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 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.
Kennedy Institute of Rheumatology, Charing Cross Campus, Imperial College, 65 Aspenlea Road, London, United Kingdom.
Stefania
S
Lymperi
Adel
A
Ersek
Francesca
F
Ferraro
Francesco
F
Dazzi
Nicole J
NJ
Horwood
D000818:Animals; D015153:Blotting, Western; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D016026:Bone Marrow Transplantation; D001862:Bone Resorption / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D004164:Diphosphonates / Q000494:pharmacology*; D005260:Female; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology*; D006413:Hematopoietic System / Q000502:physiology*; D017493:Leukocyte Common Antigens / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010281:Parathyroid Hormone / Q000494:pharmacology; D016196:S Phase / Q000502:physiology; D055153:Stem Cell Niche / Q000187:drug effects / Q000502:physiology*; D018800:Thy-1 Antigens / Q000502:physiology; D014057:Tomography, X-Ray Computed
D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D010281:Parathyroid Hormone; D018800:Thy-1 Antigens; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse