PI3K/Akt inhibitor partly decreases TNF-α-induced activation of fibroblast-like synoviocytes in osteoarthritis

Liu, Songyang; Cao, Canhui; Zhang, Yujun; Liu, Guangyu; Ren, Weixia; Ye, Yanqi; Sun, Tiezheng

doi:10.1186/s13018-019-1394-4

Cited by 47 publications

(33 citation statements)

References 30 publications

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“…Feldman has demonstrated that the PI3K/Akt pathway can be activated by several cytokines (TNF-α in RA synoviocytes) 34 . Our previous research also confirmed that inflammatory factors can activate the PI3K/Akt pathway in OA FLS 16 . In the current study, the results showed that IL-1β or TNF-α up-regulated the expression of cadherin-11 in PVNS FLS through the PI3K/Akt pathway.…”

Section: Discussionsupporting

confidence: 76%

“…In RA, studies have shown that cadherin-11 can stimulate FLS to produce inflammatory cytokines and matrix metalloproteinase 15 . Furthermore, inhibiting cadherin-11 can reduce the migration and invasion ability of OA FLS, and cadherin-11 antibodies attenuated synovitis and cartilage damage in an animal model of OA 16 . However, it remains unclear whether cadherin-11 is involved in the pathogenesis of PVNS and related to the high recurrence, invasion, migration, and cartilage destruction ability of PVNS FLS.…”

Section: Introductionmentioning

confidence: 98%

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Cadherin-11 cooperates with inflammatory factors to promote the migration and invasion of fibroblast-like synoviocytes in pigmented villonodular synovitis

Cao¹,

Wu²,

Niu³

et al. 2020

Theranostics

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Rationale: Pigmented villonodular synovitis (PVNS) is a destructive benign tumor-like hyperplastic disease that occurs in synovial tissue. Fibroblast-like synoviocytes (FLS) are the predominant cell type comprising the structure of the PVNS synovial lining layer. Due to a high recurrence rate, high invasion, migration, and cartilage destruction ability, PVNS causes substantial damage to patients and the efficacy of surgical resection is not satisfactory. Therefore, exploring the pathogenesis and identifying novel therapeutic targets for PVNS are urgently required. Currently, the pathogenesis of PVNS remains unclear, and there is uncertainty and controversy regarding whether PVNS is an inflammatory or a neoplastic disease. Cadherin-11 is a classical molecule that mediates hemophilic cell-to-cell adhesion in FLS and plays an important role in the normal synovium lining layer formation. This study aimed to explore the role of inflammation and cadherin-11 in PVNS pathogenesis and determine the effects of cadherin-11 as a molecular target for PVNS treatment. Methods: FLS were primarily cultured from PVNS patients during arthroscopic synovectomy. The level of cytokines in the PVNS synovial fluid was evaluated using a human antibody array. Cadherin-11 expression of PVNS FLS was detected by qPCR, Western blots, tissue immunohistochemistry, and cell immunofluorescence. Cadherin-11 was down-regulated by siRNA or up-regulated with a plasmid, with or without inflammatory factor stimulation, and PI3K/Akt was inhibited with LY294002. The capacity of migration and invasion of PVNS FLS was tested using Transwell and wound-healing assays. Activation of the nuclear factor-kappaB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways was detected by Western blots. Chondrocyte damage by PVNS FLS was assessed with a co-culture assay. Results: Inflammatory factors (IL-1β and TNF-α) in the synovial fluid of PVNS patients were significantly up-regulated. Cadherin-11 was highly expressed in the FLS of PVNS patients, and positively correlated with recurrence, extra-articular migration, and cartilage destruction of PVNS. Knocking down of cadherin-11 inhibited the migration and invasion of PVNS FLS. Moreover, inflammatory factors up-regulated the expression of cadherin-11, which activated the NF-κB and MAPK signaling pathways and led to cartilage destruction. Inhibition of cadherin-11 blocked IL-1β- and TNF-α-induced activation of the above pathways, migration and invasion of PVNS FLS, and damage of chondrocyte. In addition, the elevation of cadherin-11 expression, together with the migration and invasion, of PVNS FLS was down-regulated by the inhibition of the PI3K/Akt signaling pathway. Conclusions: Cadherin-11 plays an important role in the pathogenesis of PVNS and forms a positive feedback loop with inflammatory factors, which further activates the NF-κB and MAPK pathways to trigger an inflammatory cascade. Cadherin-11-mediated inflammation ...

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Section: Discussionsupporting

confidence: 76%

Section: Introductionmentioning

confidence: 98%

Cadherin-11 cooperates with inflammatory factors to promote the migration and invasion of fibroblast-like synoviocytes in pigmented villonodular synovitis

Cao¹,

Wu²,

Niu³

et al. 2020

Theranostics

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“…Several inhibitors that specifically target signaling pathways by inhibiting key proteins and upstream regulators in the pathway have shown therapeutic potential for treatment of OA in pre-clinical studies [23][24][25][26][27][28][29][30].…”

Section: Introductionmentioning

confidence: 99%

Anti-Inflammatory and Chondroprotective Effects of Vanillic Acid and Epimedin C in Human Osteoarthritic Chondrocytes

et al. 2020

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In osteoarthritis (OA), inhibition of excessively expressed pro-inflammatory cytokines in the OA joint and increasing the anabolism for cartilage regeneration are necessary. In this ex-vivo study, we used an inflammatory model of human OA chondrocytes microtissues, consisting of treatment with cytokines (interleukin 1β (IL-1β)/tumor necrosis factor α (TNF-α)) with or without supplementation of six herbal compounds with previously identified chondroprotective effect. The compounds were assessed for their capacity to modulate the key catabolic and anabolic factors using several molecular analyses. We selectively investigated the mechanism of action of the two most potent compounds Vanillic acid (VA) and Epimedin C (Epi C). After identification of the anti-inflammatory and anabolic properties of VA and Epi C, the Ingenuity Pathway Analysis showed that in both treatment groups, osteoarthritic signaling pathways were inhibited. In the treatment group with VA, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling was inhibited by attenuation of the nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (IκBα) phosphorylation. Epi C showed a significant anabolic effect by increasing the expression of collagenous and non-collagenous matrix proteins. In conclusion, VA, through inhibition of phosphorylation in NF-κB signaling pathway and Epi C, by increasing the expression of extracellular matrix components, showed significant anti-inflammatory and anabolic properties and might be potentially used in combination to treat or prevent joint OA.

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“…Allicin alleviates the progression of OA by inactivating the PI3K/AKT/NF-jB pathway [15]. Blocking PI3K/AKT signaling can reduce post-traumatic OA or tumor necrosis factor-a-induced OA [16,17]. Thus, blocking this pathway could be a promising treatment strategy for KOA.…”

mentioning

confidence: 99%

High follicle‐stimulating hormone levels accelerate cartilage damage of knee osteoarthritis in postmenopausal women through the PI3K/AKT/NF‐κB pathway

et al. 2020

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Knee osteoarthritis (KOA) is prevalent in postmenopausal women and a cause of pain and disability in elderly populations. Here, we report high follicle‐stimulating hormone (FSH) levels across postmenopausal female KOA patients aged 50–60 years. We speculate FSH might damage cartilage tissues through the phosphoinositide 3‐kinase/AKT/nuclear factor kappa B pathway. Our findings suggest that FSH modulation holds promise as a novel treatment for postmenopausal female KOA patients aged 50–60 years.

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PI3K/Akt inhibitor partly decreases TNF-α-induced activation of fibroblast-like synoviocytes in osteoarthritis

Cited by 47 publications

References 30 publications

Cadherin-11 cooperates with inflammatory factors to promote the migration and invasion of fibroblast-like synoviocytes in pigmented villonodular synovitis

Cadherin-11 cooperates with inflammatory factors to promote the migration and invasion of fibroblast-like synoviocytes in pigmented villonodular synovitis

Anti-Inflammatory and Chondroprotective Effects of Vanillic Acid and Epimedin C in Human Osteoarthritic Chondrocytes

High follicle‐stimulating hormone levels accelerate cartilage damage of knee osteoarthritis in postmenopausal women through the PI3K/AKT/NF‐κB pathway

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