Author:
Guo Hao-Han,Xiong Lei,Pan Jin-Xiu,Lee Daehoon,Liu Kevin,Ren Xiao,Wang Bo,Yang Xiao,Cui Shun,Mei Lin,Xiong Wen-Cheng
Abstract
AbstractPatients with Alzheimer’s disease (AD) often have lower bone mass than healthy individuals. However, the mechanisms underlying this change remain elusive. Previously, we found that Tg2576 mice, an AD animal model that ubiquitously expresses Swedish mutant amyloid precursor protein (APPswe), shows osteoporotic changes, reduced bone formation, and increased bone resorption. To understand how bone deficits develop in Tg2576 mice, we used a multiplex antibody array to screen for serum proteins that are altered in Tg2576 mice and identified hepcidin, a master regulator of iron homeostasis. We further investigated hepcidin’s function in bone homeostasis and found that hepcidin levels were increased not only in the serum but also in the liver, muscle, and osteoblast (OB) lineage cells in Tg2576 mice at both the mRNA and protein levels. We then generated mice selectively expressing hepcidin in hepatocytes or OB lineage cells, which showed trabecular bone loss and increased osteoclast (OC)-mediated bone resorption. Further cell studies suggested that hepcidin increased OC precursor proliferation and differentiation by downregulating ferroportin (FPN) expression and increasing intracellular iron levels. In OB lineage cells, APPswe enhanced hepcidin expression by inducing ER stress and increasing OC formation, in part through hepcidin. Together, these results suggest that increased hepcidin expression in hepatocytes and OB lineage cells in Tg2576 mice contributes to enhanced osteoclastogenesis and trabecular bone loss, identifying the hepcidin-FPN-iron axis as a potential therapeutic target to prevent AD-associated bone loss.
Funder
U.S. Department of Veterans Affairs
Publisher
Springer Science and Business Media LLC
Subject
Physiology,Histology,Endocrinology, Diabetes and Metabolism
Reference71 articles.
1. Melton, L. J. 3rd, Beard, C. M., Kokmen, E., Atkinson, E. J. & O’Fallon, W. M. Fracture risk in patients with Alzheimer’s disease. J. Am. Geriatr. Soc. 42, 614–619 (1994).
2. Tysiewicz-Dudek, M., Pietraszkiewicz, F. & Drozdzowska, B. Alzheimer’s disease and osteoporosis: common risk factors or one condition predisposing to the other? Ortop. Traumatol. Rehabil. 10, 315–323 (2008).
3. Demontiero, O., Vidal, C. & Duque, G. Aging and bone loss: new insights for the clinician. Ther. Adv. Musculoskelet. Dis. 4, 61–76 (2012).
4. Lufkin, E. G. et al. Treatment of postmenopausal osteoporosis with transdermal estrogen. Ann. Intern. Med. 117, 1–9 (1992).
5. Pacifici, R. Estrogen, cytokines, and pathogenesis of postmenopausal osteoporosis. J. Bone Min. Res 11, 1043–1051 (1996).
Cited by
13 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献