Cartilage-Specific Autophagy Deficiency Promotes ER Stress and Impairs Chondrogenesis in PERK-ATF4-CHOP–Dependent Manner

Kang, Xiaomin; Yang, Wei; Feng, Dongxu; Jin, Xinxin; Ma, Zhengmin; Qian, Zhuang; Xie, Tianping; Li, Huixia; Liu, Jiali; Wang, Ruiqi; Li, Fang; Li, Danhui; Sun, Hongzhi; Wu, Shufang

doi:10.1002/jbmr.3134

Cited by 63 publications

(68 citation statements)

References 62 publications

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“…As such, the lack of trabecular bone may suggest that Beclin1 plays a key role not only in osteoclasts but also in chodrocytes at hypertropic growth plate region chondrocytes . Indeed, ATG is known to play a critical role in the growth plate . Therefore, this seemingly paradoxical bone phenotype of our Beclin1 cKO mice is based on the strong expression of CtsK in both osteoclasts and chondrocytes at their late stages of differentiation, such that increased cortical bone thickness is caused by the inhibitory effects of beclin1 KO in osteoclasts, whereas decreased trabecular bone amounts may be caused by the inhibitory effects of beclin1 KO in chondrocytes.…”

Section: Discussionmentioning

confidence: 95%

Beclin1 Modulates Bone Homeostasis by Regulating Osteoclast and Chondrocyte Differentiation

Arai

Kim²,

Goldshteyn³

et al. 2019

Journal of Bone and Mineral Research

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Autophagy (ATG), an important cellular recycling process whereby macromolecules or organelles are encapsulated by autophagosome and degraded upon merging with lysosome, has recently been shown to play an essential role in bone biology. However, the involvement of ATG in bone and bone‐related cells remains unclear. Here, we show that Beclin1, an ATG‐related protein involved in ATG initiation, plays a pivotal role in osteoclasts. ATG was activated during osteoclast differentiation in vitro. Beclin1 was enhanced and required for osteoclast differentiation. Mechanistically, we found that TRAF6‐mediated ubiquitination of Beclin1 at K117, but not ULK1‐mediated phosphorylation, is required for RANKL‐stimulated osteoclast differentiation. In vivo, mice lacking Beclin1 in CstK‐expressing cells exhibited an increased cortical bone thickness caused by impaired osteoclasts’ function. Interestingly, these mice also exhibited diminished trabecular bone mass, which was associated with a defect in cartilage formation and chondrocyte differentiation. Collectively, our study highlights the functional importance of ATG in osteoclasts and chondrocytes, and identifies ATG as a potential therapeutic target for managing bone‐related diseases. © 2019 American Society for Bone and Mineral Research.

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Section: Discussionmentioning

confidence: 95%

Beclin1 Modulates Bone Homeostasis by Regulating Osteoclast and Chondrocyte Differentiation

Arai

Kim²,

Goldshteyn³

et al. 2019

Journal of Bone and Mineral Research

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“…ATF4 transcriptionally regulates Atg12, and ATF4‐mediated C/EBP‐homologous protein (CHOP) activation also transcriptionally induces Atg5. Atg5, Atg12, and Atg16L form Atg5‐Atg12‐ Atg16L complex, which involves the elongation process (B'chir et al, ; Kang et al, ).…”

Section: Possible Mechanisms Of Er Stress‐mediated Autophagymentioning

confidence: 99%

Crosstalk of ER stress‐mediated autophagy and ER‐phagy: Involvement of UPR and the core autophagy machinery

Song

Tan

Miao

et al. 2017

Journal Cellular Physiology

265

189

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Endoplasmic reticulum (ER) stress, a common cellular stress response, is closely related to the activation of autophagy that is an important and evolutionarily conserved mechanism for maintaining cellular homeostasis. Autophagy induced by ER stress mainly includes the ER stress-mediated autophagy and ER-phagy. The ER stress-mediated autophagy is characterized by the generation of autophagosomes that include worn-out proteins, protein aggregates, and damaged organelles. While the autophagosomes of ER-phagy selectively include ER membranes, and the double membranes also derive, at least in part, from the ER. The signaling pathways of IRE1α, PERK, ATF6, and Ca are necessary for the activation of ER stress-mediated autophagy, while the receptor-mediated selective ER-phagy degrades the ER is Atg40/FAM134B. The ER stress-mediated autophagy and ER-phagy not only have differences, but also have connections. The activation of ER-phagy requires the core autophagy machinery, and the ER-phagy may be a branch of ER stress-mediated autophagy that selectively targets the ER. However, the determined factors that control the changeover switch between ER stress-mediated autophagy and ER-phagy are largely obscure, which may be associated with the type of cells and the extent of stimulation. This review summarized the crosstalk between ER stress-mediated autophagy and ER-phagy and their signaling networks. Additionally, we discussed the possible factors that influence the type of autophagy induced by ER stress.

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“…Typically, autophagy promotes cell survival by removing pathogenic proteins, dysfunctional organelles, and intracellular pathogens that cause various diseases to maintain intracellular homeostasis. A number of researchers revealed that autophagy promotes differentiation and maturation of chondrocytes, as well as inhibits the apoptosis of growth-plate chondrocytes in the absence of nutrients (14)(15)(16)(17).…”

mentioning

confidence: 99%

Mangiferin enhances endochondral ossification‐based bone repair in massive bone defect by inducing autophagy through activating AMP‐activated protein kinase signaling pathway

Bai

Liu

et al. 2018

FASEB j.

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Endochondral ossification is crucial for bone formation in both adult bone repair process and embryo long-bone development. In endochondral ossification, bone marrow-derived mesenchymal stem cells (BMSCs) first differentiate to chondrocytes, then BMSC-derived chondrocytes endure a hypertrophic process to generate new bone. Endochondral ossification-based bone repair is a promising strategy to cure massive bone defect, which is a major clinical issue in orthopedics. However, challenges still remain for this novel strategy. One challenge is to ensure the sufficient hypertrophic differentiation. Another is to maintain the survival of the above hypertrophic chondrocytes under the hypoxic environment of massive bone defect. To solve this issue, mangiferin (MAG) was introduced to endochondral ossification-based bone repair. In this report, we proved MAG to be a novel autophagy inducer, which promoted BMSC-derived hypertrophic chondrocyte survival against hypoxia-induced injury through inducing autophagy. Furthermore, MAG enhances hypertrophic differentiation of BMSC-derived chondrocytes via upregulating key hypertrophic markers. Mechanistically, MAG induced autophagy in BMSC-derived chondrocytes by promoting AMPKα phosphorylation. Additionally, MAG balanced the expression of sex-determining region Y-box 9 and runt-related transcription factor 2 to facilitate hypertrophic differentiation. These results indicated that MAG was a potential drug to improve the efficacy of endochondral ossification-based bone repair in massive bone defects.-Bai, Y., Liu, C., Fu, L., Gong, X., Dou, C., Cao, Z., Quan, H., Li, J., Kang, F., Dai, J., Zhao, C., Dong, S. Mangiferin enhances endochondral ossification-based bone repair in massive bone defect by inducing autophagy through activating AMP-activated protein kinase signaling pathway.

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Cartilage-Specific Autophagy Deficiency Promotes ER Stress and Impairs Chondrogenesis in PERK-ATF4-CHOP–Dependent Manner

Cited by 63 publications

References 62 publications

Beclin1 Modulates Bone Homeostasis by Regulating Osteoclast and Chondrocyte Differentiation

Beclin1 Modulates Bone Homeostasis by Regulating Osteoclast and Chondrocyte Differentiation

Crosstalk of ER stress‐mediated autophagy and ER‐phagy: Involvement of UPR and the core autophagy machinery

Mangiferin enhances endochondral ossification‐based bone repair in massive bone defect by inducing autophagy through activating AMP‐activated protein kinase signaling pathway

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