Loss of autophagy in chondrocytes causes severe growth retardation

Horigome, Yoji; Ida‐Yonemochi, Hiroko; Waguri, Satoshi; Shibata, Shunichi; Endo, Naoto; Komatsu, Masaaki

doi:10.1080/15548627.2019.1628541

Cited by 39 publications

(36 citation statements)

References 45 publications

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“…As a ubiquitin activating enzyme, ATG7 plays an important role in autophagy formation and LC3 activation. Knocking out Atg7 in chondrocytes leads to growth retardation of chondrocytes, which is also related to the reduction of chondrocyte proliferation and the upregulation of apoptosis (Kang et al, 2017;Horigome et al, 2020).…”

Section: Key Molecules Involved In Autophagy and Oamentioning

confidence: 99%

The Role of Autophagy in Osteoarthritis

Duan

Xie

Liu

2020

Front. Cell Dev. Biol.

114

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Chondrocytes are the only cell type in normal cartilage. The pathological changes of osteoarthritis (OA) mostly revolve around the apoptosis and dysfunction of chondrocytes. Autophagy, as an intracellular degradation system that maintains the steady state of energy metabolism in cells, has been shown to restore the function of damaged chondrocytes, alleviating the occurrence and progression of OA. In this review, we explored the relationship between autophagy and OA and the key molecules of autophagy pathway that regulate the progression of OA, providing new ideas for OA treatment by targeting autophagy.

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Section: Key Molecules Involved In Autophagy and Oamentioning

confidence: 99%

The Role of Autophagy in Osteoarthritis

Duan

Xie

Liu

2020

Front. Cell Dev. Biol.

114

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“…We recently demonstrated that fibroblast growth factor (FGF) signaling, a critical regulator of skeletogenesis (Ornitz & Marie, 2015), activates autophagy in chondrocytes (Cinque et al, 2015). Moreover, chondrocytes that display defects in the autophagy pathway have altered ER morphology and function (Cinque et al, 2015;Bartolomeo et al, 2017;Kang et al, 2017;Horigome et al, 2019). These observations led us to hypothesize that ER-phagy in chondrocytes is regulated by the FGF signaling.…”

Section: Introductionmentioning

confidence: 99%

MiT/ TFE factors control ER ‐phagy via transcriptional regulation of FAM 134B

et al. 2020

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Lysosomal degradation of the endoplasmic reticulum (ER) via autophagy (ER‐phagy) is emerging as a critical regulator of cell homeostasis and function. The recent identification of ER‐phagy receptors has shed light on the molecular mechanisms underlining this process. However, the signaling pathways regulating ER‐phagy in response to cellular needs are still largely unknown. We found that the nutrient responsive transcription factors TFEB and TFE3—master regulators of lysosomal biogenesis and autophagy—control ER‐phagy by inducing the expression of the ER‐phagy receptor FAM134B. The TFEB/TFE3‐FAM134B axis promotes ER‐phagy activation upon prolonged starvation. In addition, this pathway is activated in chondrocytes by FGF signaling, a critical regulator of skeletal growth. FGF signaling induces JNK‐dependent proteasomal degradation of the insulin receptor substrate 1 (IRS1), which in turn inhibits the PI3K‐PKB/Akt‐mTORC1 pathway and promotes TFEB/TFE3 nuclear translocation and enhances FAM134B transcription. Notably, FAM134B is required for protein secretion in chondrocytes, and cartilage growth and bone mineralization in medaka fish. This study identifies a new signaling pathway that allows ER‐phagy to respond to both metabolic and developmental cues.

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“…In that article, they mention that the lack of proteins such as Atg5, among others, reduces ex-vivo mineralization capacity. This effect has also been observed during chondrogenesis, where it has been reported that the suppression of autophagy would reduce the growth of proliferative chondrocytes, which would cause a severe growth retardation [ 66 ].…”

Section: Discussionmentioning

confidence: 81%

Histological Evaluation and Gene Expression Profiling of Autophagy-Related Genes for Cartilage of Young and Senescent Rats

Arias

Saavedra

Leal

et al. 2020

IJMS

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Autophagy is a cellular mechanism that protects cells from stress by digesting non-functional cellular components. In the cartilage, chondrocytes depend on autophagy as a principal mechanism to maintain cellular homeostasis. This protective role diminishes prior to the structural damage that normally occurs during aging. Considering that aging is the main risk factor for osteoarthritis, evaluating the expression of genes associated with autophagy in senescent cartilage might allow for the identification of potential therapeutic targets for treatment. Thus, we studied two groups of young and senescent rats. A histological analysis of cartilage and gene expression quantification for autophagy-related genes were performed. In aged cartilage, morphological changes were observed, such as an increase in cartilage degeneration as measured by the modified Mankin score, a decrease in the number of chondrocytes and collagen II (Col2a1), and an increase in matrix metalloproteinase 13 (Mmp13). Moreover, 84 genes associated with autophagy were evaluated by a PCR array analysis, and 15 of them were found to be significantly decreased with aging. Furthermore, an in silico analysis based on by two different bioinformatics software tools revealed that several processes including cellular homeostasis, autophagosome assembly, and aging—as well as several biological pathways such as autophagy, insulin-like growth factor 1 (IGF-1) signaling, PI3K (phosphoinositide 3-kinase)/AKT (serine/threonine kinase) signaling, and mammalian target of rapamycin (mTOR) signaling—were enriched. In conclusion, the analysis identified some potential targets for osteoarthritis treatment that would allow for the development of new therapeutic strategies for this chronic disease.

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Loss of autophagy in chondrocytes causes severe growth retardation

Cited by 39 publications

References 45 publications

The Role of Autophagy in Osteoarthritis

The Role of Autophagy in Osteoarthritis

MiT/ TFE factors control ER ‐phagy via transcriptional regulation of FAM 134B

Histological Evaluation and Gene Expression Profiling of Autophagy-Related Genes for Cartilage of Young and Senescent Rats

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