G-CSF potently inhibits osteoblast activity and CXCL12 mRNA expression in the bone marrow

Area of Science:

• Hematology
• Cell Biology
• Endocrinology

Background:

• Stromal cell-derived factor 1 (SDF-1/CXCL12) and its receptor CXCR4 regulate hematopoietic progenitor cell (HPC) trafficking in bone marrow.
• Granulocyte colony-stimulating factor (G-CSF) induces HPC mobilization, accompanied by decreased CXCL12 expression in the bone marrow.

Purpose of the Study:

• To investigate the mechanism by which G-CSF induces HPC mobilization.
• To determine the relationship between G-CSF, CXCL12 expression, and osteoblast activity.

Main Methods:

• Utilized transgenic mice with G-CSF receptor mutations to study HPC mobilization.
• Measured CXCL12 mRNA and protein levels in bone marrow following G-CSF treatment.
• Assessed osteoblast activity using histomorphometry and osteocalcin expression.
• Performed cell sorting to identify CXCL12-producing cells.

Main Results:

• Decreased bone marrow CXCL12 protein expression strongly correlated with the degree of HPC mobilization in G-CSF treated mice.
• G-CSF treatment reduced both CXCL12 mRNA and protein levels, mirroring HPC mobilization.
• Osteoblasts were identified as major sources of bone marrow CXCL12.
• G-CSF treatment down-regulated osteoblast activity, but G-CSF receptor is not expressed on osteoblasts, indicating an indirect effect.

Conclusions:

• G-CSF indirectly inhibits osteoblast activity, leading to reduced CXCL12 expression in the bone marrow.
• This reduction in CXCL12 attenuates CXCR4 signaling, ultimately resulting in HPC mobilization.
• The findings elucidate an indirect mechanism of G-CSF-mediated HPC mobilization involving osteoblast-derived CXCL12.