PTEN Methylation Promotes Inflammation and Activation of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis

Abstract

Rheumatoid arthritis (RA) is characterized by a tumor-like expansion of the synovium and subsequent destruction of adjacent articular cartilage and bone. In our previous work we showed that phosphatase and tension homolog deleted on chromosome 10 (PTEN) contributes to the activation of fibroblast-like synoviocytes (FLS) in adjuvant-induced arthritis (AIA), but the underlying mechanism is not unknown. In this study, we show that PTEN is downregulated while DNA methyltransferase (DNMT)1 is upregulated in FLS from RA patients and a rat model of AIA. DNA methylation of PTEN was increased by administration of tumor necrosis factor (TNF)-α in FLS of RA patients, as determined by chromatin immunoprecipitation and methylation-specific PCR. Treatment with the methylation inhibitor 5-azacytidine suppressed cytokine and chemokine release and FLS activation in vitro and alleviated paw swelling in vivo. PTEN overexpression reduced inflammation and activation of FLS via protein kinase B (AKT) signaling in RA, and intra-articular injection of PTEN-expressing adenovirus into the knee of AIA rats markedly reduced inflammation and paw swelling. Thus, PTEN methylation promotes the inflammation and activation of FLS in the pathogenesis of RA. These findings provide insight into the molecular basis of articular cartilage destruction in RA, and indicate that therapeutic strategies that prevent PTEN methylation may an effective treatment.

DNA Methylation of T Lymphocytes as a Therapeutic Target: Implications for Rheumatoid Arthritis Etiology

“…Overexpression of PTEN can significantly reduce the expression of pro-inflammatory factors, chemokines, vascular cell adhesion factor-1, and vascular endothelial growth factor-a in AIA experimental animals. Consistent with the previous, the expression of PTEN is regulated by DNA methylation and is accompanied by changes in the AKT signal (22), and the methylation of PTEN has been shown to promote inflammation and activation of RA fibroblast-like synoviocyte (FLS) (23). Shikonin significantly reduces angiogenesis in RA.…”

DNA methyltransferase 1 knockdown reverses PTEN and VDR by mediating demethylation of promoter and protects against renal injuries in hepatitis B virus-associated glomerulonephritis

“…Similar to our findings, Xu et al confirmed that the m6A modification-related PI3K/Akt pathway modulated by methylase METTL14 through PTEN had an effect on HDAC5-induced EMT in renal tubular cells exposed to high glucose (HG) treatment [ 40 ]. DNMT1 could downregulate PTEN, while PTEN overexpression reduced inflammation and activated fibroblast-like synoviocytes via AKT signaling in rheumatoid arthritis [ 41 ]. Moreover, our results indicated that the PI3K/Akt inhibitor LY294002 attenuated PTEN downregulation-induced EMT and NF-κB activation, thereby demonstrating that activation of the PI3K/Akt pathway in response to PTEN loss could result in the activation of the downstream proinflammatory NF-κB pathway.…”

Mitochondrial Dysfunction and Oxidative Stress in Rheumatoid Arthritis

“…On this point, lactate could compensate the inflammatory setting triggered by hypoxic condition, promoting a metabolic switch from inflammatory macrophage to homeostatic M2 like-polarization by epigenetic modifications (histone lactylation) [ 95 ]. Methylation also promotes inflammation and activation of fibroblast-like synoviocytes in RA [ 228 , 229 ] as well as is associated with the level of transcript in T lymphocytes from RA patients [ 230 ]. Notably, differential DNA methylation correlates with response to methotrexate in RA PBMCs [ 231 , 232 ].…”