title: Osteoclast-mediated bone resorption is stimulated during short-term administration of granulocyte colony-stimulating factor but is not responsible for hematopoietic progenitor cell mobilization.
abstract: The cellular and molecular mechanisms responsible for hematopoietic progenitor cell (HPC) mobilization from bone marrow (BM) into peripheral blood after administration of cytokines such as granulocyte colony-stimulating factor (G-CSF) are still unknown. In this study we show that high concentrations of soluble calcium induce the detachment of BM CD34(+) HPC adherent on fibronectin, a major component of BM extracellular matrix. Because G-CSF has been shown to induce osteoporosis in patients with congenital neutropenia and in G-CSF-overexpressing transgenic mice, we hypothesized that short-term G-CSF administration may be sufficient to induce bone resorption, resulting in the release of soluble calcium in the endosteum leading in turn to the inhibition of attachment to fibronectin and the egress of HPC from the BM. We show herein that in humans, serum osteocalcin concentration, a specific marker of bone formation, is strongly reduced after 3 days of G-CSF administration. Furthermore, in patients mobilized with G-CSF either alone or in association with stem cell factor or interleukin-3, the reduction of serum osteocalcin is significantly correlated with the number of HPC mobilized in peripheral blood. Urine levels of deoxypyridinoline (DPyr), a specific marker of bone resorption, gradually elevated during the time course of G-CSF administration until day 7 after cessation of G-CSF, showing a simultaneous stimulation of bone degradation during G-CSF-induced HPC mobilization. In an in vivo murine model, we found that the number of osteoclasts was dramatically increased paralleling the elevation of DPyr after G-CSF administration. When pamidronate, an inhibitor of osteoclast-mediated bone resorption, was administered together with G-CSF in mice, the G-CSF-induced increase of DPyr levels was completely abolished whereas the numbers of colony-forming cells mobilized in peripheral blood were not decreased, but unexpectedly increased relative to the numbers elicited by G-CSF alone. Collectively, our data therefore show that short-term administration of G-CSF induces bone degradation by a simultaneous inhibition of bone formation and an enhanced osteoclast-mediated bone resorption. This increased bone resorption is inhibited by pamidronate without reducing G-CSF-induced HPC mobilization, suggesting that the activation of bone resorption after G-CSF administration is not the direct cause of HPC mobilization as initially hypothesized, but a parallel event.
authors.affiliation: Matthew Roberts Laboratory, and the Leukaemia Research Unit, the Division of Haematology, Hanson Centre for Cancer Research, Medical and Veterinary Science, Adelaide, Australia.
authors.forename: Y
authors.initials: Y
authors.lastname: Takamatsu
authors.forename: P J
authors.initials: PJ
authors.lastname: Simmons
authors.forename: R J
authors.initials: RJ
authors.lastname: Moore
authors.forename: H A
authors.initials: HA
authors.lastname: Morris
authors.forename: L B
authors.initials: LB
authors.lastname: To
authors.forename: J P
authors.initials: JP
authors.lastname: Lévesque
mesh_terms: D000328:Adult; D000596:Amino Acids / Q000652:urine; D000818:Animals; D015415:Biomarkers; D001862:Bone Resorption / Q000139:chemically induced* / Q000517:prevention & control; D001943:Breast Neoplasms / Q000097:blood / Q000628:therapy; D002118:Calcium / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D004164:Diphosphonates / Q000494:pharmacology / Q000627:therapeutic use; D004357:Drug Synergism; D005260:Female; D005353:Fibronectins; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D019650:Hematopoietic Stem Cell Mobilization; D006801:Humans; D039041:Integrin alpha4beta1; D016023:Integrins / Q000502:physiology; D007377:Interleukin-3 / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D015675:Osteocalcin / Q000097:blood; D010010:Osteoclasts / Q000187:drug effects* / Q000502:physiology; D000077268:Pamidronate; D017469:Receptors, Fibronectin / Q000502:physiology; D016201:Receptors, Lymphocyte Homing / Q000502:physiology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D019089:Stem Cell Factor / Q000494:pharmacology
chemical_list: D000596:Amino Acids; D015415:Biomarkers; D004164:Diphosphonates; D005353:Fibronectins; D039041:Integrin alpha4beta1; D016023:Integrins; D007377:Interleukin-3; D017469:Receptors, Fibronectin; D016201:Receptors, Lymphocyte Homing; D011994:Recombinant Proteins; D019089:Stem Cell Factor; D015675:Osteocalcin; D016179:Granulocyte Colony-Stimulating Factor; C036020:deoxypyridinoline; D000077268:Pamidronate; D002118:Calcium