title: Iron Chelation Inhibits Osteoclastic Differentiation In Vitro and in Tg2576 Mouse Model of Alzheimer's Disease.
abstract: Patients of Alzheimer's disease (AD) frequently have lower bone mineral density and higher rate of hip fracture. Tg2576, a well characterized AD animal model that ubiquitously express Swedish mutant amyloid precursor protein (APPswe), displays not only AD-relevant neuropathology, but also age-dependent bone deficits. However, the underlying mechanisms remain poorly understood. As APP is implicated as a regulator of iron export, and the metal chelation is considered as a potential therapeutic strategy for AD, we examined iron chelation's effect on the osteoporotic deficit in Tg2576 mice. Remarkably, in vivo treatment with iron chelator, clinoquinol (CQ), increased both trabecular and cortical bone-mass, selectively in Tg2576, but not wild type (WT) mice. Further in vitro studies showed that low concentrations of CQ as well as deferoxamine (DFO), another iron chelator, selectively inhibited osteoclast (OC) differentiation, without an obvious effect on osteoblast (OB) differentiation. Intriguingly, both CQ and DFO's inhibitory effect on OC was more potent in bone marrow macrophages (BMMs) from Tg2576 mice than that of wild type controls. The reduction of intracellular iron levels in BMMs by CQ was also more dramatic in APPswe-expressing BMMs. Taken together, these results demonstrate a potent inhibition on OC formation and activation in APPswe-expressing BMMs by iron chelation, and reveal a potential therapeutic value of CQ in treating AD-associated osteoporotic deficits.
authors.affiliation: Department of Neuroscience & Regenerative Medicine, and Department of Neurology,Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America.|Charlie Norwood VA Medical Center, Augusta, Georgia, United States of America.|Department of Pathology, Changchun University of Chinese Medicine, Changchun, Jilin, China.
authors.forename: Jun-Peng
authors.initials: JP
authors.lastname: Guo
authors.affiliation: Department of Neuroscience & Regenerative Medicine, and Department of Neurology,Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Jin-Xiu
authors.initials: JX
authors.lastname: Pan
authors.affiliation: Department of Neuroscience & Regenerative Medicine, and Department of Neurology,Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America.|Charlie Norwood VA Medical Center, Augusta, Georgia, United States of America.
authors.forename: Lei
authors.initials: L
authors.lastname: Xiong
authors.affiliation: Department of Neuroscience & Regenerative Medicine, and Department of Neurology,Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America.|Department of Rheumatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Wen-Fang
authors.initials: WF
authors.lastname: Xia
authors.affiliation: Department of Neuroscience & Regenerative Medicine, and Department of Neurology,Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America.|Department of Rheumatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Shun
authors.initials: S
authors.lastname: Cui
authors.affiliation: Department of Neuroscience & Regenerative Medicine, and Department of Neurology,Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America.|Charlie Norwood VA Medical Center, Augusta, Georgia, United States of America.
authors.forename: Wen-Cheng
authors.initials: WC
authors.lastname: Xiong
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D001862:Bone Resorption; D027682:Cation Transport Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D007464:Clioquinol / Q000494:pharmacology / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical; D007502:Iron Chelating Agents / Q000494:pharmacology / Q000627:therapeutic use*; D016173:Macrophage Colony-Stimulating Factor / Q000502:physiology; D008264:Macrophages / Q000187:drug effects; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000187:drug effects; D010010:Osteoclasts / Q000187:drug effects / Q000502:physiology*; D053245:RANK Ligand / Q000502:physiology; D000098742:Ferroportin
chemical_list: D027682:Cation Transport Proteins; D007502:Iron Chelating Agents; D053245:RANK Ligand; D000098742:Ferroportin; D007464:Clioquinol; D016173:Macrophage Colony-Stimulating Factor