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Nature Reviews. Rheumatology May 2022Osteoarthritis (OA) is a progressive degenerative disease resulting in joint deterioration. Synovial inflammation is present in the OA joint and has been associated with... (Review)
Review
Osteoarthritis (OA) is a progressive degenerative disease resulting in joint deterioration. Synovial inflammation is present in the OA joint and has been associated with radiographic and pain progression. Several OA risk factors, including ageing, obesity, trauma and mechanical loading, play a role in OA pathogenesis, likely by modifying synovial biology. In addition, other factors, such as mitochondrial dysfunction, damage-associated molecular patterns, cytokines, metabolites and crystals in the synovium, activate synovial cells and mediate synovial inflammation. An understanding of the activated pathways that are involved in OA-related synovial inflammation could form the basis for the stratification of patients and the development of novel therapeutics. This Review focuses on the biology of the OA synovium, how the cells residing in or recruited to the synovium interact with each other, how they become activated, how they contribute to OA progression and their interplay with other joint structures.
Topics: Cytokines; Humans; Inflammation; Osteoarthritis; Synovial Membrane; Synoviocytes
PubMed: 35165404
DOI: 10.1038/s41584-022-00749-9 -
Frontiers in Immunology 2022Rheumatoid arthritis (RA) is an autoimmune disease that severely affects patients' physical and mental health, leading to chronic synovitis and destruction of bone... (Review)
Review
Rheumatoid arthritis (RA) is an autoimmune disease that severely affects patients' physical and mental health, leading to chronic synovitis and destruction of bone joints. Although various available clinical treatment options exist, patients respond with varying efficacies due to multiple factors, and there is an urgent need to discover new treatment options to improve clinical outcomes. Cuproptosis is a newly characterized form of cell death. Copper causes cuproptosis by binding to lipid-acylated components of the tricarboxylic acid cycle, leading to protein aggregation, loss of iron-sulfur cluster proteins, and eventually proteotoxic stress. Targeting copper cytotoxicity and cuproptosis are considered potential options for treating oncological diseases. The synovial hypoxic environment and the presence of excessive glycolysis in multiple cells appear to act as inhibitors of cuproptosis, which can lead to excessive survival and proliferation of multiple immune cells, such as fibroblast-like synoviocytes, effector T cells, and macrophages, further mediating inflammation and bone destruction in RA. Therefore, in this study, we attempted to elaborate and summarize the linkage of cuproptosis and key genes regulating cuproptosis to the pathological mechanisms of RA and their effects on a variety of immune cells. This study aimed to provide a theoretical basis and support for translating preclinical and experimental results of RA to clinical protocols.
Topics: Humans; Arthritis, Rheumatoid; Copper; Inflammation; Synoviocytes; Synovitis; Apoptosis
PubMed: 35990673
DOI: 10.3389/fimmu.2022.930278 -
Current Opinion in Pharmacology Dec 2022Fibroblast-like synoviocytes (FLS) are mesenchymal-derived cells that play an important role in the physiology of the synovium by producing certain components of the... (Review)
Review
Fibroblast-like synoviocytes (FLS) are mesenchymal-derived cells that play an important role in the physiology of the synovium by producing certain components of the synovial fluid and articular cartilage. In rheumatoid arthritis (RA), however, fibroblasts become a key driver of synovial inflammation and joint damage. Because of this, there has been recent interest in FLS as a therapeutic target in RA to avoid side effects such as systemic immune suppression associated with many existing RA treatments. In this review, we describe how approved treatments for RA affect FLS signaling and function and discuss the effects of investigational FLS-targeted drugs for RA.
Topics: Humans; Synoviocytes; Synovial Membrane; Arthritis, Rheumatoid; Fibroblasts; Signal Transduction
PubMed: 36228471
DOI: 10.1016/j.coph.2022.102304 -
Scientific Reports Jul 2020We elucidated the molecular cross-talk between cartilage and synovium in osteoarthritis, the most widespread arthritis in the world, using the powerful tool of...
We elucidated the molecular cross-talk between cartilage and synovium in osteoarthritis, the most widespread arthritis in the world, using the powerful tool of single-cell RNA-sequencing. Multiple cell types were identified based on profiling of 10,640 synoviocytes and 26,192 chondrocytes: 12 distinct synovial cell types and 7 distinct articular chondrocyte phenotypes from matched tissues. Intact cartilage was enriched for homeostatic and hypertrophic chondrocytes, while damaged cartilage was enriched for prefibro- and fibro-, regulatory, reparative and prehypertrophic chondrocytes. A total of 61 cytokines and growth factors were predicted to regulate the 7 chondrocyte cell phenotypes. Based on production by > 1% of cells, 55% of the cytokines were produced by synovial cells (39% exclusive to synoviocytes and not expressed by chondrocytes) and their presence in osteoarthritic synovial fluid confirmed. The synoviocytes producing IL-1beta (a classic pathogenic cytokine in osteoarthritis), mainly inflammatory macrophages and dendritic cells, were characterized by co-expression of surface proteins corresponding to HLA-DQA1, HLA-DQA2, OLR1 or TLR2. Strategies to deplete these pathogenic intra-articular cell subpopulations could be a therapeutic option for human osteoarthritis.
Topics: Aged; Biomarkers; Cartilage, Articular; Case-Control Studies; Cells, Cultured; Female; Humans; Male; Osteoarthritis; RNA-Seq; Synoviocytes
PubMed: 32616761
DOI: 10.1038/s41598-020-67730-y -
Arthritis & Rheumatology (Hoboken, N.J.) Mar 2021MicroRNA-34a-5p (miR-34a-5p) expression is elevated in the synovial fluid of patients with late-stage knee osteoarthritis (OA); however, its exact role and therapeutic...
OBJECTIVE
MicroRNA-34a-5p (miR-34a-5p) expression is elevated in the synovial fluid of patients with late-stage knee osteoarthritis (OA); however, its exact role and therapeutic potential in OA remain to be fully elucidated. This study was undertaken to examine the role of miR-34a-5p in OA pathogenesis.
METHODS
Expression of miR-34a-5p was determined in joint tissues and human plasma (n = 71). Experiments using miR-34a-5p mimic or antisense oligonucleotide (ASO) treatment were performed in human OA chondrocytes, fibroblast-like synoviocytes (FLS) (n = 7-9), and mouse OA models, including destabilization of the medial meniscus (DMM; n = 22) and the accelerated, more severe model of mice fed a high-fat diet and subjected to DMM (n = 11). Wild-type (WT) mice (n = 9) and miR-34a-knockout (KO) mice (n = 11) were subjected to DMM. Results were expressed as the mean ± SEM and analyzed by t-test or analysis of variance, with appropriate post hoc tests. P values less than 0.05 were considered significant. RNA sequencing was performed on WT and KO mouse chondrocytes.
RESULTS
Expression of miR-34a-5p was significantly increased in the plasma, cartilage, and synovium of patients with late-stage OA and in the cartilage and synovium of mice subjected to DMM. Plasma miR-34a-5p expression was significantly increased in obese patients with late-stage OA, and in the plasma and knee joints of mice fed a high-fat diet. In human OA chondrocytes and FLS, miR-34a-5p mimic increased key OA pathology markers, while miR-34a-5p ASO improved cellular gene expression. Intraarticular miR-34a-5p mimic injection induced an OA-like phenotype. Conversely, miR-34a-5p ASO injection imparted cartilage-protective effects in the DMM and high-fat diet/DMM models. The miR-34a-KO mice exhibited protection against DMM-induced cartilage damage. RNA sequencing of WT and KO chondrocytes revealed a putative miR-34a-5p signaling network.
CONCLUSION
Our findings provide comprehensive evidence of the role and therapeutic potential of miR-34a-5p in OA.
Topics: Adult; Aged; Animals; Cartilage, Articular; Chondrocytes; Diet, High-Fat; Disease Models, Animal; Female; Humans; Male; Menisci, Tibial; Mice; Mice, Knockout; MicroRNAs; Middle Aged; Oligonucleotides, Antisense; Osteoarthritis; Osteoarthritis, Knee; Reverse Transcriptase Polymerase Chain Reaction; Synovial Membrane; Synoviocytes
PubMed: 33034147
DOI: 10.1002/art.41552 -
Nature Aug 2019Macrophages are considered to contribute to chronic inflammatory diseases such as rheumatoid arthritis. However, both the exact origin and the role of macrophages in...
Macrophages are considered to contribute to chronic inflammatory diseases such as rheumatoid arthritis. However, both the exact origin and the role of macrophages in inflammatory joint disease remain unclear. Here we use fate-mapping approaches in conjunction with three-dimensional light-sheet fluorescence microscopy and single-cell RNA sequencing to perform a comprehensive spatiotemporal analysis of the composition, origin and differentiation of subsets of macrophages within healthy and inflamed joints, and study the roles of these macrophages during arthritis. We find that dynamic membrane-like structures, consisting of a distinct population of CXCR1 tissue-resident macrophages, form an internal immunological barrier at the synovial lining and physically seclude the joint. These barrier-forming macrophages display features that are otherwise typical of epithelial cells, and maintain their numbers through a pool of locally proliferating CXCR1 mononuclear cells that are embedded into the synovial tissue. Unlike recruited monocyte-derived macrophages, which actively contribute to joint inflammation, these epithelial-like CXCR1 lining macrophages restrict the inflammatory reaction by providing a tight-junction-mediated shield for intra-articular structures. Our data reveal an unexpected functional diversification among synovial macrophages and have important implications for the general role of macrophages in health and disease.
Topics: Animals; Arthritis; CX3C Chemokine Receptor 1; Cell Tracking; Female; Gene Expression Profiling; Humans; Inflammation; Joints; Macrophages; Male; Mice; Mice, Inbred C57BL; Principal Component Analysis; RNA-Seq; Single-Cell Analysis; Synovial Membrane; Synoviocytes; Tight Junctions; Transcriptome
PubMed: 31391580
DOI: 10.1038/s41586-019-1471-1 -
Cell Death & Disease Feb 2020Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial hyperplasia, pannus formation, and cartilage and bone destruction. Nuclear receptor...
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial hyperplasia, pannus formation, and cartilage and bone destruction. Nuclear receptor subfamily 1 group D member 1 (NR1D1) functions as a transcriptional repressor and plays a vital role in inflammatory reactions. However, whether NR1D1 is involved in synovial inflammation and joint destruction during the pathogenesis of RA is unknown. In this study, we found that NR1D1 expression was increased in synovial tissues from patients with RA and decreased in RA Fibroblast-like synoviocytes (FLSs) stimulated with IL-1β in vitro. We showed that NR1D1 activation decreased the expression of proinflammatory cytokines and matrix metalloproteinases (MMPs), while NR1D1 silencing exerted the opposite effect. Furthermore, NR1D1 activation reduced reactive oxygen species (ROS) generation and increased the production of nuclear transcription factor E2-related factor 2 (Nrf2)-associated enzymes. Mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) pathways were blocked by the NR1D1 agonist SR9009 but activated by NR1D1 silencing. NR1D1 activation also inhibited M1 macrophage polarization and suppressed osteoclastogenesis and osteoclast-related genes expression. Treatment with NR1D1 agonist SR9009 in collagen-induced arthritis (CIA) mouse significantly suppressed the hyperplasia of synovial, infiltration of inflammatory cell and destruction of cartilage and bone. Our findings demonstrate an important role for NR1D1 in RA and suggest its therapeutic potential.
Topics: Animals; Antirheumatic Agents; Arthritis, Experimental; Arthritis, Rheumatoid; Bone Remodeling; Case-Control Studies; Cells, Cultured; Humans; Inflammation Mediators; Knee Joint; Male; Matrix Metalloproteinases; Mice, Inbred DBA; Nuclear Receptor Subfamily 1, Group D, Member 1; Pyrrolidines; Reactive Oxygen Species; Signal Transduction; Synovial Membrane; Synoviocytes; Synovitis; Thiophenes
PubMed: 32071294
DOI: 10.1038/s41419-020-2314-6 -
Frontiers in Immunology 2021Rheumatoid arthritis (RA) is a chronic prototypic immune-mediated inflammatory disease which is characterized by persistent synovial inflammation, leading to progressive... (Review)
Review
Rheumatoid arthritis (RA) is a chronic prototypic immune-mediated inflammatory disease which is characterized by persistent synovial inflammation, leading to progressive joint destruction. Whilst the introduction of targeted biological drugs has led to a step change in the management of RA, 30-40% of patients do not respond adequately to these treatments, regardless of the mechanism of action of the drug used (ceiling of therapeutic response). In addition, many patients who acheive clinical remission, quickly relapse following the withdrawal of treatment. These observations suggest the existence of additional pathways of disease persistence that remain to be identified and targeted therapeutically. A major barrier for the identification of therapeutic targets and successful clinical translation is the limited understanding of the cellular mechanisms that operate within the synovial microenvironment to sustain joint inflammation. Recent insights into the heterogeneity of tissue resident synovial cells, including macropahges and fibroblasts has revealed distinct subsets of these cells that differentially regulate specific aspects of inflammatory joint pathology, paving the way for targeted interventions to specifically modulate the behaviour of these cells. In this review, we will discuss the phenotypic and functional heterogeneity of tissue resident synovial cells and how this cellular diversity contributes to joint inflammation. We discuss how critical interactions between tissue resident cell types regulate the disease state by establishing critical cellular checkpoints within the synovium designed to suppress inflammation and restore joint homeostasis. We propose that failure of these cellular checkpoints leads to the emergence of imprinted pathogenic fibroblast cell states that drive the persistence of joint inflammation. Finally, we discuss therapeutic strategies that could be employed to specifically target pathogenic subsets of fibroblasts in RA.
Topics: Animals; Arthritis; Arthritis, Rheumatoid; Biomarkers; Cell Communication; Disease Susceptibility; Fibroblasts; Gene Expression Regulation; Humans; Macrophages; Receptors, Notch; Recurrence; Signal Transduction; Synovial Membrane; Synoviocytes
PubMed: 34539648
DOI: 10.3389/fimmu.2021.715894 -
Cell Death & Disease Dec 2022Fibroblast-like synoviocytes (FLSs), play a key role in perpetuating synovial inflammation and bone erosion in rheumatoid arthritis (RA), however, the underlying...
Fibroblast-like synoviocytes (FLSs), play a key role in perpetuating synovial inflammation and bone erosion in rheumatoid arthritis (RA), however, the underlying mechanism(s) of RA FLSs activation and aggression remain unclear. Identifying endogenous proteins that selectively target FLSs is urgently needed. Here, we systematically identified that secreted modular calcium-binding protein 2 (SMOC2), was significantly increased in RA FLSs and synovial tissues. SMOC2 knockdown specifically regulated cytoskeleton remodeling and decreased the migration and invasion of RA FLSs. Mechanistically, cytoskeleton-related genes were significantly downregulated in RA FLSs with reduced SMOC2 expression, especially the motor protein myosin1c (MYO1C). SMOC2 controlled MYO1C expression by SRY-related high-mobility group box 4 (SOX4) and AlkB homolog 5 (ALKHB5) mediated-mA modification through transcriptional and post-transcriptional regulation. Furthermore, intra-articular Ad-shRNA-SMOC2 treatment attenuated synovial inflammation as well as bone and cartilage erosion in rats with collagen-induced arthritis (CIA). Our findings suggest that increased SMOC2 expression in FLSs may contribute to synovial aggression and joint destruction in RA. SMOC2 may serve as a potential target against RA. SMOC2-mediated regulation of the synovial migration and invasion in RA FLSs. In RA FLSs, SMOC2 is significantly increased, leading to the increased level of MYO1C via SOX4-mediated transcriptional regulation and ALKBH5-mediated mA modification, thereby causing cytoskeleton remodeling and promoting RA FLSs migration and invasion. The Figure was drawn by Figdraw.
Topics: Rats; Animals; Synoviocytes; Cells, Cultured; Signal Transduction; Arthritis, Rheumatoid; Fibroblasts; Cell Movement; Inflammation; Aggression; Cell Proliferation
PubMed: 36513634
DOI: 10.1038/s41419-022-05479-0 -
Arthritis Research & Therapy Jun 2019Anti-malarial drug artesunate can suppress inflammation and prevent cartilage and bone destruction in collagen-induced arthritis model in rats-suggesting it may be a...
INTRODUCTION
Anti-malarial drug artesunate can suppress inflammation and prevent cartilage and bone destruction in collagen-induced arthritis model in rats-suggesting it may be a potent drug for rheumatoid arthritis (RA) therapy. We aimed to investigate its effect on the invasive property of fibroblast-like synoviocytes (FLS) from patients with RA.
METHODS
Synovial tissues were obtained by closed needle biopsy from active RA patients, and FLS were isolated and cultured in vitro. RA-FLS were treated with artesunate at various concentrations, while methotrexate or hydroxychloroquine was employed as comparator drugs. Cell viability, proliferation, cell cycle, apoptosis, migration, invasion, and pseudopodium formation of RA-FLS were assessed by CCK-8 assays, EdU staining, Annexin V-FITC/PI staining, transwell assays, or F-actin staining, respectively. Further, relative changes of expressed proteases were analyzed by Proteome profiler human protease array and verified by quantitative real-time PCR (qPCR), Western blot, and ELISA. The expression of signaling molecules of MAPK, NF-κB, AP-1, and PI3K/Akt pathways were measured by qPCR and Western blot. PDK-1 knockdown by specific inhibitor AR-12 or siRNA transfection was used to verify the pharmacological mechanism of artesunate on RA-FLS.
RESULTS
Artesunate significantly inhibited the migration and invasion of RA-FLS in a dose-dependent manner with or without TNF-α stimulation. The effect was mediated through artesunate inhibition of MMP-2 and MMP-9 production, and pre-treatment with exogenous MMP-9 reversed the inhibitory effect of artesunate on RA-FLS invasion. Artesunate had a stronger inhibitory effect on migration and invasion of RA-FLS as well as greater anti-inflammatory effect than those of hydroxychloroquine. Similar inhibitory effect was detected between artesunate and methotrexate, and synergy was observed when combined. Mechanistically, artesunate significantly inhibited PDK-1 expression as well as Akt and RSK2 phosphorylation-in a similar manner to PDK-1-specific inhibitor AR-12 or PDK-1 knockdown by siRNA transfection. This inhibition results in suppression of RA-FLS migration and invasion as well as decreased MMP-2 and MMP-9 expression.
CONCLUSIONS
Our study demonstrates artesunate is capable of inhibiting migration and invasion of RA-FLS through suppression of PDK1-induced activation of Akt and RSK2 phosphorylation-suggesting that artesunate may be a potential disease-modifying anti-rheumatic drug for RA.
Topics: Adult; Antimalarials; Apoptosis; Artesunate; Arthritis, Rheumatoid; Biopsy, Needle; Blotting, Western; Cell Movement; Cell Proliferation; Cells, Cultured; Enzyme-Linked Immunosorbent Assay; Female; Fibroblasts; Humans; Male; Middle Aged; Pyruvate Dehydrogenase Acetyl-Transferring Kinase; Signal Transduction; Synoviocytes; Young Adult
PubMed: 31234900
DOI: 10.1186/s13075-019-1935-6