Abstract
Recent evidence suggests that protease release by neutrophils in the bone marrow may contribute to hematopoietic progenitor cell (HPC) mobilization. Matrix metalloproteinase-9 (MMP-9), neutrophil elastase (NE), and cathepsin G (CG) accumulate in the bone marrow during granulocyte colony-stimulating factor (G-CSF) treatment, where they are thought to degrade key substrates including vascular cell adhesion molecule-1 (VCAM-1) and CXCL12. To test this hypothesis, HPC mobilization was characterized in transgenic mice deficient in one or more hematopoietic proteases. Surprisingly, HPC mobilization by G-CSF was normal in MMP-9-deficient mice, NE x CG-deficient mice, or mice lacking dipeptidyl peptidase I, an enzyme required for the functional activation of many hematopoietic serine proteases. Moreover, combined inhibition of neutrophil serine proteases and metalloproteinases had no significant effect on HPC mobilization. VCAM-1 expression on bone marrow stromal cells decreased during G-CSF treatment of wild-type mice but not NE x CG-deficient mice, indicating that VCAM-1 cleavage is not required for efficient HPC mobilization. G-CSF induced a significant decrease in CXCL12 alpha protein expression in the bone marrow of Ne x CG-deficient mice, indicating that these proteases are not required to down-regulate CXCL12 expression. Collectively, these data suggest a complex model in which both protease-dependent and -independent pathways may contribute to HPC mobilization.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Bone Marrow / metabolism
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Bone Marrow / ultrastructure
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Cathepsin C / deficiency
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Cathepsin C / genetics
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Cathepsin G
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Cathepsins / deficiency
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Cathepsins / genetics
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Chemokine CXCL12
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Chemokines, CXC / biosynthesis
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Colony-Forming Units Assay
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Endopeptidases / deficiency*
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Endopeptidases / genetics
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Granulocyte Colony-Stimulating Factor / pharmacology
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Hematopoietic Stem Cell Mobilization*
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Hematopoietic Stem Cells / cytology*
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Hematopoietic Stem Cells / drug effects
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Hematopoietic Stem Cells / enzymology
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Humans
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Interleukin-8 / genetics
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Interleukin-8 / pharmacology
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Matrix Metalloproteinase 9 / blood
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Matrix Metalloproteinase 9 / deficiency
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Matrix Metalloproteinase 9 / genetics
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Matrix Metalloproteinase Inhibitors
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Neutrophils / drug effects
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Neutrophils / enzymology
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Neutrophils / physiology
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Protease Inhibitors / pharmacology
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Receptors, Chemokine / biosynthesis
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Recombinant Proteins / pharmacology
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Serine Endopeptidases
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Vascular Cell Adhesion Molecule-1 / metabolism
Substances
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CXCL12 protein, human
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Chemokine CXCL12
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Chemokines, CXC
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Cxcl12 protein, mouse
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Interleukin-8
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Matrix Metalloproteinase Inhibitors
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Protease Inhibitors
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Receptors, Chemokine
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Recombinant Proteins
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Vascular Cell Adhesion Molecule-1
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Granulocyte Colony-Stimulating Factor
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Cathepsins
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Endopeptidases
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Cathepsin C
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Serine Endopeptidases
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CTSG protein, human
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Cathepsin G
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Ctsg protein, mouse
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Matrix Metalloproteinase 9