title: Amyloid β Peptide Enhances RANKL-Induced Osteoclast Activation through NF-κB, ERK, and Calcium Oscillation Signaling.
abstract: Osteoporosis and Alzheimer's disease (AD) are common chronic degenerative disorders which are strongly associated with advanced age. We have previously demonstrated that amyloid beta peptide (Aβ), one of the pathological hallmarks of AD, accumulated abnormally in osteoporotic bone specimens in addition to having an activation effect on osteoclast (Bone 2014,61:164-75). However, the underlying molecular mechanisms remain unclear. Activation of NF-κB, extracellular signal-regulated kinase (ERK) phosphorylates, and calcium oscillation signaling pathways by receptor activator NF-κB ligand (RANKL) plays a pivotal role in osteoclast activation. Targeting this signaling to modulate osteoclast function has been a promising strategy for osteoclast-related diseases. In this study, we investigated the effects of Aβ on RANKL-induced osteoclast signaling pathways in vitro. In mouse bone marrow monocytes (BMMs), Aβ exerted no effect on RANKL-induced osteoclastogenesis but promoted osteoclastic bone resorption. In molecular levels, Aβ enhanced NF-κB activity and IκB-α degradation, activated ERK phosphorylation and stimulated calcium oscillation, thus leading to upregulation of NFAT-c1 expression during osteoclast activation. Taken together, our data demonstrate that Aβ enhances RANKL-induced osteoclast activation through IκB-α degradation, ERK phosphorylation, and calcium oscillation signaling pathways and that Aβ may be a promising agent in the treatment of osteoclast-related disease such as osteoporosis.
authors.affiliation: Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-sen University, TianHe Road 600, TianHe District, Guangzhou 510630, China. lishangfu2013@163.com.
authors.forename: Shangfu
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-sen University, TianHe Road 600, TianHe District, Guangzhou 510630, China. xinfeibbb@gmail.com.
authors.forename: Bu
authors.initials: B
authors.lastname: Yang
authors.affiliation: Molecular Lab, School of Pathology and Laboratory Medicine, University of Western Australia, Perth 6009, WA, Australia. dian.teguh@research.uwa.edu.au.
authors.forename: Dian
authors.initials: D
authors.lastname: Teguh
authors.affiliation: Molecular Lab, School of Pathology and Laboratory Medicine, University of Western Australia, Perth 6009, WA, Australia. linzhou09250600@gmail.com.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Molecular Lab, School of Pathology and Laboratory Medicine, University of Western Australia, Perth 6009, WA, Australia. jiake.xu@uwa.edu.au.
authors.forename: Jiake
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-sen University, TianHe Road 600, TianHe District, Guangzhou 510630, China. ronglimin@21cn.com.
authors.forename: Limin
authors.initials: L
authors.lastname: Rong
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008855:Microscopy, Electron, Scanning; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D053245:RANK Ligand / Q000494:pharmacology*; D000067996:RAW 264.7 Cells; D015398:Signal Transduction / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D016229:Amyloid beta-Peptides; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D053245:RANK Ligand; D000072000:NF-KappaB Inhibitor alpha; D048049:Extracellular Signal-Regulated MAP Kinases; D002118:Calcium
keywords: MAPK; NF-κB; NFAT-c1; amyloid β peptide; osteoclast; osteoporosis