Different roles of Akt and mechanistic target of rapamycin in serum‑dependent chondroprotection of human osteoarthritic chondrocytes

Zhang, Tongen; Liu, Jijie; Zheng, Xiaomei; Zhang, Bing; Xia, Chun

doi:10.3892/ijmm.2017.3285

Cited by 5 publications

(4 citation statements)

References 34 publications

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“…Adiponectin protects chondrocytes from apoptosis related to oxidative stress by inducing autophagy possibly via PI3K/Akt/mTOR (Hu et al, 2017 ). Other biological products such as Platelet rich plasma (PRP), adipose-stem cells, and serum have also shown efficacy at protecting from degeneration and inflammation through autophagy-related mechanisms in cartilage disease (Jiang et al, 2016 ; Moussa et al, 2017 ; Zhang et al, 2018 ).…”

Section: Current Development In Innovative Therapeutic Approachesmentioning

confidence: 99%

Role of the Inflammation-Autophagy-Senescence Integrative Network in Osteoarthritis

et al. 2018

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Osteoarthritis is the most common musculoskeletal disease causing chronic disability in adults. Studying cartilage aging, chondrocyte senescence, inflammation, and autophagy mechanisms have identified promising targets and pathways with clinical translatability potential. In this review, we highlight the most recent mechanistic and therapeutic preclinical models of aging with particular relevance in the context of articular cartilage and OA. Evidence supporting the role of metabolism, nuclear receptors and transcription factors, cell senescence, and circadian rhythms in the development of musculoskeletal system degeneration assure further translational efforts. This information might be useful not only to propose hypothesis and advanced models to study the molecular mechanisms underlying joint degeneration, but also to translate our knowledge into novel disease-modifying therapies for OA.

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Section: Current Development In Innovative Therapeutic Approachesmentioning

confidence: 99%

Role of the Inflammation-Autophagy-Senescence Integrative Network in Osteoarthritis

et al. 2018

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“…Beclin-1 overexpression mitigated the phsophoinositol-3 kinase (PI3K)/protein kinase B (AKT)/mTOR signaling pathway, which led to increased cell viability, and inhibition of apoptosis and MMP expression ( 38 ). Furthermore, inhibition of mTOR by treatment with rapamycin led to significant suppression of cartilage degeneration in a surgically induced OA mouse model and chondroprotection in human OA chondrocytes ( 39 , 40 ). In our experiments, 29-kDa FN-f down-regulated LC3-II level by activating the mTOR signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

29-kDa FN-f inhibited autophagy through modulating localization of HMGB1 in human articular chondrocytes

2018

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Fibronectin fragments found in the synovial fluid of patients with osteoarthritis (OA) induce the catabolic responses in cartilage. Nuclear high-mobility group protein Box 1 (HMGB1), a damage-associated molecular pattern, is responsible for the regulation of signaling pathways related to cell death and survival in response to various stimuli. In this study, we investigated whether changes induced by 29-kDa aminoterminal fibronectin fragment (29-kDa FN-f) in HMGB1 expression influences the pathogenesis of OA via an HMGB1-modulated autophagy signaling pathway. Human articular chondrocytes were enzymatically isolated from articular cartilage. The level of mRNA was measured by quantitative real-time PCR. The expression of proteins was examined by western blot analysis, immnunofluorescence assay, and enzyme-linked immunosorbent assay. Interaction of proteins was evaluated by immunoprecipitation. The HMGB1 level was significantly lower in human OA cartilage than in normal cartilage. Although 29-kDa FN-f significantly reduced the HMGB1 expression at the mRNA and protein levels 6 h after treatment, the cytoplasmic level of HMGB1 was increased in chondrocytes treated with 29-kDa FN-f, which significantly inhibited the interaction of HMGB1 with Beclin-1, increased the interaction of Bcl-2 with Beclin-1, and decreased the levels of Beclin-1 and phosphorylated Bcl-2. In addition, the level of microtubule-associated protein 1 light chain 3-II, an autophagy marker, was down-regulated in chondrocytes treated with 29-kDa FN-f, whereas the effect was antagonized by mTOR knockdown. Furthermore, prolonged treatment with 29-kDa FN-f significantly increased the release of HMGB1 into the culture medium. These results demonstrated that 29-kDa FN-f inhibits chondrocyte autophagy by modulating the HMGB1 signaling pathway.

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“…The suppression of mTORC1 promotes autophagy, maintains cell proliferation, and reduces the expression of inflammatory factors expression in osteoarthritis [49]. Moreover, a previous experimental study showed that an intra-articularly injected mTORC1 inhibitor rapamycin could activate chondrocyte autophagy and delay cartilage degradation in an animal model [26].…”

Section: P R E P R I N Tmentioning

confidence: 97%

The Role and underlying mechanism of dental pulp stem cell-derived exosomal miR-31 in the treatment of osteoarthritis by targeting mTOR to enhance chondrocyte autophagy levels

et al. 2023

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IntroductionOsteoarthritis is the most prevalent musculoskeletal progressive disease that leads to functional impairment and decreased quality of life. However, the current treatments remain unsatisfactory. Recent studies reveal that exosomes derived from mesenchymal stem cells offer a promising approach to improve the pathological changes of osteoarthritis, cartilage tissue, and chondrocyte homeostasis.Material and methodsA randomized, controlled animal experiment was conducted on nine-week-old male C57BL/6 mice that were obtained from Charles River Laboratories. In this in vitro and in vivo study, we studied the role and mechanisms of dental pulp stem cell-derived exosomes (DPSCs-exosomes) on osteoarthritis in the mouse model.ResultsThe study findings showed that a dental pulp stem cell could generate typical-characteristic exosomes. The injection of DPSCs-exosomes ameliorated destruction of cartilage, promoted matrix synthesis, inhibited cell apoptosis, and decreased the catabolic factors expression. However, this effect was shown to be almost eliminated when miR-31 antagomir was injected.ConclusionsFurthermore, DPSCs-exosomes show an ability to promote autophagy in chondrocytes through mTOR inhibition, in addition to reducing the mTOR luciferase activity. The ability of DPSCs-exosomes to partially regulate autophagy was blocked upon inhibition of miR-31. In brief, DPSCs-exosomes have a chondroprotective role in the mice osteoarthritis model. The underlying mechanism is possibly related to miR-31-mediated suppression of the mTOR-autophagy pathway.

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Different roles of Akt and mechanistic target of rapamycin in serum‑dependent chondroprotection of human osteoarthritic chondrocytes

Cited by 5 publications

References 34 publications

Role of the Inflammation-Autophagy-Senescence Integrative Network in Osteoarthritis

Role of the Inflammation-Autophagy-Senescence Integrative Network in Osteoarthritis

29-kDa FN-f inhibited autophagy through modulating localization of HMGB1 in human articular chondrocytes

The Role and underlying mechanism of dental pulp stem cell-derived exosomal miR-31 in the treatment of osteoarthritis by targeting mTOR to enhance chondrocyte autophagy levels

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