Dataset Information

TWIST1-MicroRNA-10a-MAP3K7 Axis Ameliorates Synovitis of Osteoarthritis in Fibroblast-like Synoviocytes.

ABSTRACT: Synovitis refers to the inflammation of the synovial membrane and is commonly detected in patients with osteoarthritis (OA). Recent reports have suggested that microRNAs (miRNAs) could be a promising target for diagnosis and prognosis in OA. This study examines the effect of microRNA-10a (miR-10a) in fibroblast-like synoviocyte (FLS)-mediated synovitis obtained from patients with OA. Expression of miR-10a is negatively associated with the severity of synovitis. miR-10a inhibited proliferation, migration, and secretion of pro-inflammatory cytokines of OA-FLS that were obtained from OA patients in vitro. By using a patient-derived xenograft (PDX) model, miR-10a repressed proliferation of OA-FLSs and production of OA synovium-derived pro-inflammatory cytokines in vivo. Twist Family BHLH Transcription Factor 1 (TWIST1) and mitogen-activated protein kinase kinase kinase 7 (MAP3K7) were identified as an upstream regulator and direct target of miR-10a in OA-FLSs, respectively. Nuclear factor ?B (NF-?B) signaling pathway, a downstream pathway of MAP3K7, was also repressed by miR-10a in OA-FLSs. To summarize, the TWIST1-miR-10a-MAP3K7-NF-?B pathway mediates the development of synovitis in OA. miR-10a functions as an anti-inflammatory mediator in OA-FLS.

SUBMITTER: Tu J

PROVIDER: S-EPMC7691159 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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TWIST1-MicroRNA-10a-MAP3K7 Axis Ameliorates Synovitis of Osteoarthritis in Fibroblast-like Synoviocytes.

Tu Jiajie J Huang Wei W Zhang Weiwei W Mei Jiawei J Yu Zhiying Z Zhu Chen C

Molecular therapy. Nucleic acids 20201022

Synovitis refers to the inflammation of the synovial membrane and is commonly detected in patients with osteoarthritis (OA). Recent reports have suggested that microRNAs (miRNAs) could be a promising target for diagnosis and prognosis in OA. This study examines the effect of microRNA-10a (miR-10a) in fibroblast-like synoviocyte (FLS)-mediated synovitis obtained from patients with OA. Expression of miR-10a is negatively associated with the severity of synovitis. miR-10a inhibited proliferation, m ...[more]

PMID: 33294296

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Project description:High mobility group box 1 (HMGB1) is an important downstream product of pyroptosis in macrophages, and it serves a vital role in numerous inflammatory diseases. Previous studies have reported that HMGB1 is released by fibroblast?like synoviocytes (FLSs) that are activated by inflammatory cytokines in knee osteoarthritis (KOA); however, the mechanism via which FLS promotes HMGB1 secretion in KOA remains unknown. According to our previous study, pyroptosis occurs in FLSs of patients with KOA and is mediated by Nod?like receptor protein (NLRP)1 or NLRP3 inflammasomes. However, the specific relationship between HMGB1 secretion and FLS pyroptosis requires further investigation. In the present study, the association between HMGB1 secretion and FLS pyroptosis was investigated in vitro and in vivo. In this study, western blotting, ELISA and reverse transcription?quantitative PCR were used to measure expression levels of proteins and mRNA. Caspase?1 activity assay and Hoechst 33342/PI double staining were used to observe the pyroptosis of FLSs. Hematoxylin and eosin staining was used to observe the destruction of cartilage in KOA. Increased expression levels of pyroptosis?related proteins and HMGB1 in the synovium of rat anterior cruciate ligament transection?induced KOA models were identified, and these changes were significantly mitigated via the intra?articular injection of a caspase?1 inhibitor. In vitro, FLSs were treated with lipopolysaccharide (LPS) + ATP to induce pyroptosis, and HMGB1 secretion was subsequently measured. LPS + ATP significantly increased the expression levels of pyroptosis?related proteins and HMGB1 in FLSs, and these effects were significantly mitigated by small interfering RNAs targeting NLRP1, NLRP3, apoptosis?associated speck?like protein with a caspase?recruitment domain or caspase?1. Therefore, the present results indicated that NLRP1/NLRP3 inflammasome?mediated and caspase?1?dependent FLS pyroptosis increased HMGB1 secretion in KOA. These findings may provide a therapeutic strategy to decrease synovial inflammatory responses during KOA progression.

Project description: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 results in PVNS with high recurrence, invasiveness, and strong cartilage destruction ability, and eventually promotes the transformation of PVNS from the initial inflammatory disease to neoplastic disease. Thus, inhibition of cadherin-11 together with its related inflammatory reaction, represents a new therapeutic strategy for PVNS.

Dataset Information

TWIST1-MicroRNA-10a-MAP3K7 Axis Ameliorates Synovitis of Osteoarthritis in Fibroblast-like Synoviocytes.

Publications

TWIST1-MicroRNA-10a-MAP3K7 Axis Ameliorates Synovitis of Osteoarthritis in Fibroblast-like Synoviocytes.

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