Inhibition of osteoclast function reduces hematopoietic stem cell numbers in vivo

Stefania Lymperi, Adel Ersek, Francesca Ferraro, Francesco Dazzi, Nicole J Horwood

Research output: Contribution to journalArticle

92 Citations (Scopus)

Abstract

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 languageEnglish
Pages (from-to)1540-1549
Number of pages10
JournalBlood
Volume117
Issue number5
DOIs
Publication statusPublished - 3 Feb 2011

Keywords

  • Animals
  • Blotting, Western
  • Bone Density Conservation Agents/pharmacology
  • Bone Marrow/metabolism
  • Bone Marrow Transplantation
  • Bone Resorption/etiology
  • Cell Division/physiology
  • Cells, Cultured
  • Diphosphonates/pharmacology
  • Female
  • Flow Cytometry
  • Hematopoietic Stem Cells/metabolism
  • Hematopoietic System/physiology
  • Leukocyte Common Antigens/physiology
  • Mice
  • Mice, Inbred C57BL
  • Osteoclasts/cytology
  • Parathyroid Hormone/pharmacology
  • S Phase/physiology
  • Stem Cell Niche/drug effects
  • Thy-1 Antigens/physiology
  • Tomography, X-Ray Computed

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