Defective autophagy in osteoblasts induces endoplasmic reticulum stress and causes remarkable bone loss

Li, Huixia; Li, Danhui; Ma, Zhengmin; Qian, Zhuang; Kang, Xiaomin; Jin, Xinxin; Li, Fang; Wang, Xinluan; Chen, Qian; Sun, Hongzhi; Wu, Shufang

doi:10.1080/15548627.2018.1483807

Cited by 161 publications

(126 citation statements)

References 57 publications

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“…15 A recent study has also reported that deficiency of autophagy (autophagy-related 7; ATG7) triggers ER stress to promote apoptosis and inhibit osteoblast mineralization and induce bone loss in which CHOP may regulate the activity of RUNX2 via separation from C/EBPb. 24 In the present study, we found the significant decrease in BMD and bone microstructure of tibias in Chop À/À mice and also detected the significant inhibition of osteoblastogenesis in BMSCs isolated from Chop À/À mice. These findings are consistent with the previous results.…”

Section: Resultssupporting

confidence: 70%

“…Shirakawa et al have found that CHOP is a dominant‐negative inhibitor for C/EBPβ signaling and inhibits osteoblastogenesis, but induces osteoblast differentiation under the treatment of bone morphogenetic protein (BMP), suggesting that endogenous CHOP may play dual regulatory roles in osteoblastogenesis and bone formation . A recent study has also reported that deficiency of autophagy (autophagy‐related 7; ATG7) triggers ER stress to promote apoptosis and inhibit osteoblast mineralization and induce bone loss in which CHOP may regulate the activity of RUNX2 via separation from C/EBPβ . In the present study, we found the significant decrease in BMD and bone microstructure of tibias in Chop −/− mice and also detected the significant inhibition of osteoblastogenesis in BMSCs isolated from Chop −/− mice.…”

Section: Resultsmentioning

confidence: 99%

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Gender difference of CCAAT/enhancer binding protein homologous protein deficiency in susceptibility to osteopenia

Lin

et al. 2019

Journal Orthopaedic Research

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Expression of CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP) is induced during endoplasmic reticulum (ER) stress, which is related to apoptosis in several cell types. CHOP null mice have been exhibited to decrease bone formation. However, a study of transgenic mice overexpressing CHOP in the bone microenvironment showed that CHOP overexpression impairs the osteoblastic function leading to osteopenia. The regulatory role of CHOP in bone formation is controversial and still remains to be clarified. Here, we investigated the alterations in bone microstructure of CHOP knockout (Chop−/−) mice and tested the gender difference of CHOP deficiency in susceptibility to osteopenia. Adult female and male mice (WT) and Chop−/− mice were used. The microcomputed tomography (µCT) analysis in trabecular bone and cortical bone of tibia was determined. Trabecular bone volume fraction (BV/TV), trabecular number, and bone mineral density (BMD) in tibia are markedly decreased in both male and female Chop−/− mice compared to the control WT mice. Unexpectedly, the BMD and BV/TV in trabecular bone of tibia in female Chop−/− mice were significantly lower than in male Chop−/− mice. The similar results could also be observed in the cortical bone of tibia in Chop−/− mice. This gender difference was also observed in the decreased capacity of osteoblast differentiation of bone marrow cells isolated from Chop−/− mice. These results indicated that ER stress‐related CHOP signaling might play an important role in the bone formation in a mouse model, especially in females. There is the gender difference of CHOP deficiency in susceptibility to osteopenia. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

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Section: Resultssupporting

confidence: 70%

Section: Resultsmentioning

confidence: 99%

Gender difference of CCAAT/enhancer binding protein homologous protein deficiency in susceptibility to osteopenia

Lin

et al. 2019

Journal Orthopaedic Research

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“…Lin et al found that both deletion of the autophagy-related gene ATG7 and pharmacological inactivation of autophagy ameliorated bone loss in osteoporosis rats 29 . In contrast, Li et al suggested that defective autophagy in osteoblasts induces endoplasmic reticulum stress and causes osteoporosis 30 . However, the intracellular location of autophagy was not investigated in these studies.…”

Section: Discussionmentioning

confidence: 96%

NIPA2 regulates osteoblast function by modulating mitophagy in type 2 diabetes osteoporosis

Zhao

Zhang

et al. 2020

Sci Rep

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The highly selective magnesium transporter non-imprinted in Prader-Willi/Angelman syndrome region protein 2 (NIPA2) has recently been associated with the development and progression of type 2 diabetes osteoporosis, but the mechanisms involved are still poorly understood. Because mitophagy is involved in the pathology of type 2 diabetes osteoporosis, the present study aimed to explore the relationship among NIPA2, mitophagy and osteoblast osteogenic capacity. NIPA2 expression was reduced in C57BKS background db/db mice and in vitro models of type 2 diabetes osteoporosis, and the activation of mitophagy in primary culture osteoblast-derived from db/db mice and in high glucose-treated human fetal osteoblastic cells (hFOB1.19) was observed. Knockdown, overexpression of NIPA2 and pharmacological inhibition of peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) showed that NIPA2 increased osteoblast function, which was likely regulated by PTEN induced kinase 1 (PINK1)/E3 ubiquitin ligase PARK2 (Parkin)-mediated mitophagy via the PGC-1α/ forkhead box O3a(FoxO3a)/mitochondrial membrane potential (MMP) pathway. Furthermore, the negative effect of mitophagy on osteoblast function was confirmed by pharmacological regulation of mitophagy and knockdown of Parkin. Taken together, these results suggest that NIPA2 positively regulates the osteogenic capacity of osteoblasts via the mitophagy pathway in type 2 diabetes. Plasma measurements. Blood samples were collected from the animals' tail veins. The samples were used for measuring the fasting blood glucose (FBG) levels (Roche blood glucose instrument, Roche, Basel, Switzerland). Radioimmunoassay (3v-diagnostic Bioengineer, Shandong, China) was used for the fasting plasma insulin (FINS) analysis, while ELISA (Rat Estrogen/E ELISA Kit, 3v-diagnostic Bioengineer) was used for the plasma estrogen analysis. The insulin sensitivity index (ISI) was calculated as the -ln(FINS•FPG) 42 . Scientific RepoRtS |(2020) 10:3078 | https://doi.

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“…‒ An early study using electron microscopy showed that autophagy increased in PDL cells located on the pressured side of orthodontic teeth during OTM . In addition, previous studies also found that autophagy had a profound effect on bone mineralization and homeostasis through the RANKL and OPG signaling pathway . Autophagy proteins were demonstrated to have essential roles in generating the osteoclast ruffled border and bone resorption .…”

Section: Introductionmentioning

confidence: 92%

Compressive force‐induced autophagy in periodontal ligament cells downregulates osteoclastogenesis during tooth movement

Chen

Hua

2019

Journal of Periodontology

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Background Autophagy has recently emerged as a protective mechanism in response to compressive force and an important process in maintenance of bone homeostasis. It appears to be involved in the degradation of osteoclasts, osteoblasts, and osteocytes. The aim of this study was to investigate the role of compressive force‐induced autophagy in periodontal ligament (PDL) cells in regulating osteoclastogenesis of orthodontic tooth movement (OTM). Methods An OTM model and compressive force on PDL cells were employed to investigate the expression of autophagy markers in vivo and in vitro, respectively. Autophagosomes and autolysosomes were observed in PDL cells by transmission electron microscope (TEM) and autophagy LC3 double labelling. 3‐Methyladenine (3‐MA) and rapamycin were respectively used to inhibit and promote autophagy, and the effect of autophagy on osteoclastogenesis was explored via microcomputed tomography, hematoxylin and eosin (H&E) staining, histochemistry of titrate‐resistant acid phosphatase, and real‐time polymerase chain reaction (RT‐PCR) in vivo. Receptor activator of nuclear factor‐kappa B ligand/osteoprotegerin (RANKL/OPG) was investigated by RT‐PCR and ELISA in vitro. Results Orthodontic force‐induced autophagy was prominent on the pressured side of PDL tissues. Administration of 3‐MA downregulated bone density and upregulated osteoclasts, while rapamycin had reverse results in OTM. The autophagy activity increased initially then decreased in PDL cells during compressive force application and responded to light force. In PDL cells, administration of 3‐MA upregulated while rapamycin downregulated the RANKL/OPG ratio. Conclusion Autophagy is activated by compressive force in PDL cells. Besides, it could modulate OTM by negatively regulating osteoclastogenesis and keep bone homeostasis via RANKL/OPG signaling.

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Defective autophagy in osteoblasts induces endoplasmic reticulum stress and causes remarkable bone loss

Cited by 161 publications

References 57 publications

Gender difference of CCAAT/enhancer binding protein homologous protein deficiency in susceptibility to osteopenia

Gender difference of CCAAT/enhancer binding protein homologous protein deficiency in susceptibility to osteopenia

NIPA2 regulates osteoblast function by modulating mitophagy in type 2 diabetes osteoporosis

Compressive force‐induced autophagy in periodontal ligament cells downregulates osteoclastogenesis during tooth movement

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