Abstract
Patients 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.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia
While numerous proinflammatory cytokines are believed to contribute to the pathogenesis of both diseases,[12,13,14] the mechanisms underlying the association between AD and osteoporosis remain elusive
Hepcidin expression in Tg2576 mice compared with those from age-matched WT controls hepatocytes can be induced by multiple factors, including proinflammatory cytokines,[22,23,24,25,26,27,28] iron overload,[19,29] bone morphogenetic protein (BMP) 6,30,31 and endoplasmic reticulum (ER) stress.[32,33]. Many of these hepcidin regulators are (Fig. 1c–f). Among these 25 proteins, we focused on hepcidin because it is a key regulator of ion homeostasis, which is altered in both AD and osteoporosis,[38,39] but its function in both diseases remains elusive
Summary
Were elevated in an age-dependent manner (Supplementary Fig. S2e), which is in line with previous reports.[41]. The Runx2+ cell number in trabecular bone and cortical bone regions was not different between 3-month-old TgHamp1-Alb mice and control mice (Supplementary Fig. S9a, b) These results suggest that hepatocyte-derived hepcidin has little or no effect on OB-mediated bone formation. Bone histomorphological examinations showed a significant increase in the number of TRAP+ OCs per unit of bone surface in femurs, in the trabecular bone regions, in both TgHamp1-Alb and TgHamp1-Ocn mice (Fig. 3c–f) These in vivo results demonstrate that OC formation and activation are elevated in mice expressing hepcidin in hepatocytes or OB lineage cells. These results suggest that hepcidin expression in OB lineage cells is required for APPswe-induced osteoclastogenesis
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