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Blood, Vol. 92 No. 9 (November 1), 1998:
pp. 3465-3473
Osteoclast-Mediated Bone Resorption Is Stimulated During Short-Term
Administration of Granulocyte Colony-Stimulating Factor But Is Not
Responsible for Hematopoietic Progenitor Cell Mobilization
Yasushi Takamatsu,
Paul J. Simmons,
Robert J. Moore,
Howard A. Morris,
Luen B. To, and
Jean-Pierre Lévesque
From the Matthew Roberts Laboratory, and the Leukaemia Research Unit,
the Division of Haematology, Hanson Centre for Cancer Research; and the
Divisions of Tissue Pathology and Clinical Biochemistry, Institute of
Medical and Veterinary Science, Adelaide, Australia.
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.
© 1998 by The American Society of Hematology.
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