1 2384 108 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 2 3924 31 LIPOSOMAL UHRF1 SIRNA SHOWS LUNG FIBROSIS TREATMENT POTENTIAL THROUGH REGULATION OF FIBROBLAST ACTIVATION. PULMONARY FIBROSIS IS A CHRONIC AND PROGRESSIVE INTERSTITIAL LUNG DISEASE ASSOCIATED WITH THE DECAY OF PULMONARY FUNCTION, WHICH LEADS TO A FATAL OUTCOME. AS AN ESSENTIAL EPIGENETIC REGULATOR OF DNA METHYLATION, THE INVOLVEMENT OF UBIQUITIN-LIKE CONTAINING PHD AND RING FINGER DOMAINS 1 (UHRF1) IN FIBROBLAST ACTIVATION REMAINS LARGELY UNDEFINED IN PULMONARY FIBROSIS. IN THE PRESENT STUDY, WE FOUND THAT TGF-BETA1-MEDIATED UPREGULATION OF UHRF1 REPRESSED BECLIN 1 VIA METHYLATED INDUCTION OF ITS PROMOTER, WHICH FINALLY RESULTED IN FIBROBLAST ACTIVATION AND LUNG FIBROSIS BOTH IN VITRO AND IN VIVO. MOREOVER, KNOCKDOWN OF UHRF1 SIGNIFICANTLY ARRESTED FIBROBLAST PROLIFERATION AND REACTIVATED BECLIN 1 IN LUNG FIBROBLASTS. THUS, INTRAVENOUS ADMINISTRATION OF UHRF1 SIRNA-LOADED LIPOSOMES SIGNIFICANTLY PROTECTED MICE AGAINST EXPERIMENTAL PULMONARY FIBROSIS. ACCORDINGLY, OUR DATA SUGGEST THAT UHRF1 MIGHT BE A NOVEL POTENTIAL THERAPEUTIC TARGET IN THE PATHOGENESIS OF PULMONARY FIBROSIS. 2022 3 5695 35 SILENCING UHRF1 ENHANCES CELL AUTOPHAGY TO PREVENT ARTICULAR CHONDROCYTES FROM APOPTOSIS IN OSTEOARTHRITIS THROUGH PI3K/AKT/MTOR SIGNALING PATHWAY. OSTEOARTHRITIS (OA) IS A COMMON CHRONIC DEGENERATIVE JOINT DISEASE, AND CHONDROCYTE APOPTOSIS IS ONE OF MOST IMPORTANT PATHOLOGICAL CHANGES OF OA PATHOGENESIS. GROWING STUDIES HAVE SHOWN THAT UBIQUITIN-LIKE WITH PHD AND RING FINGER DOMAINS 1 (UHRF1) IS AN IMPORTANT EPIGENETIC REGULATORY FACTOR THAT REGULATES CELL PROLIFERATION AND APOPTOSIS OF VARIOUS TUMORS, BUT ITS ROLE IN OA REMAINS ILL-DEFINED. IN THE PRESENT STUDY, WE FOUND THAT UHRF1 EXPRESSION WAS INCREASED IN HUMAN OA CARTILAGE TISSUES, COMPARED WITH NORMAL CARTILAGE TISSUES. INTERLEUKIN-1BETA (IL-1BETA), A MAJOR INFLAMMATORY CYTOKINE THAT PROMOTES CARTILAGE DEGRADATION IN OA, WAS USED TO STIMULATE PRIMARY HUMAN CHONDROCYTES IN VITRO. THE EXPRESSION OF UHRF1 WAS ALSO ENHANCED IN IL-1BETA-INDUCED CHONDROCYTES. MOREOVER, DOWN-REGULATION OF UHRF1 INDUCED AN INCREASE ON CELL PROLIFERATION AND AUTOPHAGY, AND A DECREASE ON APOPTOSIS OF CHONDROCYTES AFTER IL-1BETA TREATMENT. FURTHER DATA INDICATED THAT SILENCING UHRF1 ATTENUATED THE UP-REGULATION OF IL-1BETA ON PHOSPHOINOSITIDE 3-KINASE (PI3K)/PROTEIN KINASE B (AKT)/MAMMALIAN TARGET OF RAPAMYCIN (MTOR) SIGNALING PATHWAY IN CHONDROCYTES. THEN, AN ACTIVATOR OF PI3K WEAKENED THE EFFECT OF UHRF1 SILENCING ON CELL PROLIFERATION, AUTOPHAGY, APOPTOSIS OF IL-1BETA-INDUCED CHONDROCYTES, AND THE CELL AUTOPHAGY SPECIAL INHIBITOR 3-METHYLADENINE (3-MA) ALSO SHOWED A SAME IMPACT ON UHRF1, HENCE SUGGESTING THAT KNOCKDOWN OF UHRF1 ENHANCES CELL AUTOPHAGY TO PROTECT CHONDROCYTES FROM APOPTOSIS IN OA THROUGH PI3K/AKT/MTOR SIGNALING PATHWAY. IN CONCLUSION, OUR STUDY SUGGESTS THAT UHRF1 MAY BE A POTENTIAL REGULATOR OF CHONDROCYTE APOPTOSIS IN THE PATHOGENESIS OF OA. 2020 4 855 30 CHROMATIN ACCESSIBILITY LANDSCAPES OF IMMUNE CELLS IN RHEUMATOID ARTHRITIS NOMINATE MONOCYTES IN DISEASE PATHOGENESIS. BACKGROUND: RHEUMATOID ARTHRITIS (RA) IS A CHRONIC, SYSTEMIC AUTOIMMUNE DISEASE THAT INVOLVES A VARIETY OF CELL TYPES. HOWEVER, HOW THE EPIGENETIC DYSREGULATIONS OF PERIPHERAL IMMUNE CELLS CONTRIBUTE TO THE PATHOGENESIS OF RA STILL REMAINS LARGELY UNCLEAR. RESULTS: HERE, WE ANALYSED THE GENOME-WIDE ACTIVE DNA REGULATORY ELEMENTS OF FOUR MAJOR IMMUNE CELLS, NAMELY MONOCYTES, B CELLS, CD4(+) T CELLS AND CD8(+) T CELLS, IN PERIPHERAL BLOOD OF RA PATIENTS, OSTEOARTHRITIS (OA) PATIENTS AND HEALTHY DONORS USING ASSAY OF TRANSPOSASE ACCESSIBLE CHROMATIN WITH SEQUENCING (ATAC-SEQ). WE FOUND A STRONG RA-ASSOCIATED CHROMATIN DYSREGULATION SIGNATURE IN MONOCYTES, BUT NO OTHER EXAMINED CELL TYPES. MOREOVER, WE FOUND THAT SERUM C-REACTIVE PROTEIN (CRP) CAN INDUCE THE RA-ASSOCIATED CHROMATIN DYSREGULATION IN MONOCYTES VIA IN VITRO EXPERIMENTS. AND THE EXTENT OF THIS DYSREGULATION WAS REGULATED THROUGH THE TRANSCRIPTION FACTOR FRA2. CONCLUSIONS: TOGETHER, OUR STUDY REVEALED A CRP-INDUCED PATHOGENIC CHROMATIN DYSREGULATION SIGNATURE IN MONOCYTES FROM RA PATIENTS AND PREDICTED THE RESPONSIBLE SIGNALLING PATHWAY AS POTENTIAL THERAPEUTIC TARGETS FOR THE DISEASE. 2021 5 911 28 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 6 4412 29 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 7 4298 32 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 8 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 9 4657 30 NEW ADVANCES OF DNA METHYLATION AND HISTONE MODIFICATIONS IN RHEUMATOID ARTHRITIS, WITH SPECIAL EMPHASIS ON MECP2. EPIGENETICS IS A STEADILY GROWING RESEARCH AREA IN MANY HUMAN DISEASES, ESPECIALLY IN AUTOIMMUNE DISEASES SUCH AS RHEUMATOID ARTHRITIS (RA). RA IS AN AUTOIMMUNE DISEASE WITH UNCLEAR ETIOLOGY CHARACTERIZED BY CHRONIC INFLAMMATION AND JOINT DESTRUCTION AND FIBROBLAST-LIKE SYNOVIOCYTES (FLS) DISPLAY A CRUCIAL ROLE IN THE PATHOGENESIS OF RA. EVEN THOUGH THE ETIOLOGY IS NOT YET FULLY UNDERSTOOD, RA IS GENERALLY CONSIDERED TO BE CAUSED BY A COMBINATION OF EPIGENETIC MODIFICATION, DEREGULATED IMMUNOMODULATION, AND ENVIRONMENTAL FACTORS. EPIGENETIC MODIFICATIONS, INCLUDING DNA METHYLATION AND POST-TRANSLATIONAL HISTONE MODIFICATIONS, SUCH AS HISTONE METHYLATION AND HISTONE (DE)ACETYLATION ARE IDENTIFIED AS REGULATORY MECHANISMS IN CONTROLLING AGGRESSIVE FLS ACTIVATION IN PATIENTS AND ANIMAL MODELS. IN THE LAST 3YEARS, THE FIELD OF EPIGENETICS IN RA HAS IMPRESSIVELY INCREASED. METHYL-CPG-BINDING PROTEIN 2 (MECP2) IS FIRST IDENTIFIED AS A TRANSCRIPTIONAL REPRESSOR THAT INHIBITS GENE EXPRESSION THROUGH THE INTERPRETATION OF TWO EPIGENETIC MARKERS, DNA METHYLATION AND HISTONE MODIFICATION. THE COOPERATIVE ACTION AMONG MECP2, DNA METHYLATION AND HISTONE MODIFICATIONS INDICATES THAT MECP2 SHOULD PARTICIPATE IN THE PATHOGENESIS OF RA THROUGH SILENCE OF CERTAIN GENE TRANSCRIPTION. IN THIS REVIEW, WE CONSIDER THE ROLE OF DNA METHYLATION AND HISTONE MODIFICATIONS IN THE DEVELOPMENT OF RA, WITH A SPECIAL FOCUS ON INCREASED MECP2 EXPRESSION IN RA ANIMAL MODELS. 2013 10 4684 27 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 11 6110 25 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 12 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 13 4416 28 MOLECULAR AND CELLULAR PATHWAYS CONTRIBUTING TO JOINT DAMAGE IN RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS IS A CHRONIC AUTOIMMUNE SYNDROME ASSOCIATED WITH SEVERAL GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS AFFECTING THE ARTICULAR JOINTS CONTRIBUTING TO CARTILAGE AND BONE DAMAGE. ALTHOUGH ETIOLOGY OF THIS DISEASE IS NOT CLEAR, SEVERAL IMMUNE PATHWAYS, INVOLVING IMMUNE (T CELLS, B CELLS, DENDRITIC CELLS, MACROPHAGES, AND NEUTROPHILS) AND NONIMMUNE (FIBROBLASTS AND CHONDROCYTES) CELLS, PARTICIPATE IN THE SECRETION OF MANY PROINFLAMMATORY CYTOKINES, CHEMOKINES, PROTEASES (MMPS, ADAMTS), AND OTHER MATRIX LYSING ENZYMES THAT COULD DISTURB THE IMMUNE BALANCE LEADING TO CARTILAGE AND BONE DAMAGE. THE PRESENCE OF AUTOANTIBODIES PRECEDING THE CLINICAL ONSET OF ARTHRITIS AND THE INDUCTION OF BONE EROSION EARLY IN THE DISEASE COURSE CLEARLY SUGGEST THAT INITIATION EVENTS DAMAGING THE CARTILAGE AND BONE START VERY EARLY DURING THE AUTOIMMUNE PHASE OF THE ARTHRITIS DEVELOPMENT. DURING THIS PROCESS, SEVERAL SIGNALING MOLECULES (RANKL-RANK, NF-KAPPAB, MAPK, NFATC1, AND SRC KINASE) ARE ACTIVATED IN THE OSTEOCLASTS, CELLS RESPONSIBLE FOR BONE RESORPTION. HENCE, COMPREHENSIVE KNOWLEDGE ON PATHOGENESIS IS A PREREQUISITE FOR PREVENTION AND DEVELOPMENT OF TARGETED CLINICAL TREATMENT FOR RA PATIENTS THAT CAN RESTORE THE IMMUNE BALANCE IMPROVING CLINICAL THERAPY. 2020 14 5505 24 RHEUMATOID ARTHRITIS AND ALZHEIMER'S DISEASE: GENETIC AND EPIGENETIC LINKS IN INFLAMMATORY REGULATION. CONTROVERSIAL DATA ARE AVAILABLE ABOUT THE RELATIONSHIP BETWEEN ALZHEIMER'S DISEASE (AD) AND RHEUMATOID ARTHRITIS (RA). AN INVERSE RELATIONSHIP BETWEEN AD AND RA, DUE TO DIFFERENT FACTORS, WAS PREVIOUSLY DESCRIBED. SIMILARLY TO RA, AD PATHOGENESIS IS MULTIFACTORIAL AND DIFFERENT FINDINGS SUPPORT THE INFLAMMATORY PATHOGENETIC HYPOTHESIS. SEVERAL INFLAMMATORY MEDIATORS ARE INVOLVED IN THE DISEASE ONSET AND PROGRESSION REGULATED BY GENETIC AND EPIGENETIC MECHANISMS. AMONG THEM, INTELEUKIN-6 (IL-6) AND INTERLEUKIN-1 (IL-1) AS PRO-INFLAMMATORY SOLUBLE FACTORS PRODUCED BY MONOCYTES-MACROPHAGES AND TUMOR NECROSIS FACTOR ALPHA (TNF-ALPHA) PRODUCED BY ACTIVATED MACROPHAGES AND MONONUCLEAR CELLS REPRESENT KEY MOLECULES IN THE INDUCTION AND MAINTENANCE OF CHRONIC INFLAMMATION IN RA. IN PARTICULAR A LINK WITH THE T ALLELE OF THE SNP 3953 T/C IN THE IL-1 GENE AND AN OVEREXPRESSION OF MIR-146A APPEARS TO BE COMMON TO BOTH RA AND AD. IN THIS REVIEW WE WILL DISCUSS THE GENETIC AND EPIGENETIC REGULATION OF THE INFLAMMATORY CASCADE IN RA AND AD TO FIND OUT THE POSSIBLE LINKS BETWEEN RA AND AD ONSET. 2012 15 6611 33 UHRF1 REGULATES GERMINAL CENTER B CELL EXPANSION AND AFFINITY MATURATION TO CONTROL VIRAL INFECTION. THE PRODUCTION OF HIGH-AFFINITY ANTIBODY IS ESSENTIAL FOR PATHOGEN CLEARANCE. ANTIBODY AFFINITY IS INCREASED THROUGH GERMINAL CENTER (GC) AFFINITY MATURATION, WHICH RELIES ON BCR SOMATIC HYPERMUTATION (SHM) FOLLOWED BY ANTIGEN-BASED SELECTION. GC B CELL PROLIFERATION IS ESSENTIALLY INVOLVED IN THESE PROCESSES; IT PROVIDES ENOUGH TEMPLATES FOR SHM AND ALSO SERVES AS A CRITICAL MECHANISM OF POSITIVE SELECTION. IN THIS STUDY, WE SHOW THAT EXPRESSION OF EPIGENETIC REGULATOR UBIQUITIN-LIKE WITH PHD AND RING FINGER DOMAINS 1 (UHRF1) WAS MARKEDLY UP-REGULATED BY C-MYC-AP4 IN GC B CELLS, AND IT WAS REQUIRED FOR GC RESPONSE. UHRF1 REGULATES CELL PROLIFERATION-ASSOCIATED GENES INCLUDING CDKN1A, SLFN1, AND SLFN2 BY DNA METHYLATION, AND ITS DEFICIENCY INHIBITED THE GC B CELL CYCLE AT G1-S PHASE. SUBSEQUENTLY, GC B CELL SHM AND AFFINITY MATURATION WERE IMPAIRED, AND UHRF1 GC B KNOCKOUT MICE WERE UNABLE TO CONTROL CHRONIC VIRUS INFECTION. COLLECTIVELY, OUR DATA SUGGEST THAT UHRF1 REGULATES GC B CELL PROLIFERATION AND AFFINITY MATURATION, AND ITS EXPRESSION IN GC B CELLS IS REQUIRED FOR VIRUS CLEARANCE. 2018 16 5476 27 RESTORING T CELL TOLERANCE, EXPLORING THE POTENTIAL OF HISTONE DEACETYLASE INHIBITORS FOR THE TREATMENT OF JUVENILE IDIOPATHIC ARTHRITIS. JUVENILE IDIOPATHIC ARTHRITIS (JIA) IS CHARACTERIZED BY A LOSS OF IMMUNE TOLERANCE. HERE, THE BALANCE BETWEEN THE ACTIVITY OF EFFECTOR T (TEFF) CELLS AND REGULATORY T (TREG) CELLS IS DISTURBED RESULTING IN CHRONIC INFLAMMATION IN THE JOINTS. PRESENTLY, THERAPEUTIC STRATEGIES ARE PREDOMINANTLY AIMED AT SUPPRESSING IMMUNE ACTIVATION AND PRO-INFLAMMATORY EFFECTOR MECHANISMS, IGNORING THE OPPORTUNITY TO ALSO PROMOTE TOLERANCE BY BOOSTING THE REGULATORY SIDE OF THE IMMUNE BALANCE. HISTONE DEACETYLASES (HDACS) CAN DEACETYLATE BOTH HISTONE AND NON-HISTONE PROTEINS AND HAVE BEEN DEMONSTRATED TO MODULATE EPIGENETIC REGULATION AS WELL AS CELLULAR SIGNALING IN VARIOUS CELL TYPES. IMPORTANTLY, HDACS ARE POTENT REGULATORS OF BOTH TEFF CELL AND TREG CELL FUNCTION AND CAN THUS BE REGARDED AS ATTRACTIVE THERAPEUTIC TARGETS IN CHRONIC INFLAMMATORY ARTHRITIS. HDAC INHIBITORS (HDACI) HAVE PROVEN THERAPEUTIC POTENTIAL IN THE CANCER FIELD, AND ARE PRESENTLY BEING EXPLORED FOR THEIR POTENTIAL IN THE TREATMENT OF AUTOIMMUNE DISEASES. SPECIFIC HDACI HAVE ALREADY BEEN DEMONSTRATED TO REDUCE THE SECRETION OF PRO-INFLAMMATORY CYTOKINES BY TEFF CELLS, AND PROMOTE TREG NUMBERS AND SUPPRESSIVE CAPACITY IN VITRO AND IN VIVO. IN THIS REVIEW, WE OUTLINE THE ROLE OF THE DIFFERENT CLASSES OF HDACS IN BOTH TEFF CELL AND TREG CELL FUNCTION. FURTHERMORE, WE WILL REVIEW THE EFFECT OF DIFFERENT HDACI ON T CELL TOLERANCE AND EXPLORE THEIR POTENTIAL AS A THERAPEUTIC STRATEGY FOR THE TREATMENT OF OLIGOARTICULAR AND POLYARTICULAR JIA. 2019 17 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 18 6741 21 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 19 1989 27 EPIGENETIC ANALYSIS IN RHEUMATOID ARTHRITIS SYNOVIOCYTES. RHEUMATOID ARTHRITIS (RA) IS A COMPLEX CHRONIC SYSTEMATIC DISEASE WITH PROGRESSIVE DESTRUCTION OF THE JOINTS BY INVASIVE SYNOVIOCYTES. TO CHARACTERIZE THE KEY REGULATORS INVOLVED IN THE DEVELOPMENT OF RA, WE OBTAINED MULTILAYER EPIGENOMICS DATA INCLUDING DNA METHYLATION BY WHOLE-GENOME BISULFITE SEQUENCING, MIRNA PROFILES, GENETIC VARIATIONS BY WHOLE-EXOME SEQUENCING, AND MRNA PROFILES FROM SYNOVIOCYTES OF RA AND OSTEOARTHRITIS (OA) PATIENTS. THE OVERALL DNA METHYLATION PATTERNS WERE NOT MUCH DIFFERENT BETWEEN RA AND OA, BUT 523 LOW-METHYLATED REGIONS (LMRS) WERE SPECIFIC TO RA. THE LMRS WERE PREFERENTIALLY LOCALIZED AT THE 5' INTRONS AND OVERLAPPED WITH TRANSCRIPTION FACTOR BINDING MOTIFS FOR GLI1, RUNX2, AND TFAP2A/C. SINGLE BASE-SCALE DIFFERENTIALLY METHYLATED CPGS WERE LINKED WITH SEVERAL NETWORKS RELATED TO WOUND RESPONSE, TISSUE DEVELOPMENT, COLLAGEN FIBRIL ORGANIZATION, AND THE TGF-BETA RECEPTOR SIGNALING PATHWAY. FURTHER, THE DNA METHYLATION OF 201 CPGS WAS SIGNIFICANTLY CORRELATED WITH 27 EXPRESSED MIRNA GENES. OUR INTERPRETATION OF EPIGENOMIC DATA OF THE SYNOVIOCYTES FROM RA AND OA PATIENTS IS AN INFORMATIVE RESOURCE TO FURTHER INVESTIGATE REGULATORY ELEMENTS AND BIOMARKERS RESPONSIBLE FOR THE PATHOPHYSIOLOGY OF RA AND OA. 2019 20 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