Amyloid β Peptide Enhances RANKL-Induced Osteoclast Activation through NF-κB, ERK, and Calcium Oscillation Signaling

Li, Shangfu; Yang, Baofeng; Teguh, Dian; Zhou, Lin; Xu, Jiake; Rong, Limin

doi:10.3390/ijms17101683

Cited by 41 publications

(37 citation statements)

References 34 publications

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“…10 Our previous in vitro study further reveals that Aβ enhances RANKL-induced osteoclast activation via IκB-α degradation, ERK phosphorylation, and calcium oscillation signaling. 11 Although abovementioned finding demonstrates a direct causal relationship between Aβ and osteoclast activation; however, the simple mono-culture system may not represent the complex in vivo environment of bone remodeling. Thus, the role of Aβ in bone remodeling remains to be further investigated.…”

Section: Introductionmentioning

confidence: 95%

“…This observation was disagreement with our previous observation that Aβ enhanced osteoclast activation through NF-κB, ERK, and the calcium oscillation signaling pathway. 11 One possible explanation for the discrepancy may be that the simple mono-culture system may not reflect the complex environment of bone remodeling. In the co-culture system, the promotive effect of Aβ on osteoblastic differentiation might infer the effect of Aβ osteoclastic differentiation, hence exhibiting different results from in mono-culture system.…”

Section: F I G U R Ementioning

confidence: 99%

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Amyloid β peptide promotes bone formation by regulating Wnt/β‐catenin signaling and the OPG/RANKL/RANK system

Yang

Chen

et al. 2020

FASEB j.

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Background Amyloid β peptide (Aβ) is involved in osteoporosis, but the effects of Aβ on osteoblast and bone formation remain unclear. In this study, we investigated the effect of Aβ on bone formation. Methods An animal model of osteoporosis was established by ovariectomy in C57BL/6 mice. The mice received intraperitoneal injection of Aβ. The effect of Aβ on the osteogenic differentiation of human bone marrow stromal stem cells (hBMSCs) and differentiation of both pre‐osteoblasts and pre‐osteoclasts in a co‐culture system were investigated. Results In the animal study, intraperitoneal injection of Aβ for 8 weeks promoted early and late osteogenic differentiation of hBMSCs. Aβ treatment significantly elevated osterix+ (osteoblastic) cells but decreased TRAP+ cells (osteoclasts) in the distal femur bone. In vitro study showed that Aβ treatment significantly enhanced matrix mineralization and osteogenic markers (Runx2 and osteocalcin). Aβ treatment activated Wnt/β‐catenin signaling in hBMSCs. The effect of Aβ was blocked by DKK1 (a Wnt/β‐catenin inhibitor) treatment. In the co‐culture system, Aβ treatment significantly increased the ALP activities of MC3T3‐E1 cells (pre‐osteoblasts) but reduced the TRAP+ RAW264.7 cells (pre‐osteoclasts). Aβ treatment upregulated TCF1 and OPG proteins in MC3T3‐E1 cells. Aβ treatment upregulated IκB‐α but downregulated NFATc1protein in RAW264.7 cells. These effects were blocked by XAV‐939 (a Wnt signaling antagonist), and then rescued by additional Wnt3a (a Wnt agonist). Conclusion Aβ treatment simultaneously promoted osteogenic differentiation via Wnt/β‐catenin signaling, and inhibited osteoclasts differentiation via the OPG/RANKL/RANK system, suggesting Aβ is a positive regulator of osteoblast differentiation and bone formation.

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Section: Introductionmentioning

confidence: 95%

Section: F I G U R Ementioning

confidence: 99%

Amyloid β peptide promotes bone formation by regulating Wnt/β‐catenin signaling and the OPG/RANKL/RANK system

Yang

Chen

et al. 2020

FASEB j.

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“…The binding of bone morphogenetic protein-9 (BMP-9) to its receptor anaplastic lymphoma kinase 1 on the cell surface activates the canonical Smad-1/5/8 pathway and the ERK pathway, and supports the formation, function, and survival of osteoclasts derived from human umbilical cord blood monocytes [ 35 ]. Interestingly, in patients with Alzheimer’s disease, who have a high risk of osteoporotic hip fracture, amyloid beta peptide, one of the pathological hallmarks of Alzheimer’s disease that is abnormally deposited in bone tissues [ 36 ], was shown to enhance RANKL-induced ERK and NF-κB activation and to promote osteoclastic bone resorption [ 37 ]. Taken together, various upstream stimulators of ERK pathway were found to positively regulate the process of osteoclast differentiation.…”

Section: Erk Signaling In Osteoclastsmentioning

confidence: 99%

Roles of Mitogen-Activated Protein Kinases in Osteoclast Biology

Lee

Seo

Choi

et al. 2018

IJMS

185

130

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Bone undergoes continuous remodeling, which is homeostatically regulated by concerted communication between bone-forming osteoblasts and bone-degrading osteoclasts. Multinucleated giant osteoclasts are the only specialized cells that degrade or resorb the organic and inorganic bone components. They secrete proteases (e.g., cathepsin K) that degrade the organic collagenous matrix and establish localized acidosis at the bone-resorbing site through proton-pumping to facilitate the dissolution of inorganic mineral. Osteoporosis, the most common bone disease, is caused by excessive bone resorption, highlighting the crucial role of osteoclasts in intact bone remodeling. Signaling mediated by mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38, has been recognized to be critical for normal osteoclast differentiation and activation. Various exogenous (e.g., toll-like receptor agonists) and endogenous (e.g., growth factors and inflammatory cytokines) stimuli contribute to determining whether MAPKs positively or negatively regulate osteoclast adhesion, migration, fusion and survival, and osteoclastic bone resorption. In this review, we delineate the unique roles of MAPKs in osteoclast metabolism and provide an overview of the upstream regulators that activate or inhibit MAPKs and their downstream targets. Furthermore, we discuss the current knowledge about the differential kinetics of ERK, JNK, and p38, and the crosstalk between MAPKs in osteoclast metabolism.

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“…Aβ42 enhances RANKL-induced osteoclastic bone resorption by upregulating IκB degradation and enhancing NF-κB activity, activating ERK phosphorylation, and stimulating the calcium oscillation signaling pathway. The Aβ42-enhanced activation of these three cytoplasmic signaling pathways eventually leads to increased NFATc1 expression in a dose-dependent manner [ 34 ]. Albeit Aβ42 alone exerted a less pronounced effect than cotreatment with RANKL in their experiment, the ability of stimulation and activation of signaling pathways by Aβ42 can be independent of RANKL as well.…”

Section: P Athophysiological Link Between a mentioning

confidence: 99%

Alzheimer's disease and osteoporosis

Chen

2017

Tzu Chi Med J

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Alzheimer's disease (AD) and osteoporosis are both common degenerative diseases in the elderly population. The incidence of both diseases increases with age and will be posing enormous societal burden worldwide. It may appear that AD and osteoporosis are two distinct diseases although many risk factors are shared. Previous observational studies have shown that patients with osteoporosis have higher risks of developing AD than those who do not have osteoporosis. Although osteoporosis, falls, and fractures are more often seen in patients with AD than other older adults, the association between these two diseases may be due to a pathophysiological link rather than one condition causing the other. Several in vitro and in vivo studies lend support to this notion. Patients with AD have excessive amyloid plaques in the brain, and the pathology may extend to peripheral organs and cause skeletal amyloid deposition, which would enhance receptor activator nuclear factor-kappa B ligand signaling and lead to greater osteoclast activities. Patients with osteoporosis may have Vitamin D deficiency or lower levels of Vitamin D binding protein, which protects against amyloid aggregation, thus linking Vitamin D deficiency and AD or osteoporosis and AD. Osteoporosis coexisting with AD provides a window to examine the amyloid hypothesis from peripheral tissues. Future studies are warranted to clarify the role of genetic background regarding Vitamin D levels, exposure to sunlight, estrogen replacement therapy, and physical activity in patients with both chronic diseases.

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Amyloid β Peptide Enhances RANKL-Induced Osteoclast Activation through NF-κB, ERK, and Calcium Oscillation Signaling

Cited by 41 publications

References 34 publications

Amyloid β peptide promotes bone formation by regulating Wnt/β‐catenin signaling and the OPG/RANKL/RANK system

Amyloid β peptide promotes bone formation by regulating Wnt/β‐catenin signaling and the OPG/RANKL/RANK system

Roles of Mitogen-Activated Protein Kinases in Osteoclast Biology

Alzheimer's disease and osteoporosis

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