Osteoclast activity regulates the size of the haematopoietic stem cell pool

A. Ersek, S. Lymperi, F. Dazzi, N. Horwood

Research output: Contribution to conferenceAbstract

Abstract

In bone, haematopoietic cells occupy a specialized microenvironment called the haematopoietic stem cell (HSC) niche that is made up of different cellular components. The role of all the cellular components of the HSC niche remains poorly defined. The dual function of osteoblasts in producing bone matrix proteins and sustaining the HSC niche has been unequivocally recognised and verified in vivo (Calvi et al., 2003; Zhang et al., 2003). Nevertheless bone resorbing osteoclasts (OCL) of myeloid origin were shown to play an essential role in mobilizing the HSC from their niche in response to injury or stress (Kollet et al., 2008). In this study we sought to investigate the OCL involvement in maintaining a physiological HSC niche by inhibiting OCL activity via: Alendronate (ALN) – a bisphosphonate widely used for the treatment of bone loss; or Salmon Calcitonin (CT) – a protective hormone that prevents skeletal calcium loss by inhibiting OCL activity.

Alendronate treated mice exhibited a significant increase in bone volume compared with control and CT treated mice, however, serum TRAPCP5b levels, which reflects OCL function, indicated that both ALN and CT successfully inhibited OCL activity. This was accompanied by a decrease in the proportion of primitive HSC in the bone marrow (BM) assessed by immunophenotypic evaluation of Lin− Sca1+ c-kit+ FlK2− cells. The number of haematopoietic progenitors as assessed by CFU-C was increased in the BM of ALN and CT treated mice compared to the control mice, while more Lin− Sca1+ c-kit+ cells were found in the S/M phase suggesting that the hematopoietic balance has changed in favour of progenitor differentiation. The ability of BM cells from OCL-impaired mice to engraft and reconstitute the hematopoietic system was also tested in a competitive transplantation assay, and it was revealed that their engraftment was inferior to control BM at all time points, confirming the decrease in HSC numbers.

Inhibiting OCL activity resulted in essential metabolic changes in the bone as well as changes in normal haematopoiesis with restricted HSC numbers in the BM. Thus, our data suggests bone resorbing OCL are important regulators of the HSC pool size in vivo and the therapeutic targeting of the haematological diseases may involve the use of OCL modifying agents.
Original languageEnglish
PagesS124-S124
Number of pages1
DOIs
Publication statusPublished - 7 May 2011
Externally publishedYes
Event3rd Joint Meeting of the European-Calcified-Tissue-Society/International-Bone-and-Mineral-Society - Athens, Greece
Duration: 7 May 201111 May 2011

Conference

Conference3rd Joint Meeting of the European-Calcified-Tissue-Society/International-Bone-and-Mineral-Society
CountryGreece
CityAthens
Period7/05/1111/05/11

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