls [40].

Analytical, diagnostic and therapeutic context of Mmp9

• The goal of this study was to investigate the role of MMP-9 in liver regeneration after partial hepatectomy [17].
• A 70% hepatectomy or sham laparotomy was performed in wild-type or MMP-9-deficient (MMP-9-/-) mice [17].
• Significantly less peribronchial mononuclear cell infiltration of the airways and less lymphocytes in the bronchoalveolar lavage fluid were detected in challenged MMP-9(-/-) as compared to WT mice [24].
• In agreement, cell culture studies revealed that both AM1 and SS1 were equipotent in pro-MMP-9 induction in human gastric epithelial cells [41].
• The MMP, 92-kDa type IV collagenase (gelatinase B), fell from 216 +/- 70 before steroids to 54 +/- 26 relative lysis zone units (p < 0.046) after treatment [42].

References