Tyrosine kinase Fyn promotes osteoarthritis by activating the β-catenin pathway

Li, Kai; Zhang, Yue; Jiang, Wenqing; Shen, Junhui; Xu, Song; Cai, Daozhang; Shen, Jie; Huang, Bin; Li, Mangmang; Song, Qiancheng; Jiang, Yu; Liu, Anling; Bai, Xia

doi:10.1136/annrheumdis-2017-212658

Cited by 45 publications

(56 citation statements)

References 32 publications

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“…the pathogenesis of OA by inducing the chondrocyte anabolic and catabolic imbalance, including the downregulation of Collagen II and Aggrecan, as well as the upregulation of ADAMTS-5 and MMP-13 [45][46][47]. Therefore, we treated chondrocytes with IL-1b to simulate the OA microenvironment in vitro, similar to other studies [10,48]. When chondrocytes were exposed to IL-1b, we observed the same SGK1 expression pattern as detected in OA cartilage.…”

Section: Discussionsupporting

confidence: 71%

“…Among these pro‐inflammatory cytokines, increased IL‐1β levels have consistently been observed in the cartilage tissue, synovial fluid and the blood of patients with OA , and it plays a critical role in the pathogenesis of OA by inducing the chondrocyte anabolic and catabolic imbalance, including the downregulation of Collagen II and Aggrecan, as well as the upregulation of ADAMTS‐5 and MMP‐13 . Therefore, we treated chondrocytes with IL‐1β to simulate the OA microenvironment in vitro , similar to other studies . When chondrocytes were exposed to IL‐1β, we observed the same SGK1 expression pattern as detected in OA cartilage.…”

Section: Discussionsupporting

confidence: 69%

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Knockdown of SGK1 alleviates the IL‐1β‐induced chondrocyte anabolic and catabolic imbalance by activating FoxO1‐mediated autophagy in human chondrocytes

et al. 2019

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Osteoarthritis (OA) is a common joint disease characterized by the progressive degeneration of articular cartilage with no effective treatment methods available. Cartilage degeneration is closely related to an anabolic and catabolic imbalance in chondrocytes, and accumulating evidence has revealed that autophagy is a crucial protective mechanism that maintains the balance of anabolic and catabolic activities. Therefore, studies aiming to identify additional genes that regulate autophagy as a promising therapeutic strategy for OA are needed. In this study, we analyzed the http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE113825 datasets from Gene Expression Omnibus and validated that serum‐ and glucocorticoid‐regulated kinase 1 (SGK1) was upregulated in OA cartilage. Based on the results from loss‐of‐function studies, SGK1 silencing promoted the deposition of glycosaminoglycans in interleukin 1 beta (IL‐1β)‐treated chondrocytes, and significantly alleviated IL‐1β‐induced downregulation of Collagen II and Aggrecan, as well as the upregulation of a disintegrin and metalloproteinase with thrombospondin motifs 5 and matrix metalloproteinase‐13. Furthermore, SGK1 knockdown reversed the IL‐1β‐induced chondrocyte anabolic and catabolic imbalance by activating autophagy. Moreover, SGK1 directly bound to forkhead box protein O1 (FoxO1) and increased its phosphorylation, which in turn resulted in its translocation from the nucleus. The decreased FoxO1 levels led to a decrease in LC3‐I/LC3‐II conversion and Beclin‐1 levels, subsequently inhibiting autophagosome formation and increasing P62 levels, thus indicating a downregulation of autophagy. Taken together, we identified a critical role of SGK1 in the IL‐1β‐induced chondrocyte anabolic and catabolic imbalance, which may represent a potential novel therapeutic target for OA.

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Section: Discussionsupporting

confidence: 71%

Section: Discussionsupporting

confidence: 69%

Knockdown of SGK1 alleviates the IL‐1β‐induced chondrocyte anabolic and catabolic imbalance by activating FoxO1‐mediated autophagy in human chondrocytes

et al. 2019

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“…Mouse primary chondrocytes were collected from the knee cartilage of new-born C57BL/6 mice as described previously ( Li et al, 2018 ). Articular cartilage derived from the knee joints was dissected into pieces in sterilized phosphate-buffered saline (PBS) and digested with 0.25% trypsin at 37°C for 30 min.…”

Section: Methodsmentioning

confidence: 99%

Necrostatin-1 Attenuates Trauma-Induced Mouse Osteoarthritis and IL-1β Induced Apoptosis via HMGB1/TLR4/SDF-1 in Primary Mouse Chondrocytes

Liang

Zhang

et al. 2018

Front. Pharmacol.

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Necrostatin-1 (Nec-1) is a specific small molecule inhibitor of receptor-interacting protein kinase 1 (RIPK1) that specifically inhibits phosphorylation of RIPK1. RIPK1 regulates inflammation and cell death by interacting with receptor-interacting serine/threonine protein kinases 3(RIPK3). We hypothesized that Nec-1 may have anti-inflammatory efficacy in patients with osteoarthritis (OA), as the pathophysiology of OA involves the activation of inflammation-related signaling pathways and apoptosis. In this study, we explored the effects of Nec-1 on interleukin (IL)-1β-induced inflammation in mouse chondrocytes and the destabilised medial meniscus (DMM) mouse model. Inhibiting RIPK1 with Nec-1 dramatically suppressed catabolism both in vivo and in vitro, but did not inhibit changes in subchondral bone. Nec-1 abolished the in vitro increases in matrix metalloproteinase (MMP) and ADAM metallopeptidase with thrombospondin type 1 motif 5 (ADAMTs5) expression induced by IL-1β. However, adding high-mobility group box 1 (HMGB1) partially abrogated this effect, indicating the essential role of HMGB1 and Nec-1 in the protection of primary chondrocytes. Furthermore, Nec-1 decreased the expression of Toll-like receptor 4 (TLR4) and stromal cell-derived factor-1 (SDF-1), and attenuated the interaction between TLR4 and HMGB1. Western blot results suggested that Nec-1 significantly suppressed IL-1β-induced NF-κB transcriptional activity, but not MAPK pathway. Micro-computed tomography, immunohistochemical staining, and Safranin O/Fast Green staining were used in vivo to assess the degree of destruction of OA cartilage. The results show that NEC-1 can significantly reduce the degree of destruction of OA cartilage. Therefore, Nec-1 may be a novel therapeutic candidate to treat OA.

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“…Further comparison with published ageing or osteoarthritis-regulated cartilage proteomic studies [15][16][17][18][19][20][21][22] revealed a list of 34 rhythmic proteins being dysregulated in disease condition and/or in aging (Table 1).…”

Section: Figure 2 Protein Interaction Network Of Rhythmic Proteins Smentioning

confidence: 99%

Circadian time series proteomics reveals daily dynamics in cartilage physiology

Dudek

Angelucci

Ruckshanthi

et al. 2019

Preprint

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Objectives: Articular cartilage undergoes cyclical heavy loading and low load recovery during the 24-hour day/night cycle. We investigated the daily changes of protein abundance in mouse femoral head articular cartilage by performing 24-hour timeseries proteomics study.Methods: Tandem mass spectrometry analysis was used to quantify proteins extracted from mouse cartilage. Bioinformatics analysis was performed to quantify rhythmic changes in protein abundance. Primary chondrocytes were isolated and cultured for independent validation of selected rhythmic proteins.Results: 145 rhythmic proteins were detected. Among these were key cartilage molecules including CCN2, MATN1, PAI-1 and PLOD1 & 2. Pathway analysis revealed that proteins related to protein synthesis, cytoskeleton and glucose metabolism exhibited time-of-day dependent peaks in their abundance. Meta-analysis of published proteomics datasets from articular cartilage revealed that numerous rhythmic proteins were dysregulated in osteoarthritis and/or ageing. Conclusions:Our circadian proteomics study revealed that articular cartilage is a much more dynamic tissue than previously thought. Chondrocytes exhibit circadian rhythms not only in gene expression but also in protein abundance. Our results clearly call for the consideration of circadian timing in understanding cartilage biology, osteoarthritis pathogenesis, treatment strategies and biomarker detection.

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Tyrosine kinase Fyn promotes osteoarthritis by activating the β-catenin pathway

Abstract: Fyn accumulates and activates β-catenin signalling in chondrocytes, accelerating the degradation of the articular cartilage and OA development. Targeting Fyn is a novel and potentially therapeutic approach to the treatment of OA.

Cited by 45 publications

References 32 publications

Knockdown of SGK1 alleviates the IL‐1β‐induced chondrocyte anabolic and catabolic imbalance by activating FoxO1‐mediated autophagy in human chondrocytes

Knockdown of SGK1 alleviates the IL‐1β‐induced chondrocyte anabolic and catabolic imbalance by activating FoxO1‐mediated autophagy in human chondrocytes

Necrostatin-1 Attenuates Trauma-Induced Mouse Osteoarthritis and IL-1β Induced Apoptosis via HMGB1/TLR4/SDF-1 in Primary Mouse Chondrocytes

Circadian time series proteomics reveals daily dynamics in cartilage physiology

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