Over-Expression of PTEN Attenuates the Inflammation of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis

Xiao-Feng Li,Man-Wen Yang,Xin Chen,Xiao-Ming Meng,Su-Qin Yin,He Chen,Biao Song,Qing-Qing Xu,Lei Zhang,Jun Li

doi:10.2139/ssrn.3476779

Abstract

Background: Rheumatoid arthritis (RA) is characterized by a tumor-like expansion of the synovium and the subsequent destruction of adjacent articular cartilage and bone. Recent studies have shown that phosphatase and tension homolog deleted on chromosome 10 (PTEN) might contribute to the survival of fibroblast-like synoviocytes (FLS) and the production of pro-inflammatory cytokines in RA. Methods: The expression was determined in RA and adjuvant-induced arthritis (AIA) synovial tissues by immunohistochemistry. FLSs were treatment with bpv, PTEN-RNAi or over-expression plasmid in RA and AIA. FLSs migration was assessed. The ad-PTEN was also injected into the knee of AIA in vivo. Chromatin Immunoprecipitation (ChIP) and Methylation-special PCR (MSP) assay were used to study the expression of PTEN mRNA in DNA methylation. Results: Down-regulated level of PTEN expression was observed in RA and AIA. Inhibition PTEN expression by bpv or PTEN-RNAi could promote the expression of pro-inflammatory cytokines, chemokines and migration of FLS with TNF-α in RA and AIA. Consistently, over-expression of PTEN reduced their low-expression of pro-inflammatory cytokines, chemokines and migration. Intra-articular injection of ad-PTEN in AIA knees dramatically reduced inflammatory and paw swelling in vivo. The ChIP and MSP assay has clearly detected the DNA methylation of PTEN was increased in FLS with TNF-α. Moreover, intraperitoneally injected 5-Aza in AIA also suppressed the inflammatory and paws swelling in vivo. Conclusions: Our findings suggest that over-expression PTEN attenuates the formation of pro-inflammatory cytokines, chemokines and migration of FLS, and it may be regulated by DNA methylation in the pathogenesis of RA. Funding Statement: This study is supported by the National Natural Science Foundation of China (No. 81770609). Declaration of Interests: All authors declare no conflict interests. Ethics Approval Statement: All experimental protocols used on the animals were approved by the institutions’ subcommittees on animal care of Anhui Medical University (approval number: 20160253).

Highlights

Rheumatoid arthritis (RA) is characterized by a tumor-like expansion of the synovium and the subsequent destruction of adjacent articular cartilage and bone
Inhibition PTEN expression by bpv or PTEN-RNAi could promote the expression of pro-inflammatory cytokines, chemokines and migration of fibroblast-like synoviocytes (FLS) with tumor necrosis factor-α (TNF-α) in RA and adjuvant-induced arthritis (AIA)
Over-expression of PTEN reduced their low-expression of pro-inflammatory cytokines, chemokines and migration

Summary

Introduction

Rheumatoid arthritis (RA) is characterized by a tumor-like expansion of the synovium and the subsequent destruction of adjacent articular cartilage and bone. Rheumatoid arthritis (RA), a chronic and systemic autoimmune disease, is characterized by hyperplasia of synovial tissues, synovial inflammation and pannus, and subsequent destruction of adjacent articular cartilage and bone [1, 2]. Activated FLS could directly secrete pro-inflammatory cytokines (tumor necrosis factor-α, TNF-α and interleukin, IL-1β) [6], chemokines (monocyte chemoattractant protein-1, CCL-2) [7], matrix metalloproteinases (MMP-3, MMP-9), [5] and angiogenic factors [8] which are carriaged into the intra-articular synovial fluid and destroy cartilage and bone in onset of RA. Various pro-inflammatory cytokines, such as TNF-α and IL-17A are requirement to onset and development of RA in synoviocyte activation. Chemokines play an important role in chronic synovitis, and macrophage inhibitory protein (MIP-1α, CCL-3) and CCL-2 show abnormal expression in different stages of RA [7]

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Results

Conclusion