Inhibition of osteoclast function reduces hematopoietic stem cell numbers in vivo.

Journal article

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.

Authors: Lymperi, S; Ersek, A; Ferraro, F; Dazzi, F; Horwood, N

• Publication status: Published
• Journal: Blood
• Volume: 117
• Issue: 5
• Pages: 1540-1549
• Publication date: 2011-02-01
• DOI: 10.1182/blood-2010-05-282855
• EISSN: 1528-0020
• ISSN: 0006-4971
• Language: English
• Keywords: Bone Resorption; Antigens, Thy-1; Hematopoietic Stem Cells; Bone Marrow; Diphosphonates; Mice; Female; Animals; Antigens, CD45; Stem Cell Niche; Parathyroid Hormone; Blotting, Western; Bone Density Conservation Agents; Osteoclasts; Bone Marrow Transplantation; Hematopoietic System; Tomography, X-Ray Computed; S Phase; Cells, Cultured; Flow Cytometry; Mice, Inbred C57BL; Cell Division