Mechanical injury suppresses autophagy regulators and pharmacologic activation of autophagy results in chondroprotection

Caramés, Beatriz; Taniguchi, Noboru; Seino, D; Blanco, Francisco J.; D’Lima, Darryl D.; Lotz, Martin

doi:10.1002/art.33444

Cited by 125 publications

(121 citation statements)

References 51 publications

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“…Mechanistic target of rapamycin complex 1 (mTORC1) intracellular signalling pathway is an autophagic regulator that when inhibited activates the process of autophagy [31]. Inhibition of mTORC1 was reported to protect against surgery-induced OA in mice [26,32]. Taken together, these findings confirmed the role of autophagy in the development of OA.…”

Section: Discussionsupporting

confidence: 74%

“…Aging is an important risk factor for the development of OA and is associated with the progressive accumulation of damaged macromolecules and organelles in somatic cells [27], potentially mediated by downregulation of the autophagic disposal of such damaged cellular components [28]. Autophagy-related proteins unc-51-like autophagy activating kinase 1 (ULK1), Beclin1 and microtubule-associated protein 1A/1B-light chain 3 (LC3) are reported to be expressed at high levels in healthy human cartilage [25,29,30], however, their expression decreases during OA [25,26]. Mechanistic target of rapamycin complex 1 (mTORC1) intracellular signalling pathway is an autophagic regulator that when inhibited activates the process of autophagy [31].…”

Section: Discussionmentioning

confidence: 99%

“…It has been suggested that autophagy plays a role in the onset of OA, the most common aging-related joint pathology [25,26]. Aging is an important risk factor for the development of OA and is associated with the progressive accumulation of damaged macromolecules and organelles in somatic cells [27], potentially mediated by downregulation of the autophagic disposal of such damaged cellular components [28].…”

Section: Discussionmentioning

confidence: 99%

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AntimiR-30b Inhibits TNF-α Mediated Apoptosis and Attenuated Cartilage Degradation through Enhancing Autophagy

Chen

Jin

2016

Cell Physiol Biochem

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Objective: Cell death plays an important role in the pathology associated with inflammatory diseases such as osteoarthritis. It has been reported that autophagy can protect cells against tumour necrosis factor-α (TNF-α)-induced apoptosis. This study aimed to determine the potential role of microRNA-30b (miR-30b) in TNF-α-induced apoptosis, autophagy and differentiation in the chondrogenic ADTC5 cell line. Methods: To analyse the effect of TNF-α on the viability of ADTC5 cells, cell counting kit-8 and Hoechst 33342 staining were employed and the expression levels of caspase-3 and -9 were assessed. Autophagy was examined by analysing the levels of LC3B-II and p62 and quantitating GFP-LC3B by fluorescence microscopy. A luciferase reporter assay investigated the putative binding sites of miR-30b. The effects of miR-30b and antimiR-30b on autophagy, apoptosis and osteogenic differentiation of TNF-α-treated cells were determined by autophagosome, apoptosis and alkaline phosphatase assays, respectively. Results: TNF-α exposure decreased cell viability, increased apoptosis and positively regulated autophagy in ADTC5 cells. A direct interaction was detected between miR-30b and the mRNA 3ʹ-UTRs of autophagy genes BECN1 and ATG5. Overexpression of miR-30b downregulated autophagy genes and upregulated pro-apoptotic gene expression in TNF-α-treated cells, while treatment with antimiR-30b had the inverse effect. Overexpression of miR-30b also downregulated ECM degradation and anti-miR-30b reverse TNF-α-induced ECM degradation. Conclusions: Anti-miR-30b enhanced autophagy and attenuated cartilage degradation and played a protective role in TNF-α-induced apoptosis of ATDC5 cells. Anti-miR-30b may therefore elevate cellular survival during inflammation and has therapeutic potential for inflammatory diseases such as osteoarthritis.

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Section: Discussionsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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AntimiR-30b Inhibits TNF-α Mediated Apoptosis and Attenuated Cartilage Degradation through Enhancing Autophagy

Chen

Jin

2016

Cell Physiol Biochem

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“…22,23 Activation of autophagy prevents the damage of articular cartilage resulting from aging, surgically induced osteoarthritis, as well as mechanical injury and glucocorticoid stimulation. [24][25][26][27] Settembre et al have found that loss of SUMF1 (sulfatase modifying factor 1), an enzyme-activating sulfatase, impairs autophagy and leads to dwarfism characterized by severely shortened skeletal elements. 28 Inactivation of CTGF/ CCN2 (connective tissue growth factor) in mice leads to severe chondrodysplasia resulting from increased stress-induced death and decreased autophagy.…”

Section: Introductionmentioning

confidence: 99%

FGFR3/fibroblast growth factor receptor 3 inhibits autophagy through decreasing the ATG12–ATG5 conjugate, leading to the delay of cartilage development in achondroplasia

Wang

et al. 2015

Autophagy

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(2015) FGFR3/fibroblast growth factor receptor 3 inhibits autophagy through decreasing the ATG12-ATG5 conjugate, leading to the delay of cartilage development in achondroplasia, Autophagy, 11:11, 1998, DOI: 10.1080/15548627.2015 G369C/C , constitutively active Fgfr3 mice; ATG5, autophagy-related 5; ATG12, autophagy-related 12; coIP, coimmunoprecipitation; CTGF/CCN2, connective tissue growth factor; FGFR3, fibroblast growth factor receptor 3; FGF, fibroblast growth factor; K D , kinase domain; PBS, phosphate-buffered saline; R3CKO, fgfr3 flox/flox mice, Fgfr3 conditional knockout mice; R3KO mice, fgfr3 global knockout mice; RCS, rat chondrosarcoma; Sumf1, sulfatase modifying factor 1; TM, 4-hydroxy tamoxifen; WT, wild type; YFP-PCA, yellow fluorescent protein-based protein-fragment complementation assay.FGFR3 (fibroblast growth factor receptor 3) is a negative regulator of endochondral ossification. Gain-of-function mutations in FGFR3 are responsible for achondroplasia, the most common genetic form of dwarfism in humans. Autophagy, an evolutionarily conserved catabolic process, maintains chondrocyte viability in the growth plate under stress conditions, such as hypoxia and nutritional deficiencies. However, the role of autophagy and its underlying molecular mechanisms in achondroplasia remain elusive. In this study, we found activated FGFR3 signaling inhibited autophagic activity in chondrocytes, both in vivo and in vitro. By employing an embryonic bone culture system, we demonstrated that treatment with autophagy inhibitor 3-MA or chloroquine led to cartilage growth retardation, which mimics the effect of activated-FGFR3 signaling on chondrogenesis. Furthermore, we found that FGFR3 interacted with ATG12-ATG5 conjugate by binding to ATG5. More intriguingly, FGFR3 signaling was found to decrease the protein level of ATG12-ATG5 conjugate. Consistently, using in vitro chondrogenic differentiation assay system, we showed that the ATG12-ATG5 conjugate was essential for the viability and differentiation of chondrocytes. Transient transfection of ATG5 partially rescued FGFR3-mediated inhibition on chondrocyte viability and differentiation. Our findings reveal that FGFR3 inhibits the autophagic activity by decreasing the ATG12-ATG5 conjugate level, which may play an essential role in the pathogenesis of achondroplasia.

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“…Autophagy, which is in part related to the reduced expression of autophagic regulators, is compromised in osteoarthritic cartilage. In articular cartilage, autophagy does not only occur in response to mechanical injury, but is also deficient with aging (8,27). Autophagy is characterized by the formation of autophagosomes and their fusion with lysosomes.…”

Section: Discussionmentioning

confidence: 99%

Tougu Xiaotong capsule promotes chondrocyte autophagy by regulating the Atg12/LC3 conjugation systems

Li¹,

Liu²,

Liang³

et al. 2014

International Journal of Molecular Medicine

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Abstract. We have previously reported that Tougu Xiaotong capsule (TXC) inhibits tidemark replication and cartilage degradation by regulating chondrocyte autophagy in vivo. Autophagy, a cell protective mechanism for maintaining cellular homeostasis, has been shown to be a constitutively active and protective process for chondrocyte survival. However, it remains unclear whether TXC promotes chondrocyte autophagy by regulating the autophagy-related (Atg)12/microtubuleassociated protein 1 light chain 3 (LC3) conjugation systems. Thus, in the present study, we investigated the effects of TXC on primary chondrocytes treated with cobalt chloride (CoCl 2 ). We found that CoCl 2 induced a decrease in chondrocyte viability and the autophagosome formation of chondrocytes, indicating that CoCl 2 induced autophagic death in a dose-and time-dependent manner. To determine the effects of TXC on CoCl 2 -exposed chondrocytes, we assessed cell viability by MTT assay. Our results revealed that TXC enhanced the viability of CoCl 2 -exposed chondrocytes. To gain insight into the mechanisms responsible for the enhancing effects of TXC on CoCl 2 -exposed chondrocytes, the expression of Atg genes was assessed in chondrocytes exposed to CoCl 2 and treated with or without TXC. The results revealed that the expression of beclin 1, Atg3, Atg5, Atg7, Atg10, Atg12 and LC3 II/LC3 I in the chondrocytes treated with TXC increased, compared to that in the untreated chondrocytes. In addition, ultrastructural analysis indicated that treated chondrocytes contained more autophagosomes than the untreated cells, suggesting that TXC increased the formation of autophagosomes in the chondrocytes to clear the CoCl 2 -induced autophagic death. Therefore, these data suggest that TXC is a potential therapeutic agent for the reduction of cartilage degradation that occurs in osteoarthritis.

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Mechanical injury suppresses autophagy regulators and pharmacologic activation of autophagy results in chondroprotection

Cited by 125 publications

References 51 publications

AntimiR-30b Inhibits TNF-α Mediated Apoptosis and Attenuated Cartilage Degradation through Enhancing Autophagy

AntimiR-30b Inhibits TNF-α Mediated Apoptosis and Attenuated Cartilage Degradation through Enhancing Autophagy

FGFR3/fibroblast growth factor receptor 3 inhibits autophagy through decreasing the ATG12–ATG5 conjugate, leading to the delay of cartilage development in achondroplasia

Tougu Xiaotong capsule promotes chondrocyte autophagy by regulating the Atg12/LC3 conjugation systems

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