scholarly journals 14-3-3η Promotes Invadosome Formation via the FOXO3–Snail Axis in Rheumatoid Arthritis Fibroblast-like Synoviocytes

2021 ◽  
Vol 23 (1) ◽  
pp. 123
Author(s):  
Maleck Kadiri ◽  
Martine Charbonneau ◽  
Catherine Lalanne ◽  
Kelly Harper ◽  
Frédéric Balg ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Joint Damage ◽  
Cartilage Degradation ◽  
Scaffolding Protein ◽  
Critical Event ◽  
Cellular Functions ◽  
Nuclear Exclusion ◽  
Wide Range ◽  
Membrane Protrusions ◽  
Fibroblast Like Synoviocytes

Erosive destruction of joint structures is a critical event in the progression of rheumatoid arthritis (RA), in which fibroblast-like synoviocytes (FLS) are the primary effectors. We previously reported that the ability of RA FLS to degrade extracellular matrix (ECM) components depends on the formation of actin-rich membrane protrusions, called invadosomes, through processes that remain elusive. 14-3-3η belongs to a family of scaffolding proteins involved in a wide range of cellular functions, and its expression is closely related to joint damage and disease activity in RA patients. In this study, we sought to assess the role of 14-3-3η in joint damage by examining its contribution to the invadosome formation phenotype of FLS. Using human primary FLS, we show that 14-3-3η expression is closely associated with their ability to form invadosomes. Furthermore, knockdown of 14-3-3η using shRNAs decreases the level of invadosome formation in RA FLS, whereas addition of the recombinant protein to FLS from healthy individuals promotes their formation. Mechanistic studies suggest that 14-3-3η regulates invadosome formation by increasing Snail expression, a mechanism that involves nuclear exclusion of the transcription repressor FOXO3. Our results implicate the 14-3-3η–FOXO3–Snail axis in promoting the aggressive ECM-degrading phenotype of RA FLS, and suggest a role for this scaffolding protein in cartilage degradation.

scholarly journals Fragment-based screening identifies molecules targeting the substrate-binding ankyrin repeat domains of tankyrase

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Katie Pollock ◽  
Manjuan Liu ◽  
Mariola Zaleska ◽  
Mirco Meniconi ◽  
Mark Pfuhl ◽  
...  
Keyword(s):  
Catalytic Domain ◽  
Substrate Binding ◽  
Ankyrin Repeat ◽  
Telomere Maintenance ◽  
Scaffolding Protein ◽  
Cellular Functions ◽  
Wide Range ◽  
Differential Scanning Fluorimetry ◽  
Potential Alternative ◽  
Hippo Signalling

AbstractThe PARP enzyme and scaffolding protein tankyrase (TNKS, TNKS2) uses its ankyrin repeat clusters (ARCs) to bind a wide range of proteins and thereby controls diverse cellular functions. A number of these are implicated in cancer-relevant processes, including Wnt/β-catenin signalling, Hippo signalling and telomere maintenance. The ARCs recognise a conserved tankyrase-binding peptide motif (TBM). All currently available tankyrase inhibitors target the catalytic domain and inhibit tankyrase’s poly(ADP-ribosyl)ation function. However, there is emerging evidence that catalysis-independent “scaffolding” mechanisms contribute to tankyrase function. Here we report a fragment-based screening programme against tankyrase ARC domains, using a combination of biophysical assays, including differential scanning fluorimetry (DSF) and nuclear magnetic resonance (NMR) spectroscopy. We identify fragment molecules that will serve as starting points for the development of tankyrase substrate binding antagonists. Such compounds will enable probing the scaffolding functions of tankyrase, and may, in the future, provide potential alternative therapeutic approaches to inhibiting tankyrase activity in cancer and other conditions.

Destructive Roles of Fibroblast-like Synoviocytes in Chronic Inflammation and Joint Damage in Rheumatoid Arthritis

Inflammation ◽  
2020 ◽  
Author(s):  
Maryam Masoumi ◽  
Hamidreza Bashiri ◽  
Hossein Khorramdelazad ◽  
Khadijeh Barzaman ◽  
Nader Hashemi ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Chronic Inflammation ◽  
Joint Damage ◽  
Fibroblast Like Synoviocytes

scholarly journals Parallel comparison of fibroblast-like synoviocytes from the surgically removed hyperplastic synovial tissues of rheumatoid arthritis and osteoarthritis patients

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Wei Huang ◽  
Linlin Zhang ◽  
Chao Cheng ◽  
Wenshan Shan ◽  
Ruixiang Ma ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Inflammatory Cytokine ◽  
Cellular Functions ◽  
Cell Surface Antigens ◽  
Necrosis Factor Alpha ◽  
Inflammatory Status ◽  
Cytokine Tumor Necrosis Factor ◽  
Anti Inflammatory ◽  
Synovial Tissues ◽  
Fibroblast Like Synoviocytes

Abstract Background Fibroblast-like synoviocytes (FLS) are essential cellular components in inflammatory joint diseases such as osteoarthritis (OA) and rheumatoid arthritis (RA). Despite the growing use of FLS isolated from OA and RA patients, a detailed functional and parallel comparison of FLS from these two types of arthritis has not been performed. Methods In the present study, FLS were isolated from surgically removed synovial tissues from twenty-two patients with OA and RA to evaluate their basic cellular functions. Results Pure populations of FLS were isolated by a sorting strategy based on stringent marker expression (CD45−CD31−CD146−CD235a−CD90+PDPN+). OA FLS and RA FLS at the same passage (P2-P4) exhibited uniform fibroblast morphology. OA FLS and RA FLS expressed a similar profile of cell surface antigens, including the fibroblast markers VCAM1 and ICAM1. RA FLS showed a more sensitive inflammatory status than OA FLS with regard to proliferation, migration, apoptosis, inflammatory gene expression and pro-inflammatory cytokine secretion. In addition, the responses of OA FLS and RA FLS to both the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) and the anti-inflammatory drug methotrexate (MTX) were also evaluated here. Conclusion The parallel comparison of OA FLS and RA FLS lays a foundation in preparation for when FLS are considered a potential therapeutic anti-inflammatory target for OA and RA.

scholarly journals Association of baseline levels of markers of bone and cartilage degradation with long-term progression of joint damage in patients with early rheumatoid arthritis

2002 ◽  
Vol 46 (11) ◽  
pp. 2847-2856 ◽  
Author(s):  
Patrick Garnero ◽  
Robert Landewé ◽  
Maarten Boers ◽  
Arco Verhoeven ◽  
Sjef Van Der Linden ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Early Rheumatoid Arthritis ◽  
Joint Damage ◽  
Cartilage Degradation ◽  
Baseline Levels ◽  
And Cartilage

scholarly journals Correction to: Destructive Roles of Fibroblast-Like Synoviocytes in Chronic Inflammation and Joint Damage in Rheumatoid Arthritis

Inflammation ◽  
2020 ◽  
Author(s):  
Maryam Masoumi ◽  
Hamidreza Bashiri ◽  
Hossein Khorramdelazad ◽  
Khadijeh Barzaman ◽  
Nader Hashemi ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Chronic Inflammation ◽  
Joint Damage ◽  
Fibroblast Like Synoviocytes

scholarly journals Fragment-based screening identifies molecules targeting the substrate-binding ankyrin repeat domains of tankyrase

2019 ◽  
Author(s):  
Katie Pollock ◽  
Manjuan Liu ◽  
Mariola Zaleska ◽  
Mark Pfuhl ◽  
Ian Collins ◽  
...  
Keyword(s):  
Catalytic Domain ◽  
Screening Program ◽  
Substrate Binding ◽  
Ankyrin Repeat ◽  
Telomere Maintenance ◽  
Scaffolding Protein ◽  
Cellular Functions ◽  
Wide Range ◽  
Differential Scanning Fluorimetry ◽  
Potential Alternative

AbstractThe PARP enzyme and scaffolding protein tankyrase (TNKS, TNKS2) uses its ankyrin repeat clusters (ARCs) to bind a wide range of proteins and thereby controls diverse cellular functions. A number of these are implicated in cancer-relevant processes, including Wnt/β-catenin signaling and telomere maintenance. The ARCs recognise a conserved tankyrase-binding peptide motif (TBM). All currently available tankyrase inhibitors target the catalytic domain and inhibit tankyrase’s poly(ADP-ribosyl)ation function. However, there is emerging evidence that catalysis-independent “scaffolding” mechanisms contribute to tankyrase function. Here we report a fragment-based screening program against tankyrase ARC domains, using a combination of biophysical assays, including differential scanning fluorimetry (DSF) and nuclear magnetic resonance (NMR). We identify fragment molecules that will serve as starting points for the development of tankyrase substrate binding antagonists. Such compounds will enable probing the scaffolding functions of tankyrase, and may, in the future, provide potential alternative therapeutic approaches to inhibiting tankyrase activity in cancer and other conditions.

scholarly journals Extra-virgin olive oil and its phenolic extract prevent inflammatory response and joint damage in murine experimental arthritis

2016 ◽  
Vol 67 (4) ◽  
pp. 158
Author(s):  
M. A. Rosillo ◽  
M. Sánchez-Hidalgo ◽  
C. Alarcón-de-la-Lastra
Keyword(s):  
Bone Erosion ◽  
Virgin Olive Oil ◽  
Joint Damage ◽  
Extra Virgin Olive Oil ◽  
Cartilage Degradation ◽  
Natural Diet ◽  
Bovine Collagen ◽  
Mediterranean Countries ◽  
Wide Range ◽  
Phenolic Extract

The consumption of EVOO in Mediterranean countries has shown beneficial effects. A wide range of evidence indicates that the phenolic compounds present in EVOO are endowed with anti-inflammatory properties. In this work, we evaluated the effects of dietary EVOO and treatment with its phenolic extract (PE) in a model of RA, the collagen-induced arthritis (CIA) in mice. On day 0, DBA-1/J mice were immunized with bovine collagen type II (CII). On day 21, the mice received a booster injection. We have demonstrated that EVOO and its PE decreases joint edema, cell migration, cartilage degradation and bone erosion. Our data indicate that dietary EVOO and PE treatment inhibit JNK, p38 and signal transducer and STAT-3. In addition, both EVOO and PE decrease NF-κB translocation leading to the down-regulation of the arthritic process. These results support the interest of natural diet components in the development of therapeutic products for arthritic conditions.

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.

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