Osteoblastic Lrp4 promotes osteoclastogenesis by regulating ATP release and adenosine-A2AR signaling

Xiong, Lei; Jung, Ji-Ung; Guo, Hao; Pan, Jin-Xiu; Sun, Xiang; Mei, Lin; Xiong, Wen-Cheng

doi:10.1083/jcb.201608002

Cited by 21 publications

(16 citation statements)

References 80 publications

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“…The V-ATPase resides within many intracellular compartments such as endosomes, lysosomes and secretory vesicles, which are crucial for maintaining the intracellular vesicular acidic environment [63]. PRR ablation in cultured cells results in the downregulation of several subunits of the V0 complex of the V-ATPase and impairs vesicle acidification [44,62,64,65]. BACE1 activity is optimal in acidic environments [17,18,19].…”

Section: Resultsmentioning

confidence: 99%

“…We then examined BACE1 activity between control and PRR-KD (knockdown) cells. PRR was knocked down by infection of MC3T3 cells (an osteoblastic cell line that expresses PRR, APP and BACE1) with shRNA-PRR lentivirus [44,66] (Figure 8E). Aβ (1–40) levels were measured by ELISA and used to represent BACE1 activity.…”

Section: Resultsmentioning

confidence: 99%

“…The PRR-KD cell line was obtained as described previously [44]. In brief, MC3T3-E1 cells were infected with shRNA-PRR lentiviral particles in medium containing 2 µg/mL polybrene.…”

Section: Methodsmentioning

confidence: 99%

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pHluorin-BACE1-mCherry Acts as a Reporter for the Intracellular Distribution of Active BACE1 In Vitro and In Vivo

Zhao

Tang

et al. 2019

Cells

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β-site APP-cleaving enzyme 1 (BACE1) initiates amyloid precursor protein (APP) cleavage and β-amyloid (Aβ) production, a critical step in the pathogenesis of Alzheimer’s disease (AD). It is thus of considerable interest to investigate how BACE1 activity is regulated. BACE1 has its maximal activity at acidic pH and GFP variant—pHluorin—displays pH dependence. In light of these observations, we generated three tandem fluorescence-tagged BACE1 fusion proteins, named pHluorin-BACE1-mCherry, BACE1-mCherry-pHluorin and BACE1-mCherry-EGFP. Comparing the fluorescence characteristics of these proteins in response to intracellular pH changes induced by chloroquine or bafilomycin A1, we found that pHluorin-BACE1-mCherry is a better pH sensor for BACE1 because its fluorescence intensity responds to pH changes more dramatically and more quickly. Additionally, we found that (pro)renin receptor (PRR), a subunit of the v-ATPase complex, which is critical for maintaining vesicular pH, regulates pHluorin’s fluorescence and BACE1 activity in pHluorin-BACE1-mCherry expressing cells. Finally, we found that the expression of Swedish mutant APP (APPswe) suppresses pHluorin fluorescence in pHluorin-BACE1-mCherry expressing cells in culture and in vivo, implicating APPswe not only as a substrate but also as an activator of BACE1. Taken together, these results suggest that the pHluorin-BACE1-mCherry fusion protein may serve as a useful tool for visualizing active/inactive BACE1 in culture and in vivo.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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pHluorin-BACE1-mCherry Acts as a Reporter for the Intracellular Distribution of Active BACE1 In Vitro and In Vivo

Zhao

Tang

et al. 2019

Cells

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“…Elevated osteoclast activity reduces the bone volume and degrades bone to the primary bone state [ 20 ]. Some scholars demonstrated that A2AR inhibits both osteoclast formation and function [ 20 , 23 , 24 ]. The MAPK signaling pathway is also important in A2AR regulation of osteoclasts.…”

Section: Discussionmentioning

confidence: 99%

Adenosine A2A Receptor Mediates Inhibition of Synovitis and Osteoclastogenesis after Electroacupuncture in Rats with Collagen-Induced Arthritis

Zhang

Xie

et al. 2019

Evidence-Based Complementary and Alternative Medicine

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Background. This study was to investigate the role of adenosine A2A receptors (A2AR) in inhibiting the effect of electroacupuncture (EA) on osteoclastogenesis in collagen-induced arthritis (CIA). Methods. Wistar rats were divided into four groups: sham-control group, CIA-control group, CIA-EA group, and CIA-EA-SCH58261 (A2AR antagonist) group. We detected tumor necrosis factor-α (TNF-α), nuclear transcription factor-κB (NF-κB), receptor activator of NF-κB ligand (RANKL), protein kinase A (PKA), and extracellular regulatory protein kinase 1/2 (ERK1/2) in peripheral blood by ELISA. PKA, ERK1/2, and NF-κB in ankle joints were determined by western blotting. We evaluated the arthritis damage by histological examination and determined the number of osteoclasts by tartrate-resistant acid phosphatase (TRAP) staining. Results. EA treatment downregulated the expression of TNF-α, RANKL, PKA, ERK1/2, and NF-κB in peripheral blood but increased the levels of PKA and ERK1/2 in ankle joints. Importantly, EA treatment reduced bone erosion as evidenced by the histological findings and inhibited osteoclastogenesis as revealed by TRAP staining. All these effects of the EA treatment were reversed by combining EA treatment with the A2AR antagonist SCH58261. Conclusion. Our data suggest that EA treatment activated A2AR. The effects of the A2AR antagonist SCH58261 suggest that the inhibition of osteoclast formation, the inhibition of TNF-α, RANKL, and NF-κB expression, and the increase of ERK1/2 are all dependent on this EA-induced A2AR activation. It is therefore likely that these pathways with clearly defined roles in inflammation and bone erosion are at least partially involved in the mediation of the inhibition of synovitis and osteoclast formation induced by EA.

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“…For example, human osteoblasts expressed low-density lipoprotein receptorrelated protein (LRP) 1 with a capacity for osteocalcin carboxylation (28). LRP4, LRP5/6, and LRP8 were involved in the maintenance of bone (29)(30)(31)(32)(33)(34)(35)(36). However, the role of LDLR in bone metabolism was unclear with controversial results in recent studies.…”

Section: Introductionmentioning

confidence: 99%

Low-density lipoprotein receptor deficiency impaired mice osteoblastogenesis <i>in vitro </i>

Zhang

Yang

Lin

et al. 2017

BST

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Osteoblastic Lrp4 promotes osteoclastogenesis by regulating ATP release and adenosine-A2AR signaling

Cited by 21 publications

References 80 publications

pHluorin-BACE1-mCherry Acts as a Reporter for the Intracellular Distribution of Active BACE1 In Vitro and In Vivo

pHluorin-BACE1-mCherry Acts as a Reporter for the Intracellular Distribution of Active BACE1 In Vitro and In Vivo

Adenosine A2A Receptor Mediates Inhibition of Synovitis and Osteoclastogenesis after Electroacupuncture in Rats with Collagen-Induced Arthritis

Low-density lipoprotein receptor deficiency impaired mice osteoblastogenesis <i>in vitro </i>

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