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 p16INK4a expression 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.
['Sim|Hyun-Jaung|HJ|', 'Kook|Sung-Ho|SH|', 'Yun|Chi-Young|CY|', 'Bhattarai|Govinda|G|', 'Cho|Eui-Sic|ES|', 'Lee|Jeong-Chae|JC|']
D019386:Alendronate D000818:Animals D000970:Antineoplastic Agents D015519:Bone Density D001854:Bone Marrow Cells D000071556:Cancellous Bone D000066673:Cell Self Renewal D005260:Female D018380:Hematopoietic Stem Cell Transplantation D006412:Hematopoietic Stem Cells D008810:Mice, Inbred C57BL D010010:Osteoclasts D000072916:Peripheral Blood Stem Cells D013154:Spleen D013312:Stress, Physiological D013997:Time Factors
Alendronate Osteoclasts Engraftment stress resistance ROS