Inhibition of osteoclast function reduces hematopoietic stem cell numbers in vivo

TY - JOUR

T1 - Inhibition of osteoclast function reduces hematopoietic stem cell numbers in vivo

AU - Lymperi, Stefania

AU - Ersek, Adel

AU - Ferraro, Francesca

AU - Dazzi, Francesco

AU - Horwood, Nicole J

PY - 2011/2/3

Y1 - 2011/2/3

N2 - 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.

AB - 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.

KW - Animals

KW - Antigens, CD45

KW - Antigens, Thy-1

KW - Blotting, Western

KW - Bone Density Conservation Agents

KW - Bone Marrow

KW - Bone Marrow Transplantation

KW - Bone Resorption

KW - Cell Division

KW - Cells, Cultured

KW - Diphosphonates

KW - Female

KW - Flow Cytometry

KW - Hematopoietic Stem Cells

KW - Hematopoietic System

KW - Mice

KW - Mice, Inbred C57BL

KW - Osteoclasts

KW - Parathyroid Hormone

KW - S Phase

KW - Stem Cell Niche

KW - Tomography, X-Ray Computed

U2 - 10.1182/blood-2010-05-282855

DO - 10.1182/blood-2010-05-282855

M3 - Article

C2 - 21131587

SN - 0006-4971

VL - 117

SP - 1540

EP - 1549

JO - Blood

JF - Blood

IS - 5

M1 - N/A

ER -