scholarly journals Smac127 Has Proapoptotic and Anti-Inflammatory Effects on Rheumatoid Arthritis Fibroblast-Like Synoviocytes

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
D. Lattuada ◽  
R. Gualtierotti ◽  
K. Crotta ◽  
P. Seneci ◽  
F. Ingegnoli ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Proteolytic Enzymes ◽  
Cartilage Destruction ◽  
Significant Inhibition ◽  
Environmental Characteristic ◽  
Apoptotic Pathway ◽  
Inflammatory State ◽  
Anti Inflammatory ◽  
Regulatory Effects ◽  
Fibroblast Like Synoviocytes

Rheumatoid arthritis (RA) is characterized by synovial inflammation and hyperplasia. Fibroblast-like synoviocytes (FLSs) are apoptosis-resistant and contribute to the pathogenesis of RA by producing cytokines and proteolytic enzymes, which degrade the extracellular matrix. We evaluated the proapoptotic and anti-inflammatory activity of the small molecule Smac127 on RA-FLSs cultured in synovial fluid (SF), in order to reproduce the physiopathological environmental characteristic of RA joints. In this context, Smac127 induces apoptosis by inhibiting apoptosis proteins (IAPs). This inhibition activates caspase 3 and restores the apoptotic pathway. In addition, Smac127 induces a significant inhibition of the secretion of IL-15 and IL-6, stimulation of pannus formation, and damage of bone and cartilage in RA. Also the secretion of the anti-inflammatory cytokine IL-10 is dramatically increased in the presence of Smac127. The cartilage destruction in RA patients is partly mediated by metalloproteinases; here we show that the MMP-1 production by fibroblasts cultured in SF is significantly antagonized by Smac127. Conversely, this molecule has no significant effects on RANKL and OPG production. Our observations demonstrate that Smac127 has beneficial regulatory effects on inflammatory state of RA-FLSs and suggest a potential use of Smac127 for the control of inflammation and disease progression in RA.

scholarly journals Smac BV6 Has Proapoptotic and Anti-Inflammatory Effects on Rheumatoid Arthritis Fibroblast-Like Synoviocytes Activated by TLR9 Ligand

2021 ◽  
Author(s):  
donatella lattuada ◽  
Claudia Casnici ◽  
Katia Crotta ◽  
Ornella marelli
Keyword(s):  
Rheumatoid Arthritis ◽  
Autoimmune Disease ◽  
Proteolytic Enzymes ◽  
Critical Role ◽  
Synovial Fibroblasts ◽  
Significant Inhibition ◽  
Inflammatory State ◽  
Anti Inflammatory ◽  
Regulatory Effects

Abstract Rheumatoid arthritis synovial fibroblasts (RASF) are one of the most important cells contributing reumathoid artritis (RA) pathogenesis. The critical role of the Toll-like receptor in inflammation and on autoimmune disease is not fully known. Data rising predominantly from human patients and animal models of autoimmune disease indicate that inappropriate triggering of TLR pathways by exogenous or endogenous ligands may cause the initiation and/or perpetuation of autoimmune reactions and tissue damage. Particularly, the role of TLR9 in RA is still a subject of debate and among TLRs, TLR9 is the only receptor which detects unmethylated CpG motifs in DNA (ODN), and is located intracellularly in endosomes and endoplasmic reticulum. RASFs stimulated by ODN are apoptosis-resistant and contribute to the pathogenesis of RA by producing cytokines and proteolytic enzymes, which degrade the extracellular matrix. Then, we evaluated the proapoptotic and anti-inflammatory activity of the smac BV6 on RASF cultured in synovial fluid (SF), to reproduce the physiopathological environmental characteristics of RA joints. Furthermore, BV6 induces a significant inhibition of the secretion of IL15, TNF alpha, IL6, stimulation of pannus formation, and damage of bone and cartilage in RA. Moreover the secretion of the anti-inflammatory cytokine IL10 and the cleavage of capase 3 and 8 are dramatically increased in the presence of BV6. Furthermore, TLR9 elicited a robust IFN induction and we reported that in RASF treated with ODN and BV6 the expression of IRF7 is enhanced. Our observations demonstrate that BV6 has beneficial regulatory effects on the inflammatory state induced by TLR9 activation.

scholarly journals Anti-Inflammatory Effects of TRAF-Interacting Protein in Rheumatoid Arthritis Fibroblast-Like Synoviocytes

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Qing-Zhu Kong ◽  
Li-Tao Guo ◽  
Jia-Ning Yang ◽  
Yan-Fei Wang ◽  
Jing-Xin Zhao ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Proinflammatory Cytokines ◽  
Transforming Growth Factor ◽  
Proteolytic Enzymes ◽  
Joint Damage ◽  
Cartilage Destruction ◽  
Interacting Protein ◽  
Systemic Inflammatory Disease ◽  
Anti Inflammatory ◽  
Fibroblast Like Synoviocytes

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease characterized by inflammatory cell infiltration, synovial inflammation, and cartilage destruction. Proliferative fibroblast-like synoviocytes (FLS) play crucial roles in both propagation of inflammation and joint damage because of their production of great amount of proinflammatory cytokines and proteolytic enzymes. In this study, we investigate the role of TRAF-interacting protein (TRIP) in regulating inflammatory process in RA-FLS. TRIP expression was attenuated in RA-FLS compared with osteoarthritis- (OA-) FLS. Overexpression of TRIP significantly inhibited the activation of NF-κB signaling and decreased the production of proinflammatory cytokines and matrix metalloproteinases (MMPs) in TNFα-stimulated RA-FLS. Furthermore, TRIP was found to interact with transforming growth factorβ-activated kinase 1 (TAK1) and promoting K48-linked polyubiquitination of TAK1 in RA-FLS. Our results demonstrate that TRIP has anti-inflammatory effects on RA-FLS and suggest TRIP as a potential therapeutic target for human RA.

Atomic Force Microscopy Study of the Anti-inflammatory Effects of Triptolide on Rheumatoid Arthritis Fibroblast-like Synoviocytes

2017 ◽  
Vol 23 (5) ◽  
pp. 1002-1012 ◽  
Author(s):  
Zhanhui Su ◽  
Han Sun ◽  
Man Ao ◽  
Chunying Zhao
Keyword(s):  
Rheumatoid Arthritis ◽  
Atomic Force Microscopy ◽  
Inflammatory Responses ◽  
Bone Destruction ◽  
Microscopy Study ◽  
Primary Role ◽  
Force Microscopy ◽  
Atomic Force ◽  
Anti Inflammatory ◽  
Fibroblast Like Synoviocytes

AbstractHigh-resolution atomic force microscopy (AFM) was used for the in situ evaluation of the anti-inflammatory effects of triptolide on rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) to understand the anti-RA effects of triptolide, based on the morphological and biophysical changes observed in RA-FLS. RA-FLS have been reported to play a primary role in inflammatory bone destruction during the development of RA and thus are regarded as an important target for RA treatment. Triptolide pretreatment significantly inhibited tumor necrosis factor-α-induced expression of the interleukin (IL)-1β, IL-6, and IL-8 genes in MH7A cells. Using AFM, we showed that triptolide-induced morphological damage in MH7A cells by inducing significant ultrastructure changes in the membrane, which were closely related to triptolide-induced apoptosis in MH7A cells. Using force measurements determined with AFM, triptolide was shown to increase the stiffness of MH7A cells. These findings not only revealed the strong anti-inflammatory effects of triptolide on RA-FLS, highlighting triptolide as a potential anti-RA agent, but also revealed the possible use of AFM for studying anti-inflammatory responses in RA-FLS, which we expect to be developed into a potential tool for anti-RA drug studies in RA-FLS.

scholarly journals Apoptosis Induction of Fibroblast-Like Synoviocytes Is an Important Molecular-Mechanism for Herbal Medicine along with its Active Components in Treating Rheumatoid Arthritis

Biomolecules ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. 795 ◽  
Author(s):  
Qing Zhang ◽  
Jia Liu ◽  
Mengmeng Zhang ◽  
Shujun Wei ◽  
Ruolan Li ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Molecular Mechanisms ◽  
Herbal Medicines ◽  
Janus Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Signal Pathways ◽  
Apoptosis Induction ◽  
Apoptotic Pathway ◽  
Induction Of Apoptosis ◽  
Fibroblast Like Synoviocytes

Rheumatoid arthritis (RA) is a known chronic autoimmune disease can cause joint deformity and even loss of joint function. Fibroblast-like synoviocytes (FLS), one of the main cell types in synovial tissues of RA patients, are key effector cells in the development of RA and are considered as promising therapeutic targets for treating RA. Herbal medicines are precious resources for finding novel agents for treating various diseases including RA. It is reported that induction of apoptosis in FLS is an important mechanism for the herbal medicines to treat RA. Consequently, this paper reviewed the current available references on pro-apoptotic effects of herbal medicines on FLS and summarized the related possible signal pathways. Taken together, the main related signal pathways are concluded as death receptors mediated apoptotic pathway, mitochondrial dependent apoptotic pathway, NF-κB mediated apoptotic pathways, mitogen-activated protein kinase (MAPK) mediated apoptotic pathway, endoplasmic reticulum stress (ERS) mediated apoptotic pathway, PI3K-Akt mediated apoptotic pathway, and other reported pathways such as janus kinase/signal transducers and activators of transcription (JAK-STAT) signal pathway. Understanding the apoptosis induction pathways in FLS of these herbal medicines will not only help clear molecular mechanisms of herbal medicines for treating RA but also be beneficial for finding novel candidate therapeutic drugs from natural herbal medicines. Thus, we expect the present review will highlight the importance of herbal medicines and its components for treating RA via induction of apoptosis in FLS, and provide some directions for the future development of these mentioned herbal medicines as anti-RA drugs in clinical.

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

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiao-Feng Li ◽  
Sha Wu ◽  
Qi Yan ◽  
Yuan-Yuan Wu ◽  
He Chen ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Articular Cartilage ◽  
Dna Methyltransferase ◽  
Underlying Mechanism ◽  
Cartilage Destruction ◽  
Specific Pcr ◽  
Methylation Inhibitor ◽  
Fibroblast Like Synoviocytes

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.

scholarly journals The Janus kinase inhibitor (baricitinib) suppresses the rheumatoid arthritis active marker gliostatin/thymidine phosphorylase in human fibroblast-like synoviocytes

2022 ◽  
Author(s):  
Yuji Joyo ◽  
Yohei Kawaguchi ◽  
Hiroki Yonezu ◽  
Hiroya Senda ◽  
Sanshiro Yasuma ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Thymidine Phosphorylase ◽  
Kinase Inhibitor ◽  
Cartilage Destruction ◽  
Janus Kinase ◽  
Enzyme Linked Immunosorbent Assay ◽  
Stat Proteins ◽  
Protein Levels ◽  
Stat Signaling ◽  
Fibroblast Like Synoviocytes

AbstractGliostatin/thymidine phosphorylase (GLS/TP) is known to have angiogenic and arthritogenic activities in the pathogenesis of rheumatoid arthritis (RA). The novel oral Janus kinase (JAK) inhibitor baricitinib has demonstrated high efficacy in RA. However, the effect of baricitinib on fibroblast-like synoviocytes (FLSs), a key component of invasive synovitis, has not been still elucidated. This study investigated whether GLS/TP production could be regulated by JAK/signal transducers and activators of transcription (STAT) signaling in FLSs derived from patients with RA. FLSs were cultured and stimulated by interferon (IFN)γ in the presence of baricitinib. Expression levels of GLS/TP were determined using reverse transcription-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and immunocytochemistry. Phosphorylation of STAT proteins was investigated by Western blot. In cultured FLSs, GLS/TP mRNA and protein levels were significantly induced by treatment with IFNγ and these inductions were suppressed by baricitinib treatment. Baricitinib inhibited IFNγ-induced STAT1 phosphorylation, while JAK/STAT activation played a pivotal role in IFNγ-mediated GLS/TP upregulation in RA. These results suggested that baricitinib suppressed IFNγ-induced GLS/TP expression by inhibiting JAK/STAT signaling, resulting in the attenuation of neovascularization, synovial inflammation, and cartilage destruction.

scholarly journals Arthritis and the role of endogenous glucocorticoids

Bone Research ◽  
2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Eugenie Macfarlane ◽  
Markus J. Seibel ◽  
Hong Zhou
Keyword(s):  
Rheumatoid Arthritis ◽  
Joint Destruction ◽  
Degenerative Joint Disease ◽  
Joint Disease ◽  
Current Evidence ◽  
Inflammatory Microenvironment ◽  
Glucocorticoid Signaling ◽  
Anti Inflammatory ◽  
Fibroblast Like Synoviocytes

Abstract Rheumatoid arthritis and osteoarthritis, the most common forms of arthritis, are chronic, painful, and disabling conditions. Although both diseases differ in etiology, they manifest in progressive joint destruction characterized by pathological changes in the articular cartilage, bone, and synovium. While the potent anti-inflammatory properties of therapeutic (i.e., exogenous) glucocorticoids have been heavily researched and are widely used in clinical practice, the role of endogenous glucocorticoids in arthritis susceptibility and disease progression remains poorly understood. Current evidence from mouse models suggests that local endogenous glucocorticoid signaling is upregulated by the pro-inflammatory microenvironment in rheumatoid arthritis and by aging-related mechanisms in osteoarthritis. Furthermore, these models indicate that endogenous glucocorticoid signaling in macrophages, mast cells, and chondrocytes has anti-inflammatory effects, while signaling in fibroblast-like synoviocytes, myocytes, osteoblasts, and osteocytes has pro-inflammatory actions in rheumatoid arthritis. Conversely, in osteoarthritis, endogenous glucocorticoid signaling in both osteoblasts and chondrocytes has destructive actions. Together these studies provide insights into the role of endogenous glucocorticoids in the pathogenesis of both inflammatory and degenerative joint disease.

scholarly journals Where to Stand with Stromal Cells and Chronic Synovitis in Rheumatoid Arthritis?

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1257 ◽  
Author(s):  
Jean-Marc Brondello ◽  
Farida Djouad ◽  
Christian Jorgensen
Keyword(s):  
Rheumatoid Arthritis ◽  
Stem Cells ◽  
Stromal Cells ◽  
Immune Cell ◽  
Cell Activity ◽  
Cartilage Destruction ◽  
Molecular Signature ◽  
Main Function ◽  
And Function ◽  
Fibroblast Like Synoviocytes

The synovium exercises its main function in joint homeostasis through the secretion of factors (such as lubricin and hyaluronic acid) that are critical for the joint lubrication and function. The main synovium cell components are fibroblast-like synoviocytes, mesenchymal stromal/stem cells and macrophage-like synovial cells. In the synovium, cells of mesenchymal origin modulate local inflammation and fibrosis, and interact with different fibroblast subtypes and with resident macrophages. In pathologic conditions, such as rheumatoid arthritis, fibroblast-like synoviocytes proliferate abnormally, recruit mesenchymal stem cells from subchondral bone marrow, and influence immune cell activity through epigenetic and metabolic adaptations. The resulting synovial hyperplasia leads to secondary cartilage destruction, joint swelling, and pain. In the present review, we summarize recent findings on the molecular signature and the roles of stromal cells during synovial pannus formation and rheumatoid arthritis progression.

scholarly journals Research Progress of Therapeutic Enzymes and Their Derivatives: Based on Herbal Medicinal Products in Rheumatoid Arthritis

2021 ◽  
Vol 12 ◽  
Author(s):  
Ming Cai ◽  
Wei-Jian Ni ◽  
Lan Han ◽  
Wei-Dong Chen ◽  
Dai-Yin Peng
Keyword(s):  
Rheumatoid Arthritis ◽  
Basic Research ◽  
Autoimmune Disorder ◽  
Cartilage Destruction ◽  
Research Progress ◽  
Medicinal Products ◽  
Herbal Medicinal Products ◽  
Wide Range ◽  
Herbal Medicinal ◽  
Anti Inflammatory

Rheumatoid arthritis (RA) acts as one of the most common, agnogenic and chronic inflammatory-autoimmune disorder which is characterized by persistent synovitis, cartilage destruction, and joint deformities, leads to a wide range of disabilities, and increased mortality, thus imposing enormous burdens. Several drugs with anti-inflammatory and immunomodulatory properties such as celecoxib, diclofenac and methotrexate are being selected as conventional drugs in the allopathic system of medicine for the treatment of RA in clinic. However, there are some serious side effects more or less when using these drugs because of their short poor bioavailability and biological half-life for a long time. These shortcomings greatly promote the exploration and application of new low- or no-toxicity drugs for treating the RA. Meanwhile, a growing number of studies demonstrate that several herbs present certain anti-inflammatory and anti-arthritic activities through different enzymes and their derivatives, which indicate that they are promising therapeutic strategies when targeting these mediators based on herbal medicinal products in RA research. This review article summarizes the roles of the main enzymes and their derivatives during the pathogenesis of RA, and clearly clarifies the explicit and potential targeted actions of herbal medicinal products that have anti-RA activity. Our review provides timely and critical reference for the scientific rationale use of herbal medicinal products, with the increasing basic research and clinical application of herbal medicinal products by patients with RA.

Sign in / Sign up

Export Citation Format

Share Document