title: G-CSF potently inhibits osteoblast activity and CXCL12 mRNA expression in the bone marrow.
abstract: Accumulating evidence indicates that interaction of stromal cell-derived factor 1 (SDF-1/CXCL12 [CXC motif, ligand 12]) with its cognate receptor, CXCR4 (CXC motif, receptor 4), generates signals that regulate hematopoietic progenitor cell (HPC) trafficking in the bone marrow. During granulocyte colony-stimulating factor (G-CSF)-induced HPC mobilization, CXCL12 protein expression in the bone marrow decreases. Herein, we show that in a series of transgenic mice carrying targeted mutations of their G-CSF receptor and displaying markedly different G-CSF-induced HPC mobilization responses, the decrease in bone marrow CXCL12 protein expression closely correlates with the degree of HPC mobilization. G-CSF treatment induced a decrease in bone marrow CXCL12 mRNA that closely mirrored the fall in CXCL12 protein. Cell sorting experiments showed that osteoblasts and to a lesser degree endothelial cells are the major sources of CXCL12 production in the bone marrow. Interestingly, osteoblast activity, as measured by histomorphometry and osteocalcin expression, is strongly down-regulated during G-CSF treatment. However, the G-CSF receptor is not expressed on osteoblasts; accordingly, G-CSF had no direct effect on osteoblast function. Collectively, these data suggest a model in which G-CSF, through an indirect mechanism, potently inhibits osteoblast activity resulting in decreased CXCL12 expression in the bone marrow. The consequent attenuation of CXCR4 signaling ultimately leads to HPC mobilization.
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, 660 S Euclid Ave, Campus Box 8007, St Louis, MO 63110, USA.
authors.forename: Craig L
authors.initials: CL
authors.lastname: Semerad
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Christopher
authors.forename: Fulu
authors.initials: F
authors.lastname: Liu
authors.forename: Brenton
authors.initials: B
authors.lastname: Short
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Simmons
authors.forename: Ingrid
authors.initials: I
authors.lastname: Winkler
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Levesque
authors.forename: Jean
authors.initials: J
authors.lastname: Chappel
authors.forename: F Patrick
authors.initials: FP
authors.lastname: Ross
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Link
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000187:drug effects* / Q000378:metabolism*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002465:Cell Movement; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects*; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology* / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D012333:RNA, Messenger; D016179:Granulocyte Colony-Stimulating Factor