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MiR-145-5p mitigates dysregulated Wnt1/β-catenin signaling pathway in rheumatoid arthritis.

MiR-145-5p 缓解类风湿性关节炎中 Wnt1/β-catenin 信号通路失调。

  • 影响因子:3.32
  • DOI:10.1016/j.intimp.2020.106328
  • 作者列表:"Dinesh P","Kalaiselvan S","Sujitha S","Rasool M
  • 发表时间:2020-02-20
Abstract

:Fibroblast-like synoviocytes (FLS) lining the arthritic synovial joint region have been implicated to be a key player in bone remodeling. The uncontrolled proliferation of this cell subtype is strictly regulated by various molecular elements including microRNAs (miRNAs). The Wnt1/β-catenin signaling pathway plays a crucial role in the survival of FLS cells. This study explores the underlying mechanism of miR-145-5p towards the Wnt1/β-catenin pathway. MiR-145-5p depicted a strong binding affinity towards frizzled class receptor 4 (FZD4) 3' UTR, a key receptor complex essential for recognizing circulating Wnt1 molecules. Adjuvant induced arthritic fibroblast-like synoviocytes (AA-FLS) isolated from rats stimulated with Wnt1 (10 ng/ml) elicited active Wnt1/β-catenin signaling. Transfection of miR-145-5p mimic (50 pmol) to AA-FLS stimulated with Wnt1 elicited reduced expression levels of various factors of Wnt1/β-catenin signaling including low-density lipoprotein receptor-related protein 5 (LRP5), dishevelled segment polarity protein 1 (Dvl1) and β-catenin transcription factor. Moreover, pro-inflammatory cytokines (TNFα, IL-1β, IL-6 and IL-23) were regulated compared to the diseased groups. Furthermore, miR-145-5p counterbalanced the levels of receptor activator of nuclear factor kappa B ligand (RANKL) and osteoprotegerin (OPG) at the cellular level, essential for bone remodeling. Hence, we suggest that miR-145-5p regulates the survival/proliferation of FLS cells in RA disease condition through attenuation of Wnt1/β-catenin signaling.

摘要

: 关节滑膜区衬里的成纤维细胞样滑膜细胞 (FLS) 被认为是骨重建的关键参与者。这种细胞亚型不受控制的增殖受到包括 microRNAs (miRNAs) 在内的各种分子元件的严格调控。Wnt1/β-catenin 信号通路在 FLS 细胞的存活中起着至关重要的作用。本研究探讨 miR-145-5p Wnt1/β-catenin 通路的潜在机制。MiR-145-5p 描述了对 frizzled 4 类受体 (FZD4) 3 'UTR 的强结合亲和力,这是识别循环 Wnt1 分子所必需的关键受体复合物。从 Wnt1 (10 ng/ml) 刺激的大鼠中分离的佐剂诱导的关节炎成纤维样滑膜细胞 (AA-FLS) 激发了活跃的 Wnt1/β-catenin 信号。转染 miR-145-5p 模拟物 (50 pmol) 对接受 Wnt1 刺激的 AA-FLS,Wnt1/β-catenin 信号传导的各种因子表达水平降低,包括低密度脂蛋白受体相关蛋白 5 (LRP5), 蓬乱的片段极性蛋白 1 (Dvl1) 和 β-catenin 转录因子。此外,与病变组相比,促炎细胞因子 (tnf α 、 il-1 β 、 IL-6 和 IL-23) 受到调节。此外,miR-145-5p 在细胞水平平衡核因子 κ B 受体活化因子配体 (RANKL) 和骨保护素 (OPG) 的水平,这对骨重建至关重要。因此,我们认为 miR-145-5p 通过减弱 Wnt1/β-catenin 信号来调节 RA 疾病状态下 FLS 细胞的存活/增殖。

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作者列表:["Zhang X","Ehrlich KC","Yu F","Hu X","Meng XH","Deng HW","Shen H","Ehrlich M"]

METHODS::A major challenge in translating findings from genome-wide association studies (GWAS) to biological mechanisms is pinpointing functional variants because only a very small percentage of variants associated with a given trait actually impact the trait. We used an extensive epigenetics, transcriptomics, and genetics analysis of the TBX15/WARS2 neighbourhood to prioritize this region's best-candidate causal variants for the genetic risk of osteoporosis (estimated bone density, eBMD) and obesity (waist-hip ratio or waist circumference adjusted for body mass index). TBX15 encodes a transcription factor that is important in bone development and adipose biology. Manual curation of 692 GWAS-derived variants gave eight strong candidates for causal SNPs that modulate TBX15 transcription in subcutaneous adipose tissue (SAT) or osteoblasts, which highly and specifically express this gene. None of these SNPs were prioritized by Bayesian fine-mapping. The eight regulatory causal SNPs were in enhancer or promoter chromatin seen preferentially in SAT or osteoblasts at TBX15 intron-1 or upstream. They overlap strongly predicted, allele-specific transcription factor binding sites. Our analysis suggests that these SNPs act independently of two missense SNPs in TBX15. Remarkably, five of the regulatory SNPs were associated with eBMD and obesity and had the same trait-increasing allele for both. We found that WARS2 obesity-related SNPs can be ascribed to high linkage disequilibrium with TBX15 intron-1 SNPs. Our findings from GWAS index, proxy, and imputed SNPs suggest that a few SNPs, including three in a 0.7-kb cluster, act as causal regulatory variants to fine-tune TBX15 expression and, thereby, affect both obesity and osteoporosis risk.

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METHODS:PURPOSE:Systemic mastocytosis (SM) is characterized by the expansion of clonal mast cells that infiltrate various organ systems. The extent of organ infiltration and subsequent organ damage distinguishes between indolent SM (ISM) defined by a nearly normal life expectancy and advanced SM (AdvSM) defined by poor prognosis. In ISM, measurement of the bone mineral density (BMD) frequently reveals osteoporosis. In contrast, the clinical implication of an increased BMD and osteosclerosis remains unclear. METHODS:BMD was evaluated in 61 patients with mastocytosis (ISM, n = 29, 48%; AdvSM, n = 32, 52%). We correlated the prevalence of osteoporosis, increased BMD and osteosclerosis with clinical parameters, disease variant and prognosis. RESULTS:Osteoporosis was detected in 11/29 (38%) patients with ISM but only in 2/32 (6%) patients with AdvSM (p = 0.004). An increased BMD was detected in 1/29 (3%) patients with ISM and 24/32 (75%) patients with AdvSM (p < 0.001) while osteosclerosis was only detected in AdvSM patients (16/32, 50%). AdvSM patients with increased BMD had higher levels of bone marrow mast cell infiltration, higher serum tryptase and alkaline phosphatase levels compared to ISM as well as higher number of high-molecular risk mutations (p < 0.05). In addition, we found that the prognosis of AdvSM patients with increased BMD is inferior compared to those without increased BMD (median overall survival 3.6 years versus not reached, p = 0.031). CONCLUSIONS:Osteoporosis is a common feature in ISM but not in AdvSM. An increased BMD is frequently present in AdvSM but not in ISM and is associated with more advanced disease and inferior outcome.

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