Brief Report: Consecutive Alendronate Administration-Mediated Inhibition of Osteoclasts Improves Long-Term Engraftment Potential and Stress Resistance of HSCs.
Osteoclasts form a bone marrow (BM) cavity serving as a hematopoietic niche for the maintenance of hematopoietic stem cells (HSCs). However, the role of osteoclasts in the BM has been controversially reported and remains to be further understood. In the present study, we investigated how osteoclasts affect the modulation of hematopoietic stem/progenitor cells in the BM by administering bisphosphate alendronate (ALN) to B6 mice for 21 consecutive days to inhibit osteoclast activity. ALN treatment caused a reduction in the number of tartrate-resistant acid phosphate (TRAP)-positive osteoclast cells and an increase in bone mineral density, particularly in the trabecular zone, but not in the cortical zone of the BM. Osteoclast inhibition caused by ALN treatment decreased mitochondrial reactive oxygen species (ROS) generation and SA-β-gal activity of CD150+CD48-Lineage-Sca-1+c-Kit+(LSK) cells, eventually leading to an improvement in the engraftment potential and self-renewal activity of HSCs. Moreover, ALN-treated mice exhibited an enhanced resistance of HSCs in response to the genotoxic stress of 5-fluorouracil, as determined by mitochondrial ROS generation, SA-β-gal activity, and p16INK4aexpression in subsets of LSK and CD150+CD48-LSK cells as well as competitive assay. Collectively, our findings indicate that inhibition of osteoclast activity improves the long-term engraftment potential and stress resistance of HSCs. Stem Cells 2016;34:2601-2607.
Department of Bioactive Material Sciences, Institute of Molecular Biology and Genetics, Institute of Oral Biosciences and School of Dentistry, Jeonju, 561-756, South Korea.|Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Bioscience, Chonbuk National University School of Dentistry, Jeonju, 561-756, South Korea.
Hyun-Jaung
HJ
Sim
Department of Bioactive Material Sciences, Institute of Molecular Biology and Genetics, Institute of Oral Biosciences and School of Dentistry, Jeonju, 561-756, South Korea.|Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Bioscience, Chonbuk National University School of Dentistry, Jeonju, 561-756, South Korea.
Sung-Ho
SH
Kook
Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Bioscience, Chonbuk National University School of Dentistry, Jeonju, 561-756, South Korea.
Chi-Young
CY
Yun
Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Bioscience, Chonbuk National University School of Dentistry, Jeonju, 561-756, South Korea.
Govinda
G
Bhattarai
Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Bioscience, Chonbuk National University School of Dentistry, Jeonju, 561-756, South Korea. oasis@jbnu.ac.kr.
Eui-Sic
ES
Cho
Department of Bioactive Material Sciences, Institute of Molecular Biology and Genetics, Institute of Oral Biosciences and School of Dentistry, Jeonju, 561-756, South Korea. leejc88@jbnu.ac.kr.|Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Bioscience, Chonbuk National University School of Dentistry, Jeonju, 561-756, South Korea. leejc88@jbnu.ac.kr.
Jeong-Chae
JC
Lee
D019386:Alendronate / Q000008:administration & dosage* / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects; D015519:Bone Density / Q000187:drug effects; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000071556:Cancellous Bone / Q000187:drug effects / Q000502:physiology; D000066673:Cell Self Renewal / Q000187:drug effects; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism*; D000072916:Peripheral Blood Stem Cells / Q000166:cytology; D013154:Spleen / Q000166:cytology; D013312:Stress, Physiological / Q000187:drug effects; D013997:Time Factors
D000970:Antineoplastic Agents; D019386:Alendronate
Alendronate; Engraftment; Osteoclasts; ROS; stress resistance