Inhibition of osteoclast function reduces hematopoietic stem cell numbers in vivo

Osteoblasts play a crucial role in the hematopoietic stem cell (HSC) niche; however, an overall increase in their number does not necessarily promote hematopoiesis. Because the activity of osteoblasts and osteoclasts is coordinately regulated, we hypothesized that active bone-resorbing osteoclasts w...

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Bibliographic Details
Published in:Blood 2011-02, Vol.117 (5), p.1540-1549
Main Authors: Lymperi, Stefania, Ersek, Adel, Ferraro, Francesca, Dazzi, Francesco, Horwood, Nicole J.
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Blotting, Western
Bone Density Conservation Agents - pharmacology
Bone Marrow - metabolism
Bone Marrow - pathology
Bone Marrow Transplantation
Bone Resorption - etiology
Bone Resorption - metabolism
Bone Resorption - pathology
Cell Division - physiology
Cells, Cultured
Diphosphonates - pharmacology
Female
Flow Cytometry
Hematologic and hematopoietic diseases
Hematopoietic Stem Cells - metabolism
Hematopoietic Stem Cells - pathology
Hematopoietic System - physiology
Leukocyte Common Antigens - physiology
Medical sciences
Mice
Mice, Inbred C57BL
Osteoclasts - cytology
Osteoclasts - drug effects
Osteoclasts - metabolism
Parathyroid Hormone - pharmacology
S Phase - physiology
Stem Cell Niche - drug effects
Stem Cell Niche - physiology
Thy-1 Antigens - physiology
Tomography, X-Ray Computed
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Summary:Osteoblasts play a crucial role in the hematopoietic stem cell (HSC) niche; however, an overall increase in their number does not necessarily promote hematopoiesis. Because the activity of osteoblasts and osteoclasts is coordinately regulated, we hypothesized that active bone-resorbing osteoclasts would participate in HSC niche maintenance. Mice treated with bisphosphonates exhibited a decrease in proportion and absolute number of Lin−cKit+Sca1+ Flk2− (LKS Flk2−) and long-term culture–initiating cells in bone marrow (BM). In competitive transplantation assays, the engraftment of treated BM cells was inferior to that of controls, confirming a decrease in HSC numbers. Accordingly, bisphosphonates abolished the HSC increment produced by parathyroid hormone. In contrast, the number of colony-forming-unit cells in BM was increased. Because a larger fraction of LKS in the BM of treated mice was found in the S/M phase of the cell cycle, osteoclast impairment makes a proportion of HSCs enter the cell cycle and differentiate. To prove that HSC impairment was a consequence of niche manipulation, a group of mice was treated with bisphosphonates and then subjected to BM transplantation from untreated donors. Treated recipient mice experienced a delayed hematopoietic recovery compared with untreated controls. Our findings demonstrate that osteoclast function is fundamental in the HSC niche.
ISSN:0006-4971
1528-0020
1528-0020
DOI:10.1182/blood-2010-05-282855