(in Cottler-Fox et al). A model for stress-induced mobilization.

DNA-damaging chemotherapy drugs such as Cy and inflammatory cytokines such as G-CSF first induce a transient increase in SDF-1 levels within the BM as part of the alarm situation. Next, G-CSF directly and indirectly (via secretion of IL-8, SDF-1, and other factors) triggers neutrophils to proliferate and release proteases such as elastase, cathepsin G, and proteinase 3. In parallel, proliferation and activation of osteoclasts, which release the mobilizing chemokine IL-8 and secrete MMP-9 in response to SDF-1 stimulation, take place. The massive inflammatory proteolytic enzyme activity leads to degradation of stem cell anchorage and retention signals (VCAM-1 and SDF-1), inactivation of G-CSF, and remodeling of the BM extracellular matrix. MMP-9 mediates shedding of membrane-bound SCF, which together with proteinase 3 induces progenitor cell proliferation and CXCR4 upregulation, followed by partial inactivation of CXCR4 and c-kit by the proteolytic machinery. These sequential events, which are repeated and intensified after each cycle of G-CSF stimulation, orchestrate the egress of progenitors from the BM into the circulation.

Abbreviations: BM, bone marrow; CXCR4, CXC chemokine receptor 4; Cy, cyclophosphamide; G-CSF, granulocyte colony-stimulating factor; IL-8, interleukin-8; MMP-9, matrix metalloproteinase 9; SCF, stem cell factor; SDF-1, stromal-derived cell factor-1; VCAM-1, vascular cell adhesion molecule 1.