1 4305 115 MICRORNA-27A-3P ENHANCES THE INFLAMMATORY PHENOTYPE OF JUVENILE IDIOPATHIC ARTHRITIS FIBROBLAST-LIKE SYNOVIOCYTES. BACKGROUND: JUVENILE IDIOPATHIC ARTHRITIS (JIA) IS THE MOST PREVALENT CHRONIC PEDIATRIC RHEUMATIC DISORDER. IN JOINTS OF JIA PATIENTS, AGGRESSIVE PHENOTYPIC CHANGES IN FIBROBLAST-LIKE SYNOVIOCYTES (FLS) OF THE SYNOVIAL LINING PLAY A KEY ROLE IN INFLAMMATION. MICRORNAS ARE DYSREGULATED IN RHEUMATOID ARTHRITIS AND JIA, INCLUDING MIR-27A-3P. HOWEVER, IT IS NOT UNDERSTOOD IF MIR-27A-3P, ENRICHED IN JIA SYNOVIAL FLUID (SF) AND LEUKOCYTES, ALTERS FLS FUNCTION. METHODS: PRIMARY JIA FLS CELLS WERE TRANSFECTED WITH A MIR-27A-3P MIMIC OR A NEGATIVE CONTROL MICRORNA (MIR-NC) AND STIMULATED WITH POOLED JIA SF OR INFLAMMATORY CYTOKINES. VIABILITY AND APOPTOSIS WERE ANALYZED BY FLOW CYTOMETRY. PROLIFERATION WAS EVALUATED USING A (3)H-THYMIDINE INCORPORATION ASSAY. CYTOKINE PRODUCTION WAS ASSESSED BY QPCR AND ELISA. EXPRESSION OF TGF-BETA PATHWAY GENES WAS DETERMINED USING A QPCR ARRAY. RESULTS: MIR-27A-3P WAS CONSTITUTIVELY EXPRESSED IN FLS. OVEREXPRESSION OF MIR-27A-3P CAUSED INCREASED INTERLEUKIN-8 SECRETION IN RESTING FLS, AND INTERLEUKIN-6 WAS ELEVATED IN SF-ACTIVATED FLS COMPARED TO MIR-NC. FURTHERMORE, STIMULATION WITH PRO-INFLAMMATORY CYTOKINES AUGMENTED FLS PROLIFERATION IN MIR-27A-3P-TRANSFECTED FLS RELATIVE TO MIR-NC. EXPRESSION OF MULTIPLE TGF-BETA PATHWAY GENES WAS MODULATED BY OVEREXPRESSION OF MIR-27A-3P. CONCLUSIONS: MIR-27A-3P SIGNIFICANTLY CONTRIBUTES TO FLS PROLIFERATION AND CYTOKINE PRODUCTION, MAKING IT A POTENTIAL CANDIDATE FOR EPIGENETIC THERAPY THAT TARGETS FLS IN ARTHRITIS. 2023 2 5507 23 RHEUMATOID ARTHRITIS PROGRESSION MEDIATED BY ACTIVATED SYNOVIAL FIBROBLASTS. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC INFLAMMATORY DISEASE CHARACTERIZED BY SYNOVIAL HYPERPLASIA AND PROGRESSIVE JOINT DESTRUCTION. RHEUMATOID ARTHRITIS SYNOVIAL FIBROBLASTS (RASFS) ARE LEADING CELLS IN JOINT EROSION AND CONTRIBUTE ACTIVELY TO INFLAMMATION. RASFS SHOW AN ACTIVATED PHENOTYPE THAT IS INDEPENDENT OF THE INFLAMMATORY ENVIRONMENT AND REQUIRES THE COMBINATION OF SEVERAL FACTORS. ALTHOUGH NEW ASPECTS REGARDING RASF ACTIVATION VIA MATRIX DEGRADATION PRODUCTS, EPIGENETIC MODIFICATIONS, INFLAMMATORY FACTORS, TOLL-LIKE RECEPTOR (TLR) ACTIVATION AND OTHERS HAVE RECENTLY BEEN UNCOVERED, THE PRIMARY PATHOPHYSIOLOGICAL PROCESSES IN EARLY ARTHRITIS LEADING TO PERMANENT ACTIVATION ARE MOSTLY UNKNOWN. HERE, WE REVIEW NEW FINDINGS REGARDING RASF ACTIVATION AND THEIR ALTERED BEHAVIOR THAT CONTRIBUTE TO MATRIX DESTRUCTION AND INFLAMMATION AS WELL AS THEIR POTENTIAL TO SPREAD RA. 2010 3 5417 37 REGULATION OF DNA METHYLATION IN RHEUMATOID ARTHRITIS SYNOVIOCYTES. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC INFLAMMATORY DISEASE IN WHICH FIBROBLAST-LIKE SYNOVIOCYTES (FLS) EXHIBIT AN AGGRESSIVE PHENOTYPE. ALTHOUGH THE MECHANISMS RESPONSIBLE ARE NOT WELL DEFINED, EPIGENETIC DETERMINANTS SUCH AS DNA METHYLATION MIGHT CONTRIBUTE. DNA METHYLTRANSFERASES (DNMTS) ARE CRITICAL ENZYMES THAT ESTABLISH AND MAINTAIN DNA METHYLATION. WE EVALUATED WHETHER PROINFLAMMATORY CYTOKINES MIGHT CONTRIBUTE TO DIFFERENTIAL DNA METHYLATION PREVIOUSLY DESCRIBED IN RA FLS THROUGH ALTERED DNMT EXPRESSION. FLS WERE OBTAINED FROM RA AND OSTEOARTHRITIS (OA) SYNOVIUM AT THE TIME OF TOTAL JOINT REPLACEMENT. GENE EXPRESSION WAS DETERMINED BY QUANTITATIVE REAL-TIME PCR AND PROTEIN EXPRESSION BY WESTERN BLOT ANALYSIS. DNMT ACTIVITY WAS MEASURED WITH A FUNCTIONAL ASSAY, AND GLOBAL METHYLATION WAS DETERMINED BY AN IMMUNOASSAY THAT DETECTS METHYLCYTOSINE. RESTING EXPRESSION OF DNMT1, -3A, AND -3B MRNA WERE SIMILAR IN RA AND OA FLS. WESTERN BLOT SHOWED ABUNDANT DNMT1 AND DNMT3A PROTEIN. EXPOSURE TO IL-1 DECREASED DNMT1 AND DNMT3A MRNA EXPRESSION IN FLS. DOSE RESPONSES DEMONSTRATED DECREASED DNMT EXPRESSION AT CONCENTRATIONS AS LOW AS 1 PG/ML OF IL-1. DNMT MRNA LEVELS DECREASED RAPIDLY, WITH SIGNIFICANT SUPPRESSION AFTER 2-8 H OF IL-1 STIMULATION. IL-1 STIMULATION OF OA FLS DID NOT AFFECT METHYLATION OF LINE1 SITES BUT LED TO DEMETHYLATION OF A CHI3L1 LOCUS THAT IS HYPOMETHYLATED IN RA FLS. CHRONIC IL-1 STIMULATION ALSO MIMICKED THE EFFECT OF A DNMT INHIBITOR ON FLS GENE EXPRESSION. EXPOSURE TO PROINFLAMMATORY MEDIATORS REVERSIBLY ALTERS DNA METHYLATION IN FLS BY DECREASING DNMT EXPRESSION AND FUNCTION. THESE DATA SUGGEST THAT IL-1 CAN POTENTIALLY IMPRINT CELLS IN CHRONIC INFLAMMATORY DISEASES. 2013 4 6009 23 THE ANTI-INFLAMMATORY MEDIATOR, VASOACTIVE INTESTINAL PEPTIDE, MODULATES THE DIFFERENTIATION AND FUNCTION OF TH SUBSETS IN RHEUMATOID ARTHRITIS. GENETIC BACKGROUND, EPIGENETIC MODIFICATIONS, AND ENVIRONMENTAL FACTORS TRIGGER AUTOIMMUNE RESPONSE IN RHEUMATOID ARTHRITIS (RA). SEVERAL PATHOGENIC INFECTIONS HAVE BEEN RELATED TO THE ONSET OF RA AND MAY CAUSE AN INADEQUATE IMMUNOLOGICAL TOLERANCE TOWARDS CRITICAL SELF-ANTIGENS LEADING TO CHRONIC JOINT INFLAMMATION AND AN IMBALANCE BETWEEN DIFFERENT T HELPER (TH) SUBSETS. VASOACTIVE INTESTINAL PEPTIDE (VIP) IS A MEDIATOR THAT MODULATES ALL THE STAGES COMPRISED BETWEEN THE ARRIVAL OF PATHOGENS AND TH CELL DIFFERENTIATION IN RA THROUGH ITS KNOWN ANTI-INFLAMMATORY AND IMMUNOMODULATORY ACTIONS. THIS "NEUROIMMUNOPEPTIDE" MODULATES THE PATHOGENIC ACTIVITY OF DIVERSE CELL SUBPOPULATIONS INVOLVED IN RA AS LYMPHOCYTES, FIBROBLAST-LIKE SYNOVIOCYTES (FLS), OR MACROPHAGES. IN ADDITION, VIP DECREASES THE EXPRESSION OF PATTERN RECOGNITION RECEPTOR (PRR) SUCH AS TOLL-LIKE RECEPTORS (TLRS) IN FLS FROM RA PATIENTS. THESE RECEPTORS ACT AS SENSORS OF PATHOGEN-ASSOCIATED MOLECULAR PATTERN (PAMP) AND DAMAGE-ASSOCIATED MOLECULAR PATTERN (DAMP) CONNECTING THE INNATE AND ADAPTIVE IMMUNE SYSTEM. MOREOVER, VIP MODULATES THE IMBALANCE BETWEEN TH SUBSETS IN RA, DECREASING PATHOGENIC TH1 AND TH17 SUBSETS AND FAVORING TH2 OR TREG PROFILE DURING THE DIFFERENTIATION/POLARIZATION OF NAIVE OR MEMORY TH CELLS. FINALLY, VIP REGULATES THE PLASTICITY BETWEEN THESES SUBSETS. IN THIS REVIEW, WE PROVIDE AN OVERVIEW OF VIP EFFECTS ON THE AFOREMENTIONED FEATURES OF RA PATHOLOGY. 2018 5 4162 32 MECP2 REGULATES PTCH1 EXPRESSION THROUGH DNA METHYLATION IN RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC AUTOIMMUNE INFLAMMATORY DISEASE, IN WHICH PATHOGENESIS IS NOT CLEAR. MANY RESEARCH DEMONSTRATED THAT FIBROBLAST-LIKE SYNOVIOCYTES (FLSS) PLAY A KEY ROLE IN RA PATHOGENESIS, JOIN IN THE CARTILAGE INJURY AND HYPERPLASIA OF THE SYNOVIUM, AND CONTRIBUTE TO THE RELEASE OF INFLAMMATORY CYTOKINES. WE USED ADJUVANT ARTHRITIS (AA) RATS AS RA ANIMAL MODELS. THE METHYL-CPG-BINDING PROTEIN 2 (MECP2) ENABLES THE SUPPRESSED CHROMATIN STRUCTURE TO BE SELECTIVELY DETECTED IN AA FLSS. OVEREXPRESSION OF THIS PROTEIN LEADS TO AN INCREASE OF INTEGRAL METHYLATION LEVELS. SOME RESEARCH HAS CONFIRMED THE HEDGEHOG (HH) SIGNALING PATHWAY PLAYS AN IMPORTANT ROLE IN RA PATHOGENESIS; FURTHERMORE, PATCHED 1 (PTCH1) IS A NEGATIVE FRACTION OF HH SIGNALING PATHWAY. WE USED 5-AZA-2'-DEOXYCYTIDINE (5-AZADC) AS DNA METHYLATION INHIBITOR. IN OUR RESEARCH, WE FOUND MECP2 REDUCED PTCH1 EXPRESSION IN AA FLSS; 5-AZADC OBSTRUCTED THE LOSS OF PTCH1 EXPRESSION. 5-AZADC, TREATMENT OF AA FLSS, ALSO BLOCKS THE RELEASE OF INFLAMMATORY CYTOKINES. IN ORDER TO PROBE THE POTENTIAL MOLECULAR MECHANISM, WE ASSUMED THE EPIGENETIC PARTICIPATION IN THE REGULATION OF PTCH1. RESULTS DEMONSTRATED THAT PTCH1 HYPERMETHYLATION IS RELATED TO THE PERSISTENT FLS ACTIVATION AND INFLAMMATION IN AA RATS. KNOCKDOWN OF MECP2 USING SMALL-INTERFERING RNA TECHNIQUE ADDED PTCH1 EXPRESSION IN AA FLSS. OUR RESULTS INDICATE THAT DNA METHYLATION MAY OFFER MOLECULE MECHANISMS, AND THE REDUCED PTCH1 METHYLATION LEVEL COULD REGULATE INFLAMMATION THROUGH KNOCKDOWN OF MECP2. GRAPHICAL ABSTRACT PTCH1 IS AN INHIBITORY PROTEIN OF THE HEDGEHOG SIGNALING PATHWAY. INCREASED EXPRESSION OF PTCH1 CAN INHIBIT THE EXPRESSION OF GLI1 AND SHH, THEREBY INHIBITING THE ACTIVATION OF HEDGEHOG SIGNALING PATHWAY. INACTIVATED HEDGEHOG SIGNALING PATHWAY INHIBITS THE SECRETION OF IL-6 AND TNF-ALPHA. MECP2 MEDIATES HYPERMETHYLATION OF PTCH1 GENE AND DECREASES THE EXPRESSION OF PTCH1 PROTEIN, THUS ACTIVATING HEDGEHOG SIGNALING PATHWAY AND INCREASING SECRETION OF IL-6 AND TNF-ALPHA. 2017 6 6741 22 WHERE TO STAND WITH STROMAL CELLS AND CHRONIC SYNOVITIS IN RHEUMATOID ARTHRITIS? 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. 2019 7 2384 31 EPIGENETIC REGULATOR UHRF1 ORCHESTRATES PROINFLAMMATORY GENE EXPRESSION IN RHEUMATOID ARTHRITIS IN A SUPPRESSIVE MANNER. RHEUMATOID ARTHRITIS (RA) IS CHARACTERIZED BY CHRONIC SYNOVIAL INFLAMMATION WITH ABERRANT EPIGENETIC ALTERATIONS, EVENTUALLY LEADING TO JOINT DESTRUCTION. HOWEVER, THE EPIGENETIC REGULATORY MECHANISMS UNDERLYING RA PATHOGENESIS REMAIN LARGELY UNKNOWN. HERE, WE SHOWED THAT UBIQUITIN-LIKE CONTAINING PHD AND RING FINGER DOMAINS 1 (UHRF1) IS A CENTRAL EPIGENETIC REGULATOR THAT ORCHESTRATES MULTIPLE PATHOGENESES IN RA IN A SUPPRESSIVE MANNER. UHRF1 EXPRESSION WAS REMARKABLY UPREGULATED IN SYNOVIAL FIBROBLASTS (SFS) FROM ARTHRITIS MODEL MICE AND PATIENTS WITH RA. MICE WITH SF-SPECIFIC UHRF1 CONDITIONAL KNOCKOUT SHOWED MORE SEVERE ARTHRITIC PHENOTYPES THAN LITTERMATE CONTROLS. UHRF1-DEFICIENT SFS ALSO EXHIBITED ENHANCED APOPTOSIS RESISTANCE AND UPREGULATED EXPRESSION OF SEVERAL CYTOKINES, INCLUDING CCL20. IN PATIENTS WITH RA, DAS28, CRP, AND TH17 ACCUMULATION AND APOPTOSIS RESISTANCE WERE NEGATIVELY CORRELATED WITH UHRF1 EXPRESSION IN SYNOVIUM. FINALLY, RYUVIDINE ADMINISTRATION STABILIZED UHRF1 AMELIORATED ARTHRITIS PATHOGENESES IN A MOUSE MODEL OF RA. THIS STUDY DEMONSTRATED THAT UHRF1 EXPRESSED IN RA SFS CAN CONTRIBUTE TO NEGATIVE FEEDBACK MECHANISMS THAT SUPPRESS MULTIPLE PATHOGENIC EVENTS IN ARTHRITIS, SUGGESTING THAT TARGETING UHRF1 COULD BE ONE OF THE THERAPEUTIC STRATEGIES FOR RA. 2022 8 6245 31 THE MECHANISMS UNDERLYING CHRONIC INFLAMMATION IN RHEUMATOID ARTHRITIS FROM THE PERSPECTIVE OF THE EPIGENETIC LANDSCAPE. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC INFLAMMATORY AUTOIMMUNE DISEASE THAT IS CHARACTERIZED BY SYNOVIAL HYPERPLASIA AND PROGRESSIVE JOINT DESTRUCTION. THE ACTIVATION OF RA SYNOVIAL FIBROBLASTS (SFS), ALSO CALLED FIBROBLAST-LIKE SYNOVIOCYTES (FLS), CONTRIBUTES SIGNIFICANTLY TO PERPETUATION OF THE DISEASE. GENETIC AND ENVIRONMENTAL FACTORS HAVE BEEN REPORTED TO BE INVOLVED IN THE ETIOLOGY OF RA BUT ARE INSUFFICIENT TO EXPLAIN IT. IN RECENT YEARS, ACCUMULATING RESULTS HAVE SHOWN THE POTENTIAL ROLE OF EPIGENETIC MECHANISMS, INCLUDING HISTONE MODIFICATIONS, DNA METHYLATION, AND MICRORNAS, IN THE DEVELOPMENT OF RA. EPIGENETIC MECHANISMS REGULATE CHROMATIN STATE AND GENE TRANSCRIPTION WITHOUT ANY CHANGE IN DNA SEQUENCE, RESULTING IN THE ALTERATION OF PHENOTYPES IN SEVERAL CELL TYPES, ESPECIALLY RASFS. EPIGENETIC CHANGES POSSIBLY PROVIDE RASFS WITH AN ACTIVATED PHENOTYPE. IN THIS PAPER, WE REVIEW THE ROLES OF EPIGENETIC MECHANISMS RELEVANT FOR THE PROGRESSION OF RA. 2016 9 4412 28 MOLECULAR AND CELLULAR BASIS OF RHEUMATOID JOINT DESTRUCTION. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC INFLAMMATORY DISEASE ASSOCIATED WITH JOINT DESTRUCTION. SYNOVIAL FIBROBLASTS ARE KEY PLAYERS IN THIS PATHOLOGICAL PROCESS. THEY FAVORISE A PRO-INFLAMMATORY ENVIRONMENT IN THE SYNOVIAL TISSUE, INTERACT WITH THE IMMUNE SYSTEM AND REGULATE THE DIFFERENTIATION OF MONOCYTES INTO OSTEOCLASTS. SYNOVIAL HYPERPLASIA IS ANOTHER CHARACTERISTIC OF RA, REFLECTING NOT ONLY AN IMBALANCE BETWEEN PROLIFERATION AND APOPTOSIS, BUT ALSO THE MIGRATION OF CELLS INTO THE SYNOVIAL TISSUE. GENE TRANSFER EXPERIMENTS HAVE BEEN USED AS IMPORTANT TOOLS FOR THE UNDERSTANDING OF MOLECULAR AND CELLULAR CHANGES THAT CHARACTERIZE THE ACTIVATED RA SYNOVIAL FIBROBLASTS. ACTIVATED SYNOVIAL FIBROBLASTS CAN INVADE CARTILAGE AND BONE. SYNOVIAL ACTIVATION IS DRIVEN BY CYTOKINES, SUCH AS TNFALPHA AND IL-1, AS WELL AS IL-15, 16, 17, 18, 22, 23, BUT ALSO BY CYTOKINE-INDEPENDENT MECHANISMS THAT INVOLVE THE INNATE IMMUNE SYSTEM (I.E. TLRS), A UNIQUE COMMUNICATION NETWORK OF MICROPARTICLES AND EPIGENETIC CHANGES (E.G. L1 RETROELEMENTS). 2006 10 2221 26 EPIGENETIC MODIFICATIONS IN RHEUMATOID ARTHRITIS, A REVIEW. RHEUMATOID ARTHRITIS IS AN AUTOIMMUNE DISEASE CHARACTERIZED BY CHRONIC JOINT INFLAMMATION AND PROGRESSIVE DESTRUCTION OF CARTILAGE AND BONE WHICH LEADS TO ULTIMATELY LOSS OF FUNCTION AND PAIN. ACTIVATED SYNOVIAL FIBROBLASTS ARE KEY EFFECTOR CELLS IN THE PATHOGENESIS OF RHEUMATOID ARTHRITIS. IN THE RECENT YEARS, EPIGENETIC CHANGES INCLUDING DNA METHYLATION, HISTONE ACETYLATION AND OTHER HISTONE MODIFICATIONS WERE IDENTIFIED THAT ARE ASSOCIATED WITH AN INTRINSIC ACTIVATION AND THE AGGRESSIVE PHENOTYPE OF THESE CELLS. SO FAR, NO THERAPIES TARGETING RHEUMATOID ARTHRITIS SYNOVIAL FIBROBLASTS EXIST. THIS REVIEW COMPRISES RECENT RESEARCH EFFORTS THAT PROPOSE EPIGENETIC MECHANISMS BEHIND THE ACTIVATION OF RHEUMATOID ARTHRITIS SYNOVIAL FIBROBLASTS AND OTHER CELL TYPES. 2013 11 3789 30 INTERLEUKIN 17 CONTRIBUTES TO THE CHRONICITY OF INFLAMMATORY DISEASES SUCH AS RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC INFLAMMATORY DISEASE LEADING TO JOINT DESTRUCTION AND BONE RESORPTION. THE PROINFLAMMATORY CYTOKINE INTERLEUKIN 17 (IL-17), PRIMARILY PRODUCED BY TH17 CELLS, HAS BEEN SHOWN TO BE INVOLVED IN ALL STAGES OF THE DISEASE AND TO BE AN IMPORTANT CONTRIBUTOR OF RA CHRONICITY. THREE MAJOR PROCESSES DRIVE THE IL-17-MEDIATED CHRONICITY. SEVERAL EPIGENETIC EVENTS, ENHANCED IN RA PATIENTS, LEAD TO THE INCREASED PRODUCTION OF IL-17 BY TH17 CELLS. IL-17 THEN INDUCES THE PRODUCTION OF SEVERAL INFLAMMATORY MEDIATORS IN THE DISEASED SYNOVIUM, WHICH ARE FURTHER SYNERGISTICALLY ENHANCED VIA COMBINATIONS OF IL-17 WITH OTHER CYTOKINES. IL-17 ALSO PROMOTES THE SURVIVAL OF BOTH THE SYNOVIOCYTES AND INFLAMMATORY CELLS AND PROMOTES THE MATURATION OF THESE IMMUNE CELLS. THIS LEADS TO AN INCREASED NUMBER OF SYNOVIOCYTES AND INFLAMMATORY CELLS IN THE SYNOVIAL FLUID AND IN THE SYNOVIUM LEADING TO THE HYPERPLASIA AND EXACERBATED INFLAMMATION OBSERVED IN JOINTS OF RA PATIENTS. FURTHERMORE, THESE IL-17-DRIVEN EVENTS INITIATE SEVERAL FEEDBACK-LOOP MECHANISMS LEADING TO INCREASED EXPANSION OF TH17 CELLS AND THEREBY INCREASED PRODUCTION OF IL-17. IN THIS REVIEW, WE AIM TO DEPICT A COMPLETE PICTURE OF THE IL-17-DRIVEN VICIOUS CIRCLE LEADING TO RA CHRONICITY AND TO PINPOINT THE KEY ASPECTS THAT REQUIRE FURTHER EXPLORATION. 2014 12 4684 30 NEW POTENTIAL THERAPEUTIC APPROACHES TARGETING SYNOVIAL FIBROBLASTS IN RHEUMATOID ARTHRITIS. SYNOVIAL CELLS PLAY A KEY ROLE IN JOINT DESTRUCTION DURING CHRONIC INFLAMMATION. IN PARTICULAR, ACTIVATED SYNOVIAL FIBROBLASTS (SFS) UNDERGO INTRINSIC ALTERATIONS LEADING TO AN AGGRESSIVE PHENOTYPE MEDIATING CARTILAGE DESTRUCTION AND BONE EROSION IN RHEUMATOID ARTHRITIS (RA). RECENT RESEARCH HAS REVEALED A NUMBER OF TARGETS TO CONTROL ARTHRITOGENIC CHANGES IN SFS. THEREFORE, IDENTIFICATION OF SF PHENOTYPES, CONTROL OF EPIGENETIC CHANGES, MODULATION OF CELLULAR FUNCTIONS, OR REGULATION OF THE ACTIVITY OF CATION CHANNELS AND DIFFERENT SIGNALING PATHWAYS HAS BEEN INVESTIGATED. ALTHOUGH MANY OF THESE APPROACHES HAVE SHOWN EFFICACY IN VITRO AND IN ANIMAL MODELS OF RA, FURTHER RESEARCH IS NEEDED TO SELECT THE MOST RELEVANT TARGETS FOR DRUG DEVELOPMENT. THIS REVIEW IS FOCUSED ON THE ROLE OF SFS AS A POTENTIAL STRATEGY TO DISCOVER NOVEL THERAPEUTIC TARGETS IN RA AIMED AT PRESERVING JOINT ARCHITECTURE AND FUNCTION. 2021 13 6110 27 THE EPIGENETIC ALTERATION OF SYNOVIAL CELL GENE EXPRESSION IN RHEUMATOID ARTHRITIS AND THE ROLES OF NUCLEAR FACTOR KAPPAB AND NOTCH SIGNALING PATHWAYS. RHEUMATOID ARTHRITIS (RA) IS A COMPLEX PROCESS OF CHRONIC AND PROGRESSIVE INFLAMMATION ASSOCIATED WITH ACTIVATION OF NUMEROUS SIGNALING MOLECULES AND TRANSCRIPTION FACTORS AND HYPERPROLIFERATION OF SYNOVIOCYTES OF THE AFFECTED JOINTS, ALTHOUGH THE GREATER PART OF ITS PATHOPHYSIOLOGICAL PROCESS IS EXPLAINED BY ACTIVATION OF NUCLEAR FACTOR KAPPAB (NF-KAPPAB). FOR EXAMPLE, THE SELF-PERPETUATING NATURE OF THE RHEUMATOID INFLAMMATION IS ASCRIBABLE TO OVEREXPRESSION OF THE PROINFLAMMATORY CYTOKINES TUMOR NECROSIS FACTOR ALPHA AND INTERLEUKIN-1BETA, KNOWN TO ELICIT THE ACTIVATION CASCADE FOR NF-KAPPAB AND ACTIVATOR PROTEIN-1 THAT ARE RESPONSIBLE FOR TRANSCRIPTIONAL INDUCTION OF THESE CYTOKINES AMONG OTHER TARGET GENES, WHICH CONFORM A POSITIVE FEEDBACK LOOP FOR CONTINUATION AND EXPANSION OF THE INFLAMMATORY RESPONSES. IN ADDITION, COMPARATIVE GENE EXPRESSION PROFILE ANALYSES HAVE REVEALED ACTIVATION OF A NUMBER OF GENES THAT EXPLAIN THE "TRANSFORMED-LIKE" PHENOTYPE OF SYNOVIOCYTES. AMONG THE GENES EXPRESSED IN RHEUMATOID SYNOVIOCYTES UPON INFLAMMATORY STIMULI, INDUCTION OF GENE EXPRESSION OF NOTCH PROTEINS AND ITS LIGAND HAVE BEEN FOUND. POSSIBLE ROLES OF NOTCH SIGNALING IN RA SYNOVIOCYTES ARE DISCUSSED. 2005 14 2557 35 EPIGENETICS IN RHEUMATOID ARTHRITIS; FIBROBLAST-LIKE SYNOVIOCYTES AS AN EMERGING PARADIGM IN THE PATHOGENESIS OF THE DISEASE. RHEUMATOID ARTHRITIS (RA) IS CHARACTERIZED BY IMMUNE DYSFUNCTIONS AND CHRONIC INFLAMMATION THAT MAINLY AFFECTS DIARTHRODIAL JOINTS. GENETICS HAS LONG BEEN SURVEYED IN SEARCHING FOR THE ETIOPATHOGENESIS OF THE DISEASE AND PARTIALLY CLARIFIED THE CONUNDRUMS WITHIN THIS CONTEXT. EPIGENETIC ALTERATIONS, SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS, AND NONCODING RNAS, WHICH HAVE BEEN CONSIDERED TO BE INVOLVED IN RA PATHOGENESIS, LIKELY EXPLAIN THE NONGENETIC RISK FACTORS. EPIGENETIC MODIFICATIONS MAY INFLUENCE RA THROUGH FIBROBLAST-LIKE SYNOVIOCYTES (FLSS). IT HAS BEEN SHOWN THAT FLSS PLAY AN ESSENTIAL ROLE IN THE ONSET AND EXACERBATION OF RA, AND THEREFORE, THEY MAY ILLUSTRATE SOME ASPECTS OF RA PATHOGENESIS. THESE CELLS EXHIBIT A UNIQUE DNA METHYLATION PROFILE IN THE EARLY STAGE OF THE DISEASE THAT CHANGES WITH DISEASE PROGRESSION. HISTONE ACETYLATION PROFILE IN RA FLSS IS DISRUPTED THROUGH THE IMBALANCE OF HISTONE ACETYLTRANSFERASES AND HISTONE DEACETYLASE ACTIVITY. FURTHERMORE, DYSREGULATION OF MICRORNAS (MIRNAS) IS IMMENSE. MOST OF THESE MIRNAS HAVE SHOWN AN ABERRANT EXPRESSION IN FLSS THAT ARE INVOLVED IN PROLIFERATION AND CYTOKINE PRODUCTION. BESIDES, DYSREGULATION OF LONG NONCODING RNAS IN FLSS HAS BEEN REVEALED AND ATTRIBUTED TO RA PATHOGENESIS. FURTHER INVESTIGATIONS ARE NEEDED TO GET A BETTER VIEW OF EPIGENETIC ALTERATIONS AND THEIR INTERACTIONS. WE ALSO DISCUSS THE ROLE OF THESE EPIGENETIC ALTERATIONS IN RA PATHOGENESIS AND THEIR THERAPEUTIC POTENTIAL. 2020 15 911 30 CHRONIC EXPOSURE TO TNF REPROGRAMS CELL SIGNALING PATHWAYS IN FIBROBLAST-LIKE SYNOVIOCYTES BY ESTABLISHING LONG-TERM INFLAMMATORY MEMORY. FIBROBLAST-LIKE SYNOVIOCYTES (FLS) PLAY A CRITICAL ROLE IN THE PATHOGENESIS OF RHEUMATOID ARTHRITIS (RA). CHRONIC INFLAMMATION INDUCES TRANSCRIPTOMIC AND EPIGENETIC MODIFICATIONS THAT IMPARTS A PERSISTENT CATABOLIC PHENOTYPE TO THE FLS, DESPITE THEIR DISSOCIATION FROM THE INFLAMMATORY ENVIRONMENT. WE ANALYZED HIGH THROUGHPUT GENE EXPRESSION AND CHROMATIN ACCESSIBILITY DATA FROM HUMAN AND MOUSE FLS FROM OUR AND OTHER STUDIES AVAILABLE ON PUBLIC REPOSITORIES, WITH THE GOAL OF IDENTIFYING THE PERSISTENTLY REPROGRAMMED SIGNALING PATHWAYS DRIVEN BY CHRONIC INFLAMMATION. WE FOUND THAT THE GENE EXPRESSION CHANGES INDUCED BY SHORT-TERM TUMOR NECROSIS FACTOR-ALPHA (TNF) TREATMENT WERE LARGELY SUSTAINED IN THE FLS EXPOSED TO CHRONIC INFLAMMATION. THESE CHANGES THAT INCLUDED BOTH ACTIVATION AND REPRESSION OF GENE EXPRESSION, WERE ACCOMPANIED BY THE REMODELING OF CHROMATIN ACCESSIBILITY. THE SUSTAINED ACTIVATED GENES (SAGS) INCLUDED ESTABLISHED PRO-INFLAMMATORY SIGNALING COMPONENTS KNOWN TO ACT AT MULTIPLE LEVELS OF NF-KAPPAB, STAT AND AP-1 SIGNALING CASCADES. INTERESTINGLY, THE SUSTAINED REPRESSED GENES (SRGS) INCLUDED CRITICAL MEDIATORS AND TARGETS OF THE BMP SIGNALING PATHWAY. WE THUS IDENTIFIED SUSTAINED REPRESSION OF BMP SIGNALING AS A UNIQUE CONSTITUENT OF THE LONG-TERM INFLAMMATORY MEMORY INDUCED BY CHRONIC INFLAMMATION. WE POSTULATE THAT SIMULTANEOUS TARGETING OF THESE ACTIVATED AND REPRESSED SIGNALING PATHWAYS MAY BE NECESSARY TO COMBAT RA PERSISTENCE. 2020 16 4842 28 ONE YEAR IN REVIEW 2017: PATHOGENESIS OF RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC INFLAMMATORY AUTOIMMUNE DISEASE INFLUENCED BY BOTH GENETIC AND ENVIRONMENTAL FACTORS. IT HAS BEEN POSTULATED THAT A HIGH-RISK GENETIC BACKGROUND, IN COMBINATION WITH EPIGENETIC MARKS AND ENVIRONMENTAL EXPOSURES, LEADS TO A CASCADE OF EVENTS INDUCING SYNOVITIS AND CONSEQUENT DESTRUCTIVE ARTHRITIS. THE CLINICAL PICTURE OF JOINT INVOLVEMENT IN RA IS THE RESULT OF CHRONIC INFLAMMATION OF THE SYNOVIUM, CHARACTERISED BY INTERACTIONS OF RESIDENT CELLS SUCH AS FIBROBLAST-LIKE SYNOVIOCYTES (FLS) WITH CELLS OF THE INNATE (E.G. MACROPHAGES, DENDRITIC CELLS, MAST CELLS AND NK CELLS, NEUTROPHILS) AND ADAPTIVE IMMUNE SYSTEM (E.G. B AND T LYMPHOCYTES). CURRENTLY, OUR UNDERSTANDING OF THE ROLE OF INNATE AND ADAPTIVE IMMUNITY IN THE PATHOGENESIS OF RA IS EXPANDING. THE CONCEPT OF HOW IMMUNE RESPONSES CONTRIBUTE TO THE DISEASE HAS DRAMATICALLY EVOLVED OVER THE LAST 50 YEARS. SHEDDING SOME LIGHT ON THE DIFFERENT ASPECTS OF RA PATHOGENESIS WILL HELP TO IDENTIFY NEW TARGETS FOR THE DEVELOPMENT OF DISEASE-MODIFYING THERAPIES. THUS, IN THIS REVIEW WE REPORT NEW INSIGHTS IN RA PATHOGENESIS, RESULTING FROM A LITERATURE RESEARCH DATE PUBLISHED IN THE LAST YEAR. 2017 17 4298 27 MICRORNA-146A GOVERNS FIBROBLAST ACTIVATION AND JOINT PATHOLOGY IN ARTHRITIS. SYNOVIAL FIBROBLASTS ARE KEY CELLS ORCHESTRATING THE INFLAMMATORY RESPONSE IN ARTHRITIS. HERE WE DEMONSTRATE THAT LOSS OF MIR-146A, A KEY EPIGENETIC REGULATOR OF THE INNATE IMMUNE RESPONSE, LEADS TO INCREASED JOINT DESTRUCTION IN A TNF-DRIVEN MODEL OF ARTHRITIS BY SPECIFICALLY REGULATING THE BEHAVIOR OF SYNOVIAL FIBROBLASTS. ABSENCE OF MIR-146A IN SYNOVIAL FIBROBLASTS DISPLAY A HIGHLY DEREGULATED GENE EXPRESSION PATTERN AND ENHANCED PROLIFERATION IN VITRO AND IN VIVO. DEFICIENCY OF MIR-146A INDUCES DEREGULATION OF TUMOR NECROSIS FACTOR (TNF) RECEPTOR ASSOCIATED FACTOR 6 (TRAF6) IN SYNOVIAL FIBROBLASTS, LEADING TO INCREASED PROLIFERATION. IN ADDITION, LOSS OF MIR-146A SHIFTS THE METABOLIC STATE OF FIBROBLASTS TOWARDS GLYCOLYSIS AND AUGMENTS THE ABILITY OF SYNOVIAL FIBROBLASTS TO SUPPORT THE GENERATION OF OSTEOCLASTS BY CONTROLLING THE BALANCE OF OSTEOCLASTOGENIC REGULATORY FACTORS RECEPTOR ACTIVATOR OF NF-KAPPAB LIGAND (RANKL) AND OSTEOPROTEGERIN (OPG). BONE MARROW TRANSPLANTATION EXPERIMENTS CONFIRMED THE IMPORTANCE OF MIR-146A IN THE RADIORESISTANT MESENCHYMAL COMPARTMENT FOR THE CONTROL OF ARTHRITIS SEVERITY, IN PARTICULAR FOR INFLAMMATORY JOINT DESTRUCTION. THIS STUDY THEREFORE IDENTIFIES MICRORNA-146A AS AN IMPORTANT LOCAL EPIGENETIC REGULATOR OF THE INFLAMMATORY RESPONSE IN ARTHRITIS. IT IS A CENTRAL ELEMENT OF AN ANTI-INFLAMMATORY FEEDBACK LOOP IN RESIDENT SYNOVIAL FIBROBLASTS, WHO ARE ORCHESTRATING THE INFLAMMATORY RESPONSE IN CHRONIC ARTHRITIS. MIR-146A RESTRICTS THEIR ACTIVATION, THEREBY PREVENTING EXCESSIVE TISSUE DAMAGE DURING ARTHRITIS. 2017 18 6102 26 THE EMERGING ROLE OF FIBROBLAST-LIKE SYNOVIOCYTES-MEDIATED SYNOVITIS IN OSTEOARTHRITIS: AN UPDATE. OSTEOARTHRITIS (OA), THE MOST UBIQUITOUS DEGENERATIVE DISEASE AFFECTING THE ENTIRE JOINT, IS CHARACTERIZED BY CARTILAGE DEGRADATION AND SYNOVIAL INFLAMMATION. ALTHOUGH THE PATHOGENESIS OF OA REMAINS POORLY UNDERSTOOD, SYNOVIAL INFLAMMATION IS KNOWN TO PLAY AN IMPORTANT ROLE IN OA DEVELOPMENT. HOWEVER, STUDIES ON OA PATHOPHYSIOLOGY HAVE FOCUSED MORE ON CARTILAGE DEGENERATION AND OSTEOPHYTES, RATHER THAN ON THE INFLAMED AND THICKENED SYNOVIUM. FIBROBLAST-LIKE SYNOVIOCYTES (FLS) PRODUCE A SERIES OF PRO-INFLAMMATORY REGULATORS, SUCH AS INFLAMMATORY CYTOKINES, NITRIC OXIDE (NO) AND PROSTAGLANDIN E(2) (PGE(2) ). THESE REGULATORS ARE POSITIVELY ASSOCIATED WITH THE CLINICAL SYMPTOMS OF OA, SUCH AS INFLAMMATORY PAIN, JOINT SWELLING AND DISEASE DEVELOPMENT. A BETTER UNDERSTANDING OF THE INFLAMMATORY IMMUNE RESPONSE IN OA-FLS COULD PROVIDE A NOVEL APPROACH TO COMPREHENSIVE TREATMENT STRATEGIES FOR OA. HERE, WE HAVE SUMMARIZED RECENTLY PUBLISHED LITERATURES REFERRING TO EPIGENETIC MODIFICATIONS, ACTIVATED SIGNALLING PATHWAYS AND INFLAMMATION-ASSOCIATED FACTORS THAT ARE INVOLVED IN OA-FLS-MEDIATED INFLAMMATION. IN ADDITION, THE CURRENT RELATED CLINICAL TRIALS AND FUTURE PERSPECTIVES WERE ALSO SUMMARIZED. 2020 19 3699 25 INFLAMMATORY MEMORIES: IS EPIGENETICS THE MISSING LINK TO PERSISTENT STROMAL CELL ACTIVATION IN RHEUMATOID ARTHRITIS? RHEUMATOID ARTHRITIS (RA) IS A CHRONIC INFLAMMATORY DISEASE LEADING TO JOINT DESTRUCTION. SYNOVIAL FIBROBLASTS ARE RECOGNIZED AS KEY CELLS IN THE PATHOGENESIS OF RA SINCE THEY ATTRACT AND ACTIVATE IMMUNE CELLS AND PRODUCE MATRIX DEGRADING ENZYMES. MOST NOTABLY SYNOVIAL FIBROBLASTS FROM PATIENTS WITH RA ARE STABLY ACTIVATED AND PRODUCE HIGH LEVELS OF DISEASE-PROMOTING MOLECULES WITHOUT FURTHER STIMULATION BY IMMUNE CELLS. ACCUMULATING DATA SUGGEST THAT EPIGENETIC CHANGES IN STROMAL CELL POPULATIONS MIGHT BE CRUCIALLY INVOLVED IN THE PATHOLOGY OF RA AND OTHER CHRONIC INFLAMMATORY DISEASES. IN THE CURRENT REVIEW, WE DISCUSS THE MECHANISMS BY WHICH EPIGENETIC CHANGES MIGHT CAUSE THE STABLE ACTIVATION OF SYNOVIAL FIBROBLASTS IN RA AND HOW CHANGES IN THE EPIGENOME MIGHT ALTER IMMUNE FUNCTION AND INFLAMMATORY RESPONSE AND THEREBY PROMOTE THE DEVELOPMENT OF CHRONIC DISEASES. 2011 20 6218 30 THE JOINT SYNOVIUM: A CRITICAL DETERMINANT OF ARTICULAR CARTILAGE FATE IN INFLAMMATORY JOINT DISEASES. THE SYNOVIUM CONSTITUTES THE ENVELOPE OF ARTICULAR JOINTS AND IS A CRITICAL PROVIDER OF SYNOVIAL FLUID COMPONENTS AND ARTICULAR CARTILAGE NUTRIENTS. ITS INFLAMMATION IS A PREDOMINANT FEATURE AND CAUSE OF JOINT DEGENERATION IN DISEASES AS DIVERSE AS RHEUMATOID, PSORIATIC, JUVENILE AND IDIOPATHIC ARTHRITIS, AND LUPUS, GOUT AND LYME DISEASE. THESE INFLAMMATORY JOINT DISEASES (IJDS) ARE DUE TO A WIDE VARIETY OF GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS THAT TRIGGER, PROMOTE, AND PERPETUATE JOINT DESTABILIZATION. IN SPITE OF THIS VARIETY OF CAUSES, IJDS SHARE MAIN PATHOLOGICAL FEATURES, NAMELY INFLAMMATION OF THE JOINT SYNOVIUM (SYNOVITIS) AND PROGRESSIVE DEGENERATION OF ARTICULAR CARTILAGE. IN ADDITION TO BEING A DRIVING FORCE BEHIND THE DESTRUCTION OF ARTICULAR CARTILAGE IN IJD, SYNOVITIS IS ALSO INCREASINGLY BEING RECOGNIZED AS A SIGNIFICANT CONTRIBUTOR OF ARTICULAR CARTILAGE DEGENERATION IN OSTEOARTHRITIS, A DISEASE PRIMARILY DUE TO AGING- OR TRAUMA-RELATED WEAR AND TEAR OF CARTILAGE SURFACES. IN VIEW OF THIS IMPORTANT ROLE OF THE SYNOVIUM IN DETERMINING THE FATE OF ARTICULAR CARTILAGE, THIS REVIEW FOCUSES ON ITS UNDERLYING MECHANISMS IN THE PATHOLOGY OF IJD. WE ADDRESS THE ROLES OF SYNOVIAL FIBROBLASTS, MACROPHAGES AND ENDOTHELIAL CELLS IN THE MAINTENANCE OF JOINT HEALTH AND IN THE DESTRUCTION OF ARTICULAR CARTILAGE INTEGRITY DURING IJD. MOLECULAR MECHANISMS THAT HAVE BEEN RECENTLY SHOWN TO GOVERN THE PATHOLOGICAL ACTIVITIES OF THE RESIDENT SYNOVIAL CELLS ARE HIGHLIGHTED. FINALLY, ADVANTAGES AND DISADVANTAGES OF TARGETING THESE NEW MOLECULAR MECHANISMS FOR PREVENTING CARTILAGE DEGENERATION DUE TO CHRONIC INFLAMMATION ARE ALSO DISCUSSED. 2017