Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.23 (MMP)
 4,246 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The use of mobilized hematopoietic progenitor cells (HPC) has largely replaced the use of bone marrow HPC for autologous and allogeneic transplantation; however, the mechanisms of HPC mobilization remain unclear. A better understanding of these mechanisms, may allow the development of improved (potentially more rapid and/or higher yield) HPC mobilization strategies, especially for patients who mobilize poorly using current mobilization protocols. Clinically, granulocyte colony-stimulating factor (G-CSF) is widely used to induce HPC mobilization, and evidence suggests that metalloproteinase enzymes released by activated granulocytes play an important role in the G-CSF-induced HPC mobilization. These enzymes may act to disrupt putative cell-cell and/or cell-extracellular matrix interactions within the hematopoietic microenvironment thereby releasing HPC into the blood. Matrix metalloproteinase-9 (MMP-9) appears to be important for G-CSF-induced mobilization. Using an MMP-9 knock-out (KO) mouse model, we investigated the role of MMP-9 in G-CSF and erythropoietin (EPO)-based HPC mobilization at clinically relevant cytokine doses. There were few hematologic or hematopoietic differences between the wild-type and MMP-9KO mice during steady-state hematopoiesis. When treated subcutaneously with EPO (500 U/kg per day) and G-CSF (15 microg/kg per day) for 5 days and assayed on day 6, similarly increased extramedullary hematopoiesis and numbers of HPC in the spleen and blood were observed for both the wild-type and MMP-9KO mice. These data demonstrate that MMP-9 is not required for EPO + G-CSF mobilization and that alternative mobilization mechanisms must be active at clinically relevant cytokine concentrations.
 ...
PMID:Hematopoietic progenitor cell mobilization by granulocyte colony-stimulating factor and erythropoietin in the absence of matrix metalloproteinase-9. 1596 27

We investigated the hypothesis that endothelial cells activated by erythropoietin (EPO) promote the migration of neuroblasts. This hypothesis is based on observations in vivo that treatment of focal cerebral ischemia with EPO enhances the migration of neuroblasts to the ischemic boundary, a site containing activated endothelial cells and angiogenic microvasculature. To model the microenvironment within the ischemic boundary zone, we used a coculture system of mouse brain endothelial cells (MBECs) and neural progenitor cells derived from the subventricular zone of the adult mouse. Treatment of MBECs with recombinant human EPO (rhEPO) significantly increased secretion of matrix metalloproteinase 2 (MMP2) and MMP9. rhEPO-treated MBEC supernatant as conditioned medium significantly increased the migration of neural progenitor cells. Application of an MMP inhibitor abolished the supernatant-enhanced migration. Incubation of neurospheres alone with rhEPO failed to increase progenitor cell migration. rhEPO activated phosphatidylinositol 3-kinase/Akt (PI3K/Akt) and extracellular signal-regulated kinase (ERK1/2) in MBECs. Selective inhibition of the PI3K/Akt and ERK1/2 pathways significantly attenuated the rhEPO-induced MMP2 and MMP9, which suppressed neural progenitor cell migration promoted by the rhEPO-activated MBECs. Collectively, our data show that rhEPO-activated endothelial cells enhance neural progenitor cell migration by secreting MMP2 and MMP9 via the PI3K/Akt and ERK1/2 signaling pathways. These data demonstrate that activated endothelial cells can promote neural progenitor cell migration, and provide insight into the molecular mechanisms underlying the attraction of newly generated neurons to injured areas in brain.
 ...
PMID:Matrix metalloproteinase 2 (MMP2) and MMP9 secreted by erythropoietin-activated endothelial cells promote neural progenitor cell migration. 1673 42

To better understand the transcriptional program that accompanies orderly lineage-specific hematopoietic differentiation, we analyzed expression changes during the lineage-specific differentiation of human hematopoietic stem cells (HSC; CD34+/CD38-/CD33-); HSC and multipotent myeloid progenitors (MMP; CD34+/CD38-/CD33+) were isolated from the bone marrow of healthy individuals by MACS. CD34+ cells in semi-solid culture were stimulated with the cytokines erythropoietin, IL-6, and G-CSF to promote differentiation to committed erythroid, megakaryocytic, and granulocytic clones, respectively. Differential display RT-PCR analysis was performed to compare the mRNA transcripts in HSC, MMP, and the committed lineage-specific clones derived from these committed lineage-specific progenitors. Expressed sequence tags (n=256), which were differentially expressed, were identified. One hundred ninety-four were homologous to known genes, and some were associated with hematopoiesis. These known genes were classified as involved in transcription/translation, signal transduction, cell surface receptors/ligands, cell signaling, cell metabolism, cell cycle, cell apoptosis, and oncogenesis. We identified genes, which were up- or down-regulated specifically in the lineage-committed clones compared with HSC or/and MMP, suggesting that specific gene activation and repression might be necessary for specific lineage commitment and differentiation. Our data provide an extensive transcriptional profile of human hematopoiesis during in vitro, lineage-specific differentiation.
 ...
PMID:Differential gene expression in human hematopoietic stem cells specified toward erythroid, megakaryocytic, and granulocytic lineage. 1762 99

HSC fate decisions are regulated by cell-intrinsic and cell-extrinsic cues. The latter cues are derived from the BM niche. Membrane-type 1 matrix metalloproteinase (MT1-MMP), which is best known for its proteolytic role in pericellular matrix remodeling, is highly expressed in HSCs and stromal/niche cells. We found that, in MT1-MMP(-/-) mice, in addition to a stem cell defect, the transcription and release of kit ligand (KitL), stromal cell-derived factor-1 (SDF-1/CXCL12), erythropoietin (Epo), and IL-7 was impaired, resulting in a trilineage hematopoietic differentiation block, while addition of exogenous KitL and SDF-1 restored hematopoiesis. Further mechanistic studies revealed that MT1-MMP activates the hypoxia-inducible factor-1 (HIF-1) pathway via factor inhibiting HIF-1 (FIH-1) within niche cells, thereby inducing the transcription of HIF-responsive genes, which induce terminal hematopoietic differentiation. Thus, MT1-MMP in niche cells regulates postnatal hematopoiesis, by modulating hematopoietic HIF-dependent niche factors that are critical for terminal differentiation and migration.
 ...
PMID:MT1-MMP plays a critical role in hematopoiesis by regulating HIF-mediated chemokine/cytokine gene transcription within niche cells. 2254 1

Because membrane type 1-matrix metalloproteinase 1 (MT1-MMP) and erythropoietin-producing hepatocellular receptor 2 (EphA2) expression are upregulated by the Ras/mitogen-activated protein kinase pathway, they are frequently coexpressed in malignant tumors. MT1-MMP cleaves the N-terminal ligand-binding domain of EphA2 and inactivates its ligand-dependent tumor-suppressing activity. Therefore, specific detection of the cleaved N-terminal EphA2 fragment in blood might be an effective biomarker to diagnose malignant tumors. To evaluate this possibility, we developed three monoclonal antibodies against the soluble EphA2 fragment. One of them recognized this fragment specifically, with negligible cross-reactivity to the intact form. We used the cleaved form-specific antibody to develop a quantitative enzyme-linked immunosorbent assay and confirmed the linear reactivity to the recombinant fragment. We applied this assay on commercially available serum specimens obtained from patients with several types of cancer including gastric, pancreatic, esophageal, gastroesophageal, and head-and-neck cancers, and healthy donors. Soluble EphA2 fragment levels in cancer-patient sera were higher than those in healthy donors (n=50). In particular, levels of eight out of nine (89%) pancreatic cancer patients and ten out of seventeen (59%) gastric cancer patients significantly exceeded cutoff values obtained from the healthy donors, whereas those of esophageal and head-and-neck cancer-patient sera were low. The preliminary receiver operating characteristic curve analysis for pancreatic cancer demonstrated that the sensitivity and specificity were 89.0% and 90.0%, respectively, whereas those of the conventional digestive tumor marker CA19-9 were 88.9% and 72.0%, respectively. These results indicated that specific detection of soluble EphA2 fragment levels in serum could be potentially useful as a biomarker to diagnose pancreatic cancer.
 ...
PMID:Specific detection of soluble EphA2 fragments in blood as a new biomarker for pancreatic cancer. 2907 78