1 5507 77 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 2 6741 24 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 3 6218 31 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 4 2221 28 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 5 4412 30 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 6 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 7 6245 38 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 8 2384 27 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 9 1257 26 CURRENT TRENDS IN EPIGENETIC, CELLULAR AND MOLECULAR PATHWAYS IN MANAGEMENT OF RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS IS A SYSTEMIC CHRONIC POLYARTICULAR AUTOIMMUNE DISORDER OF JOINTS AND JOINT MEMBRANE MAINLY AFFECTING FEET AND HANDS. THE PATHOLOGICAL MANIFESTATION OF THE DISEASE INCLUDES INFILTRATION OF IMMUNE CELLS, HYPERPLASIA OF THE LINING OF SYNOVIUM, FORMATION OF PANNUS AND BONE AND CARTILAGE DESTRUCTION. IF LEFT UNTREATED, THE APPEARANCE OF SMALL FOCAL NECROSIS, ADHESION OF GRANULATION, AND FORMATION OF FIBROUS TISSUE ON THE SURFACE OF ARTICULAR CARTILAGE IS NOTED. THE DISEASE PRIMARILY AFFECTS NEARLY 1% OF THE POPULATION GLOBALLY, WOMEN BEING MORE AFFECTED THAN MEN WITH A RATIO 2:1 AND CAN INITIATE REGARDLESS OF ANY AGE. THE SYNOVIAL FIBROBLAST IN RHEUMATOID ARTHRITIS INDIVIDUALS EXHIBITS AN AGGRESSIVE PHENOTYPE WHICH UPREGULATES THE MANIFESTATION OF PROTOONCOGENES, ADHESIVE COMPOUNDS, INFLAMMATORY CYTOKINES AND MATRIX-DETERIORATING ENZYMES. APART FROM THE INFLAMMATORY EFFECTS OF CYTOKINES, CHEMOKINES ARE ALSO NOTED TO INDUCE SWELLING AND PAIN IN ARTHRITIC INDIVIDUALS BY RESIDING IN SYNOVIAL MEMBRANE AND FORMING PANNUS. THE CURRENT TREATMENT OF RHEUMATOID ARTHRITIS INCLUDES TREATMENT WITH NON-STEROIDAL ANTI-INFLAMMATORY DRUGS, DISEASE-MODIFYING ANTIRHEUMATIC DRUGS, TREATMENT WITH BIOLOGICS SUCH AS INHIBITORS OF TNF-ALPHA, INTERLEUKINS, PLATELET ACTIVATING FACTOR, ETC. WHICH PROVIDES SIGNIFICANT RELIEF FROM SYMPTOMS AND AIDS IN MANAGEMENT OF THE DISEASE. THE CURRENT REVIEW HIGHLIGHTS THE PATHOGENESIS INVOLVED IN THE ONSET OF RHEUMATOID ARTHRITIS AND ALSO COVERS EPIGENETIC, CELLULAR AND MOLECULAR PARAMETERS ASSOCIATED WITH IT TO AID BETTER AND ADVANCED THERAPEUTIC APPROACHES FOR MANAGEMENT OF THE DEBILITATING DISEASE. 2023 10 3699 28 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 11 2556 25 EPIGENETICS IN RHEUMATOID ARTHRITIS. EPIGENETICS IS A STEADILY GROWING RESEARCH AREA. IN MANY HUMAN DISEASES, ESPECIALLY IN CANCERS, BUT ALSO IN AUTOIMMUNE DISEASES, EPIGENETIC ABERRATIONS HAVE BEEN FOUND. RHEUMATOID ARTHRITIS IS AN AUTOIMMUNE DISEASE CHARACTERIZED BY CHRONIC INFLAMMATION AND DESTRUCTION OF SYNOVIAL JOINTS. EVEN THOUGH THE ETIOLOGY IS NOT YET FULLY UNDERSTOOD, RHEUMATOID ARTHRITIS IS GENERALLY CONSIDERED TO BE CAUSED BY A COMBINATION OF GENETIC PREDISPOSITION, DEREGULATED IMMUNOMODULATION, AND ENVIRONMENTAL INFLUENCES. TO GAIN A BETTER UNDERSTANDING OF THIS DISEASE, RESEARCHERS HAVE BECOME INTERESTED IN STUDYING EPIGENETIC CHANGES IN RHEUMATOID ARTHRITIS. HERE, WE WANT TO REVIEW THE CURRENT KNOWLEDGE ON EPIGENETICS IN RHEUMATOID ARTHRITIS. 2010 12 6102 29 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 13 6657 25 UPREGULATED KAT7 IN SYNOVIAL FIBROBLASTS PROMOTES TH17 CELL DIFFERENTIATION AND INFILTRATION IN RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC AUTOIMMUNE DISEASE INVOLVING MULTIPLE CELLULAR PARTICIPANTS, OF WHICH SYNOVIAL FIBROBLASTS (SFS) ARE TIGHTLY CONNECTED WITH THE DEVELOPMENT AND PROGRESSION OF RA. HERE, WE PROVIDE EVIDENCE CONFIRMING THAT KAT7, AN H4-SPECIFIC HISTONE ACETYLASE, IS UPREGULATED IN SFS OF RA PATIENTS, WHICH IS AT LEAST ATTRIBUTED TO THE STIMULATION BY RA-ASSOCIATED PROINFLAMMATORY CYTOKINES, SUCH AS TNF-ALPHA, IL-1BETA OR IFN-GAMMA. IN ADDITION, KAT7 OVEREXPRESSION IN CULTURED HUMAN FIBROBLAST-LIKE SYNOVIOCYTES (HFLSS) INDUCES IL-6 AND TGF-BETA EXPRESSION THROUGH AN EPIGENETIC MECHANISM, AND IN VITRO T HELPER 17 (TH17) CELL POLARIZATION CULTURED IN THESE SUPERNATANTS SHOWS PROMOTED CELL DIFFERENTIATION. MOREOVER, KAT7 OVEREXPRESSION IN HFLSS INDUCES CCL20 EXPRESSION VIA P44/42 MAPK PATHWAY, WHEREBY PROMOTING TH17 CELL MIGRATION. THESE TWO ACTIVITIES OF KAT7 IN RA SFS INDICATE ITS POTENTIAL ROLES IN ACCELERATING RA PATHOLOGY. OVERALL, THESE RESULTS DEMONSTRATE SOME CONNECTIONS BETWEEN KAT7 UPREGULATED IN RA SFS AND RA PROGRESSION AND PRESENT THE INHIBITION OF KAT7 ACTIVITY AS A NOVEL THERAPEUTIC TARGET FOR INTERFERING RA DISEASE. 2017 14 6328 19 THE ROLE OF CELL ORGANELLES IN RHEUMATOID ARTHRITIS WITH FOCUS ON EXOSOMES. AUTO-IMMUNE DISEASES INVOLVED AT LEAST 25% OF THE POPULATION IN WEALTHY COUNTRIES. SEVERAL FACTORS INCLUDING GENETIC, EPIGENETIC, AND ENVIRONMENTAL ELEMENTS ARE IMPLICATED IN DEVELOPMENT OF RHEUMATOID ARTHRITIS AS AN AUTOIMMUNE DISEASE. AUTOANTIBODIES CAUSE SYNOVIAL INFLAMMATION AND ARTHRITIS, IF LEFT UNTREATED OR BEING UNDER CONTINUAL EXTERNAL STIMULATION, COULD RESULT IN CHRONIC INFLAMMATION, JOINT INJURY, AND DISABILITY. T- AND B-CELLS, SIGNALING MOLECULES, PROINFLAMMATORY MEDIATORS, AND SYNOVIUM-SPECIFIC TARGETS ARE AMONG THE NEW THERAPEUTIC TARGETS. EXOSOMES COULD BE EMPLOYED AS THERAPEUTIC VECTORS IN THE TREATMENT OF AUTOIMMUNE DISEASES. HEREIN, THE ROLE OF CELL ORGANELLE PARTICULARLY EXOSOMES IN RHEUMATOID ARTHRITIS HAD DISCUSSED AND SOME THERAPEUTIC APPLICATIONS OF EXOSOME HIGHLIGHTED. 2021 15 2054 40 EPIGENETIC CONTRIBUTIONS IN THE DEVELOPMENT OF RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS (RA) IS AN AUTOIMMUNE DISEASE, CHARACTERIZED BY CHRONIC INFLAMMATION OF THE JOINTS WITH SEVERE PAIN AND SWELLING, JOINT DAMAGE AND DISABILITY, WHICH LEADS TO JOINT DESTRUCTION AND LOSS OF FUNCTION. DESPITE EXTENSIVE RESEARCH EFFORTS, THE UNDERLYING CAUSE FOR RA IS STILL UNKNOWN AND CURRENT THERAPIES ARE MORE OR LESS EFFECTIVE IN CONTROLLING SYMPTOMS BUT STILL FAIL TO CURE THE DISEASE. IN RECENT YEARS, EPIGENETIC MODIFICATIONS WERE FOUND TO STRONGLY CONTRIBUTE TO THE DEVELOPMENT OF RA BY AFFECTING DIVERSE ASPECTS OF THE DISEASE AND MODIFYING GENE EXPRESSION LEVELS AND BEHAVIOR OF SEVERAL CELL TYPES, FIRST AND FOREMOST JOINT RESIDENT SYNOVIAL FIBROBLASTS (SF). RASF ARE THE MOST COMMON CELL TYPE AT THE SITE OF INVASION. OWING TO THEIR AGGRESSIVE, INTRINSICALLY ACTIVATED PHENOTYPE, RASF ARE ACTIVE CONTRIBUTORS IN JOINT DAMAGE. RASF ARE CHARACTERIZED BY THEIR ABILITY TO SECRETE CYTOKINES, CHEMOKINES AND JOINT-DAMAGING ENZYMES. FURTHERMORE, THESE CELLS ARE RESISTANT TO APOPTOSIS, LEADING TO HYPERPLASIA OF THE SYNOVIUM. IN ADDITION, RASF HAVE INVASIVE AND MIGRATORY PROPERTIES THAT COULD LEAD TO SPREADING OF THE DISEASE TO UNAFFECTED JOINTS. EPIGENETIC MODIFICATIONS, INCLUDING DNA METHYLATION AND POST-TRANSLATIONAL HISTONE MODIFICATIONS, SUCH AS HISTONE (DE)ACETYLATION, HISTONE METHYLATION AND HISTONE SUMOYLATION WERE IDENTIFIED AS REGULATORY MECHANISMS IN CONTROLLING AGGRESSIVE CELL ACTIVATION IN VITRO AND IN DISEASE OUTCOME IN ANIMAL MODELS IN VIVO. IN THE LAST 5 YEARS, THE FIELD OF EPIGENETICS IN RA HAS IMPRESSIVELY INCREASED. IN THIS REVIEW WE CONSIDER THE ROLE OF DIVERSE EPIGENETIC MODIFICATIONS IN THE DEVELOPMENT OF RA, WITH A SPECIAL FOCUS ON EPIGENETIC MODIFICATIONS IN RASF. 2012 16 3789 35 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 17 1726 32 DYSREGULATION OF LNCRNAS IN RHEUMATOID ARTHRITIS: BIOMARKERS, PATHOGENESIS AND POTENTIAL THERAPEUTIC TARGETS. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC AUTOIMMUNE DISEASE OF UNKNOWN ETIOLOGY, MAINLY MANIFESTED BY PERSISTENT ABNORMAL PROLIFERATION OF FIBROBLAST-LIKE SYNOVIOCYTES (FLSS), INFLAMMATION, SYNOVIAL HYPERPLASIA AND CARTILAGE EROSION, ACCOMPANIED BY JOINT SWELLING AND JOINT DESTRUCTION. ABNORMAL EXPRESSION OR FUNCTION OF LONG NONCODING RNAS (LNCRNAS) ARE CLOSELY RELATED TO HUMAN DISEASES, INCLUDING CANCERS, MENTAL DISEASES, AUTOIMMUNE DISEASES AND OTHERS. THE ABNORMAL SEQUENCE AND SPATIAL STRUCTURE OF LNCRNAS, THE DISORDER EXPRESSION AND THE ABNORMAL INTERACTION WITH THE BINDING PROTEIN WILL LEAD TO THE CHANGE OF GENE EXPRESSION IN THE WAY OF EPIGENETIC MODIFICATION. INCREASING EVIDENCE DEMONSTRATED THAT LNCRNAS WERE INVOLVED IN THE ACTIVATION OF FLSS, WHICH PLAYED A KEY ROLE IN THE PATHOGENESIS OF RA. IN THIS REVIEW, THE RESEARCH PROGRESS OF LNCRNAS IN THE PATHOGENESIS OF RA WAS SYSTEMATICALLY SUMMARIZED, INCLUDING THE ROLE OF LNCRNAS IN THE DIAGNOSIS OF RA, THE REGULATORY MECHANISM OF LNCRNAS IN THE PATHOGENESIS OF RA, AND THE INTERVENTION ROLE OF LNCRNAS IN THE TREATMENT OF RA. FURTHERMORE, THE ACTIVATED SIGNAL PATHWAYS, THE ROLE OF DNA METHYLATION AND OTHER MECHANISM HAVE ALSO BEEN OVERVIEW IN THIS REVIEW. 2021 18 5265 23 PROMISING THERAPEUTIC TARGETS FOR TREATMENT OF RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS (RA) IS A SYSTEMIC POLY-ARTICULAR CHRONIC AUTOIMMUNE JOINT DISEASE THAT MAINLY DAMAGES THE HANDS AND FEET, WHICH AFFECTS 0.5% TO 1.0% OF THE POPULATION WORLDWIDE. WITH THE SUSTAINED DEVELOPMENT OF DISEASE-MODIFYING ANTIRHEUMATIC DRUGS (DMARDS), SIGNIFICANT SUCCESS HAS BEEN ACHIEVED FOR PREVENTING AND RELIEVING DISEASE ACTIVITY IN RA PATIENTS. UNFORTUNATELY, SOME PATIENTS STILL SHOW LIMITED RESPONSE TO DMARDS, WHICH PUTS FORWARD NEW REQUIREMENTS FOR SPECIAL TARGETS AND NOVEL THERAPIES. UNDERSTANDING THE PATHOGENETIC ROLES OF THE VARIOUS MOLECULES IN RA COULD FACILITATE DISCOVERY OF POTENTIAL THERAPEUTIC TARGETS AND APPROACHES. IN THIS REVIEW, BOTH EXISTING AND EMERGING TARGETS, INCLUDING THE PROTEINS, SMALL MOLECULAR METABOLITES, AND EPIGENETIC REGULATORS RELATED TO RA, ARE DISCUSSED, WITH A FOCUS ON THE MECHANISMS THAT RESULT IN INFLAMMATION AND THE DEVELOPMENT OF NEW DRUGS FOR BLOCKING THE VARIOUS MODULATORS IN RA. 2021 19 4298 29 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 20 6884 26 [RHEUMATOID ARTHRITIS]. RHEUMATOID ARTHRITIS ABSTRACT. RHEUMATOID ARTHRITIS (RA) IS THE MOST FREQUENT CHRONIC INFLAMMATORY JOINT DISEASE WITH A PREVALENCE OF APPROXIMATELY 1% WORLDWIDE. THE PATHOGENESIS IS A COMPLEX INTERPLAY OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS, WHICH ARE STILL INCOMPLETELY UNDERSTOOD. THE DISEASE IS CHARACTERIZED BY A POLYARTICULAR SYNOVITIS WITH SYMMETRICAL INVOLVEMENT OF SMALL AND LARGE JOINTS. THE MAJORITY OF PATIENTS HAS DETECTABLE AUTOANTIBODIES IN THE SERUM, RHEUMATOID FACTOR AND ANTI-CCP ANTIBODIES WHICH ARE SPECIFIC FOR RA. THE UNCONTROLLED CHRONIC JOINT INFLAMMATION RESULTS IN DESTRUCTIVE CHANGES OF JOINT CARTILAGE AND BONE. AN EARLY DIAGNOSIS AND INITIATION OF TREATMENT IS THEREFORE OF CENTRAL IMPORTANCE. DISEASE-MODIFYING ANTI-RHEUMATIC DRUGS (DMARD) ARE ABLE TO INHIBIT JOINT DESTRUCTION AND SHOULD BE STARTED AS SOON AS POSSIBLE. THERAPY SHOULD BE TARGETED TO REACH A STATE OF REMISSION. THE INTRODUCTION OF HIGHLY EFFECTIVE BIOLOGIC AND TARGETED SYNTHETIC DMARD HAS ALLOWED TO REACH THIS GOAL OF THERAPY IN MANY PATIENTS AND TO PREVENT DISABILITY. HOWEVER, RISKS OF MEDICATION NEED TO BE CONSIDERED, AS WELL AS COMORBIDITIES. 2023