Suppression of CXCL12 production by bone marrow osteoblasts is a common and critical pathway for cytokine-induced mobilization.

Journal Article (Journal Article)

Current evidence suggests that hematopoietic stem/progenitor cell (HSPC) mobilization by granulocyte colony-stimulating factor (G-CSF) is mediated by induction of bone marrow proteases, attenuation of adhesion molecule function, and disruption of CXCL12/CXCR4 signaling in the bone marrow. The relative importance and extent to which these pathways overlap or function independently are uncertain. Despite evidence of protease activation in the bone marrow, HSPC mobilization by G-CSF or the chemokine Grobeta was abrogated in CXCR4(-/-) bone marrow chimeras. In contrast, HSPC mobilization by a VLA-4 antagonist was intact. To determine whether other mobilizing cytokines disrupt CXCR4 signaling, we characterized CXCR4 and CXCL12 expression after HSPC mobilization with Flt3 ligand (Flt3L) and stem cell factor (SCF). Indeed, treatment with Flt3L or SCF resulted in a marked decrease in CXCL12 expression in the bone marrow and a loss of surface expression of CXCR4 on HSPCs. RNA in situ and sorting experiments suggested that the decreased CXCL12 expression is secondary to a loss of osteoblast lineage cells. Collectively, these data suggest that disruption of CXCR4 signaling and attenuation of VLA-4 function are independent mechanisms of mobilization by G-CSF. Loss of CXCL12 expression by osteoblast appears to be a common and key step in cytokine-induced mobilization.

Full Text

Duke Authors

Cited Authors

  • Christopher, MJ; Liu, F; Hilton, MJ; Long, F; Link, DC

Published Date

  • August 13, 2009

Published In

Volume / Issue

  • 114 / 7

Start / End Page

  • 1331 - 1339

PubMed ID

  • 19141863

Pubmed Central ID

  • PMC2727413

Electronic International Standard Serial Number (EISSN)

  • 1528-0020

Digital Object Identifier (DOI)

  • 10.1182/blood-2008-10-184754


  • eng

Conference Location

  • United States