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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.

Original publication




Journal article



Publication Date





1540 - 1549


Kennedy Institute of Rheumatology, Charing Cross Campus, Imperial College, 65 Aspenlea Road, London, United Kingdom.


Hematopoietic Stem Cells, Cells, Cultured, Osteoclasts, Hematopoietic System, Bone Marrow, Animals, Mice, Inbred C57BL, Mice, Bone Resorption, Diphosphonates, Parathyroid Hormone, Antigens, CD45, Antigens, Thy-1, Tomography, X-Ray Computed, Blotting, Western, Bone Marrow Transplantation, Flow Cytometry, Cell Division, S Phase, Female, Bone Density Conservation Agents, Stem Cell Niche