title: The effects of zoledronic acid in the bone and vasculature support of hematopoietic stem cell niches.
abstract: Hematopoietic stem cells (HSC) are maintained in a tightly regulated bone microenvironment constituted by a rich milieu of cells. Bone cells such as osteoblasts are associated with niche maintenance as regulators of the endosteal microenvironment. Bone remodeling also plays a role in HSC mobilization although it is poorly defined. The effects of zoledronic acid (ZA), a potent bisphosphonate that inhibits bone resorption, were investigated on bone marrow cell populations focusing on HSCs, and the endosteal and vascular niches in bone. ZA treatment significantly increased bone volume and HSCs in both young and adult mice (4 week and 4 month old, respectively). ZA increased vessel numbers with no overall change in vascular volume in bones of young and had no effect on vasculature in adult mice. Since both young and adult mice had increased HSCs and bone mass with differing vasculature responses, this suggests that ZA indirectly supports HSCs via the osteoblastic niche and not the vascular niche. Additionally, gene expression in Lin- cells demonstrated increased expression of self-renewal-related genes Bmi1 and Ink4a suggesting a role of ZA in the modulation of cell commitment and differentiation toward a long-term self-renewing cell. Genes that support the osteoblastic niche, BMP2 and BMP6 were also augmented in ZA treated mice. In conclusion, ZA-induced HSC expansion occurs independent of the vascular niche via indirect modulation of the osteoblastic niche.
authors: Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA.
authors: Fabiana N
authors: FN
authors: Soki
authors: Xin
authors: X
authors: Li
authors: Janice
authors: J
authors: Berry
authors: Amy
authors: A
authors: Koh
authors: Benjamin P
authors: BP
authors: Sinder
authors: Xu
authors: X
authors: Qian
authors: Kenneth M
authors: KM
authors: Kozloff
authors: Russell S
authors: RS
authors: Taichman
authors: Laurie K
authors: LK
authors: McCauley
mesh_terms: D000367:Age Factors; D000818:Animals; D015519:Bone Density / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism; D055418:Bone Morphogenetic Protein 6 / Q000235:genetics / Q000378:metabolism; D016723:Bone Remodeling / Q000187:drug effects; D001842:Bone and Bones / Q000098:blood supply* / Q000187:drug effects* / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D004164:Diphosphonates / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D055153:Stem Cell Niche / Q000187:drug effects* / Q000502:physiology; D000077211:Zoledronic Acid
chemical_list: C489421:Bmi1 protein, mouse; C525719:Bmp2 protein, mouse; C525817:Bmp6 protein, mouse; D050071:Bone Density Conservation Agents; D055396:Bone Morphogenetic Protein 2; D055418:Bone Morphogenetic Protein 6; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004164:Diphosphonates; D007093:Imidazoles; D011518:Proto-Oncogene Proteins; D000077211:Zoledronic Acid; D063150:Polycomb Repressive Complex 1