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Blood, 1 July 2004, Vol. 104, No. 1, pp. 65-72.
Prepublished online as a Blood First Edition Paper on March 9, 2004; DOI 10.1182/blood-2003-05-1589.
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HEMATOPOIESIS
Characterization of hematopoietic progenitor mobilization in protease-deficient mice
Jean-Pierre Levesque,
Fulu Liu,
Paul J. Simmons,
Tomoko Betsuyaku,
Robert M. Senior,
Christine Pham, and
Daniel C. Link
From the Stem Cell Biology Laboratory, Peter MacCallum Cancer Institute, Melbourne, Victoria, Australia; the Divisions of Oncology, Pulmonary and Critical Care Medicine, and Rheumatology, Washington University School of Medicine, St Louis, MO; and the First Department of Medicine, Hokkaido University School of Medicine, Sapparo, Japan.
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-9deficient 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 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.

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