HEMATOPOIESIS Characterization of hematopoietic progenitor mobilization in protease-deficient mice

Recent evidence suggests that protease release by neutrophils in the bone mar-row may contribute to hematopoietic pro-genitor cell (HPC) mobilization. Matrix metalloproteinase-9 (MMP-9), neutrophil elastase (NE), and cathepsin G (CG) accu-mulate in the bone marrow during granu-locyte colony-stimulating factor (G-CSF) treatment, where they are thought to de-grade key substrates including vascular cell adhesion molecule-1 (VCAM-1) and CXCL12. To test this hypothesis, HPC mobilization was characterized in trans-genic mice deficient in one or more hema-topoietic proteases. Surprisingly, HPC mobilization by G-CSF was normal in MMP-9–deficient mice, NE CG-deficient mice, or mice lacking dipeptidyl pepti-dase I, an enzyme required for the func-tional activation of many hematopoietic serine proteases. Moreover, combined in-hibition of neutrophil serine proteases and metalloproteinases had no signifi-cant effect on HPC mobilization. VCAM-1 expression on bone marrow stromal cells decreased during G-CSF treatment of wild-type mice but not NE CG-deficient mice, indicating that VCAM-1 cleavage is not required for efficient HPC mobiliza-tion. G-CSF induced a significant de-crease in CXCL12 protein expression in the bone marrow of Ne CG-deficient mice, indicating that these proteases are not required to down-regulate CXCL12 expression. Collectively, these data sug-gest a complex model in which both pro-tease-dependent and-independent path-ways may contribute to HPC mobilization