1 2959 133 GENETIC AND EPIGENETIC INSTABILITY INDUCED BY BETEL QUID ASSOCIATED CHEMICALS. OVER THE YEARS, BETEL QUID CHEWING AND TOBACCO USE HAVE ATTRACTED CONSIDERABLE INTEREST AS THEY ARE IMPLICATED AS THE MOST LIKELY CAUSATIVE RISK FACTORS OF ORAL AND ESOPHAGEAL CANCERS. ALTHOUGH ARECA NUT USE AND BETEL QUID CHEWING MAY LEAD TO APOPTOSIS, CHRONIC EXPOSURE TO ARECA NUT AND SLAKED LIME MAY PROMOTE PRE-MALIGNANT AND MALIGNANT TRANSFORMATION OF ORAL CELLS. THE PUTATIVE MUTAGENIC AND CARCINOGENIC MECHANISMS MAY INVOLVE ENDOGENOUS NITROSATION OF ARECA AND TOBACCO ALKALOIDS AS WELL AS THE PRESENCE OF DIRECT ALKYLATING AGENTS IN BETEL QUID AND SMOKELESS TOBACCO. METABOLIC ACTIVATION OF CARCINOGENIC N-NITROSAMINES BY PHASE-I ENZYMES IS REQUIRED NOT ONLY TO ELICIT THE GENOTOXICITY VIA THE REACTIVE INTERMEDIATES BUT ALSO TO POTENTIATE THE MUTAGENICITY WITH THE SPORADIC ALKYLATIONS OF NUCLEOTIDE BASES, RESULTING IN THE FORMATION OF DIVERSE DNA ADDUCTS. PERSISTENT DNA ADDUCTS PROVIDES THE IMPETUS FOR GENETIC AND EPIGENETIC LESIONS. THE GENETIC AND EPIGENETIC FACTORS CUMULATIVELY INFLUENCE THE DEVELOPMENT AND PROGRESSION OF DISORDERS SUCH AS CANCER. ACCUMULATION OF NUMEROUS GENETIC AND EPIGENETIC ABERRATIONS DUE TO LONG-TERM BETEL QUID (WITH OR WITHOUT TOBACCO) CHEWING AND TOBACCO USE CULMINATES INTO THE DEVELOPMENT OF HEAD AND NECK CANCERS. WE REVIEW RECENT EVIDENCE THAT SUPPORTS PUTATIVE MECHANISMS FOR MUTAGENICITY AND CARCINOGENICITY OF BETEL QUID CHEWING ALONG WITH TOBACCO (SMOKING AND SMOKELESS) USE. THE DETAILED MOLECULAR MECHANISMS OF THE EXTENT OF ACCUMULATION AND PATTERNS OF GENETIC ALTERATIONS, INDICATIVE OF THE PRIOR EXPOSURE TO CARCINOGENS AND ALKYLATING AGENTS BECAUSE OF BQ CHEWING AND TOBACCO USE, HAVE NOT YET BEEN ELUCIDATED. 2023 2 5145 28 POTENTIAL ROLE OF NUTRACEUTICALS VIA TARGETING A WNT/BETA-CATENIN AND NF-KAPPAB PATHWAY IN TREATMENT OF OSTEOARTHRITIS. OSTEOARTHRITIS (OA) IS A DISEASE DUE TO THE AGING OF THE ARTICULAR CARTILAGE, A POST-MITOTIC TISSUE THAT STAYS FUNCTIONING UNTIL PRIMARY HOMEOSTATIC PROCESSES FAIL. BECAUSE OF PAIN AND DISABILITY, OA SIGNIFICANTLY INFLUENCES NATIONAL HEALTHCARE EXPENSES AND PATIENT QUALITY OF LIFE. IT IS A WHOLE-JOINT ILLNESS CHARACTERIZED BY INFLAMMATORY AND OXIDATIVE SIGNALING PATHWAYS AND SIGNIFICANT EPIGENETIC ALTERATIONS THAT CAUSE CARTILAGE EXTRACELLULAR MATRIX DEGRADATION. THE CANONICAL WNT PATHWAY (WNT/BETA-CATENIN PATHWAY) AND NUCLEAR FACTOR KAPPA B (NF-KAPPAB) SIGNALING PATHWAYS MAY FUNCTION IN JOINT TISSUES BY MODULATING THE ACTIVITY OF SYNOVIAL CELLS, OSTEOBLASTS, AND CHONDROCYTES. HOWEVER, FINDING INNOVATIVE WAYS TO TREAT OSTEOARTHRITIS AND GET THE JOINT BACK TO AVERAGE BALANCE IS STILL A STRUGGLE. NUTRACEUTICALS ARE DIETARY SUPPLEMENTS THAT PROMOTE JOINT HEALTH BY BALANCING ANABOLIC AND CATABOLIC SIGNALS. NEW THERAPEUTIC METHODS FOR OA TREATMENT HAVE BEEN DEVELOPED BASED ON MANY RESEARCH FINDINGS THAT SHOW NUTRACEUTICALS HAVE STRONG ANTI-INFLAMMATION, ANTIOXIDANT, ANTI-BONE RESORPTION, AND ANABOLIC PROPERTIES. FOR THE TREATMENT OF OSTEOARTHRITIS, WE EXPLORE THE POSSIBLE INVOLVEMENT OF NUTRACEUTICALS THAT TARGET THE WNT/BETA-CATENIN AND NF-KAPPAB PATHWAYS. PRACTICAL APPLICATIONS: IN KEEPING WITH THE AGING POPULATION, OSTEOARTHRITIS IS BECOMING MORE WIDESPREAD. IN THIS EXTENSIVE RESEARCH, WE STUDIED THE ROLE OF THE WNT/BETA-CATENIN AND NF-KAPPAB PATHWAY IN OA FORMATION AND PROGRESSION. NUTRACEUTICALS THAT TARGET THESE OA-RELATED SIGNALING PATHWAYS ARE A VIABLE THERAPY OPTION. WNT/BETA-CATENIN AND NF-KAPPAB SIGNALING PATHWAY ARE INHIBITED BY POLYPHENOLS, FLAVONOIDS, ALKALOIDS, AND VITAMINS FROM THE NUTRACEUTICAL CATEGORY, MAKING THEM POSSIBLE THERAPEUTIC DRUGS FOR OA THERAPY. 2022 3 6750 19 WHOLE-GENOME METHYLATION PROFILING FROM PBMCS IN ACUTE-EXACERBATION COPD PATIENTS WITH GOOD AND POOR RESPONSES TO CORTICOSTEROID TREATMENT. IDENTIFYING HETEROGENEITY IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) PHENOTYPES IS IMPORTANT FOR THE DEVELOPMENT OF PERSONALIZED MEDICINE. GENOME-WIDE ANALYSIS WAS USED TO COMPARE THE METHYLATION LEVELS OF PERIPHERAL BLOOD MONONUCLEAR CELL (PBMC) SAMPLES FROM 24 ACUTE-EXACERBATION (AE) COPD PATIENTS WITH GOOD/POOR RESPONSE TO CORTICOSTEROID THERAPY AND 12 NON-COPD CONTROLS. PYROSEQUENCING WAS EMPLOYED TO VALIDATE THE GENOME-WIDE ANALYSIS. IN THE DATASET SPECIFIC TO COPD PATIENTS WITH A GOOD RESPONSE, ENRICHMENT WAS IDENTIFIED FOR THE FOLLOWING: GENES IN THE UBL CONJUGATION PATHWAY, NICOTINAMIDE NUCLEOTIDE METABOLISM, THE ALKALOID METABOLIC PROCESS, AND REGULATION OF THE GLUCOSE METABOLIC PROCESS. VALIDATION RESULTS CONFIRMED CPG SITES IN PRKAG2 WITH DIFFERENT METHYLATION LEVELS IN COPD PATIENTS AND NORMAL SUBJECTS. THE CPG SITES OF ALOX5AP WERE SPECIFICALLY ASSOCIATED WITH A GOOD RESPONSE. THE RESULTS SUGGESTED THAT A GOOD RESPONSE TO CORTICOSTEROID TREATMENT FOR AE-COPD SHOULD BE CONSIDERED A DISTINCT SUBTYPE ACCORDING TO THE PUTATIVE EPIGENETIC MECHANISM. 2019 4 4776 22 NUTRACEUTICAL ACTIVITY IN OSTEOARTHRITIS BIOLOGY: A FOCUS ON THE NUTRIGENOMIC ROLE. OSTEOARTHRITIS (OA) IS A DISEASE ASSOCIATED TO AGE OR CONDITIONS THAT PRECIPITATE AGING OF ARTICULAR CARTILAGE, A POST-MITOTIC TISSUE THAT REMAINS FUNCTIONAL UNTIL THE FAILURE OF MAJOR HOMEOSTATIC MECHANISMS. OA SEVERELY IMPACTS THE NATIONAL HEALTH SYSTEM COSTS AND PATIENTS' QUALITY OF LIFE BECAUSE OF PAIN AND DISABILITY. IT IS A WHOLE-JOINT DISEASE SUSTAINED BY INFLAMMATORY AND OXIDATIVE SIGNALING PATHWAYS AND MARKED EPIGENETIC CHANGES RESPONSIBLE FOR CATABOLISM OF THE CARTILAGE EXTRACELLULAR MATRIX. OA USUALLY PROGRESSES UNTIL ITS SEVERITY REQUIRES JOINT ARTHROPLASTY. TO DELAY THIS PROGRESSION AND TO IMPROVE SYMPTOMS, A WIDE RANGE OF NATURALLY DERIVED COMPOUNDS HAVE BEEN PROPOSED AND ARE SUMMARIZED IN THIS REVIEW. PRECLINICAL IN VITRO AND IN VIVO STUDIES HAVE PROVIDED PROOF OF PRINCIPLE THAT MANY OF THESE NUTRACEUTICALS ARE ABLE TO EXERT PLEIOTROPIC AND SYNERGISTIC EFFECTS AND EFFECTIVELY COUNTERACT OA PATHOGENESIS BY EXERTING BOTH ANTI-INFLAMMATORY AND ANTIOXIDANT ACTIVITIES AND BY TUNING MAJOR OA-RELATED SIGNALING PATHWAYS. THE LATTER ARE THE BASIS FOR THE NUTRIGENOMIC ROLE PLAYED BY SOME OF THESE COMPOUNDS, GIVEN THE MARKED CHANGES IN THE TRANSCRIPTOME, MIRNOME, AND METHYLOME. ONGOING AND FUTURE CLINICAL TRIALS WILL HOPEFULLY CONFIRM THE DISEASE-MODIFYING ABILITY OF THESE BIOACTIVE MOLECULES IN OA PATIENTS. 2020 5 296 28 AGING, CELL SENESCENCE, THE PATHOGENESIS AND TARGETED THERAPIES OF OSTEOARTHRITIS. OSTEOARTHRITIS (OA) IS A CHRONIC, DEBILITATING JOINT DISEASE CHARACTERIZED BY PROGRESSIVE DESTRUCTION OF ARTICULAR CARTILAGE. FOR A LONG TIME, OA HAS BEEN CONSIDERED AS A DEGENERATIVE DISEASE, WHILE RECENT OBSERVATIONS INDICATE THE MECHANISMS RESPONSIBLE FOR THE PATHOGENESIS OF OA ARE MULTIFACETED. AGING IS A KEY FACTOR IN ITS DEVELOPMENT. CURRENT TREATMENTS ARE PALLIATIVE AND NO DISEASE MODIFYING ANTI-OSTEOARTHRITIS DRUGS (DMOADS) ARE AVAILABLE. IN ADDITION TO ARTICULAR CARTILAGE DEGRADATION, CELLULAR SENESCENCE, SYNOVIAL INFLAMMATION, AND EPIGENETIC ALTERATIONS MAY ALL HAVE A ROLE IN ITS FORMATION. ACCUMULATING DATA DEMONSTRATE A CLEAR RELATIONSHIP BETWEEN THE SENESCENCE OF ARTICULAR CHONDROCYTES AND OA FORMATION AND PROGRESSION. INHIBITION OF CELL SENESCENCE MAY HELP IDENTIFY NEW AGENTS WITH THE PROPERTIES OF DMOADS. SEVERAL ANTI-CELLULAR SENESCENCE STRATEGIES HAVE BEEN PROPOSED AND THESE INCLUDE SIRTUIN-ACTIVATING COMPOUNDS (STACS), SENOLYTICS, AND SENOMORPHICS DRUGS. THESE AGENTS MAY SELECTIVELY REMOVE SENESCENT CELLS OR AMELIORATE THEIR HARMFUL EFFECTS. THE RESULTS FROM PRECLINICAL EXPERIMENTS AND CLINICAL TRIALS ARE INSPIRING. HOWEVER, MORE STUDIES ARE WARRANTED TO CONFIRM THEIR EFFICACY, SAFETY PROFILES AND ADVERSE EFFECTS OF THESE AGENTS. 2021 6 4880 23 OVERVIEW OF MMP-13 AS A PROMISING TARGET FOR THE TREATMENT OF OSTEOARTHRITIS. OSTEOARTHRITIS (OA) IS A COMMON DEGENERATIVE DISEASE CHARACTERIZED BY THE DESTRUCTION OF ARTICULAR CARTILAGE AND CHRONIC INFLAMMATION OF SURROUNDING TISSUES. MATRIX METALLOPROTEINASE-13 (MMP-13) IS THE PRIMARY MMP INVOLVED IN CARTILAGE DEGRADATION THROUGH ITS PARTICULAR ABILITY TO CLEAVE TYPE II COLLAGEN. HENCE, IT IS AN ATTRACTIVE TARGET FOR THE TREATMENT OF OA. HOWEVER, THE DETAILED MOLECULAR MECHANISMS OF OA INITIATION AND PROGRESSION REMAIN ELUSIVE, AND, CURRENTLY, THERE ARE NO INTERVENTIONS AVAILABLE TO RESTORE DEGRADED CARTILAGE. THIS REVIEW FULLY ILLUSTRATES THE INVOLVEMENT OF MMP-13 IN THE INITIATION AND PROGRESSION OF OA THROUGH THE REGULATION OF MMP-13 ACTIVITY AT THE MOLECULAR AND EPIGENETIC LEVELS, AS WELL AS THE STRATEGIES THAT HAVE BEEN EMPLOYED AGAINST MMP-13. THE AIM OF THIS REVIEW IS TO IDENTIFY MMP-13 AS AN ATTRACTIVE TARGET FOR INHIBITOR DEVELOPMENT IN THE TREATMENT OF OA. 2021 7 4296 20 MICRORNA-1 MODULATES CHONDROCYTE PHENOTYPE BY REGULATING FZD7 OF WNT/ BETA-CATENIN SIGNALING PATHWAY. OBJECTIVE: OSTEOARTHRITIS (OA) IS AN INCURABLE JOINT DISEASE CHARACTERIZED BY PRONOUNCED PAIN. MICRORNAS CONSTITUTE EPIGENETIC MECHANISMS THAT MAY AFFECT OA PROGRESSION BY CONTRIBUTING TO CHANGES IN CHONDROCYTE PHENOTYPE. THIS STUDY INVESTIGATES FOR THE FIRST TIME WHETHER THERE IS A LINK BETWEEN MIRNA-1 (MIR-1) AND OA PATHOGENESIS, AND THE MOLECULAR MECHANISMS INVOLVED. DESIGN: OA-ASSOCIATED GENE EXPRESSION, INCLUDING MMP-13, ADAMTS5, AND COL2A1 WAS COMPARED IN CHONDROCYTES FROM NON-OA AND OA CARTILAGE, AND IN SW1353 CELLS OVER- AND UNDEREXPRESSING MIR-1. BIOINFORMATICS AND LUCIFERASE REPORTER ASSAY WERE CONDUCTED TO CONFIRM WHETHER FZD7 WAS A TARGET OF MIR-1. THE EFFECTS OF MIR-1 ON FZD7 EXPRESSION AND DOWNSTREAM WNT/BETA-CATENIN SIGNALLING WERE INVESTIGATED. RESULTS: NON-OA AND OA CHONDROCYTES DIFFERED SIGNIFICANTLY IN THE EXPRESSION OF MIR-1 AND OA-ASSOCIATED GENES. MIR-1 OVER- AND UNDEREXPRESSION IN SW1353 CELLS, RESPECTIVELY, REDUCED AND ENHANCED GENE EXPRESSION ASSOCIATED WITH CARTILAGE CATABOLISM. FZD7, WHICH HAS AN IMPORTANT ROLE IN THE WNT/BETA-CATENIN SIGNALING PATHWAY, WAS SHOWN TO BE A POTENTIAL TARGET OF MIR-1. MIR-1 BINDING TO FZD7 INCREASED THE LEVELS OF PHOSPHORYLATED (INACTIVATED) BETA-CATENIN, THEREBY PREVENTING DOWNSTREAM BETA-CATENIN SIGNALING. CONCLUSIONS: INHIBITION OF WNT/BETA-CATENIN SIGNALING BY MIR-1 IN CHONDROCYTES MAY ATTENUATE THE EXPRESSION OF GENES THAT REGULATE THE ACTIVITY OF CATABOLIC ENZYMES. THIS FINDING MAY BE USEFUL FOR FUTURE INVESTIGATIONS OF MOLECULAR TARGETS FOR OA TREATMENT. 2021 8 5052 23 PHARMACOLOGICAL TARGETING OF HEME OXYGENASE-1 IN OSTEOARTHRITIS. OSTEOARTHRITIS (OA) IS A COMMON AGING-ASSOCIATED DISEASE THAT CLINICALLY MANIFESTS AS JOINT PAIN, MOBILITY LIMITATIONS, AND COMPROMISED QUALITY OF LIFE. TODAY, OA TREATMENT IS LIMITED TO PAIN MANAGEMENT AND JOINT ARTHROPLASTY AT THE LATER STAGES OF DISEASE PROGRESSION. OA PATHOGENESIS IS PREDOMINANTLY MEDIATED BY OXIDATIVE DAMAGE TO JOINT CARTILAGE EXTRACELLULAR MATRIX AND LOCAL CELLS SUCH AS CHONDROCYTES, OSTEOCLASTS, OSTEOBLASTS, AND SYNOVIAL FIBROBLASTS. UNDER NORMAL CONDITIONS, CELLS PREVENT THE ACCUMULATION OF REACTIVE OXYGEN SPECIES (ROS) UNDER OXIDATIVELY STRESSFUL CONDITIONS THROUGH THEIR ADAPTIVE CYTOPROTECTIVE MECHANISMS. HEME OXYGENASE-1 (HO-1) IS AN IRON-DEPENDENT CYTOPROTECTIVE ENZYME THAT FUNCTIONS AS THE INDUCIBLE FORM OF HO. HO-1 AND ITS METABOLITES CARBON MONOXIDE AND BILIVERDIN CONTRIBUTE TOWARDS THE MAINTENANCE OF REDOX HOMEOSTASIS. HO-1 EXPRESSION IS PRIMARILY REGULATED AT THE TRANSCRIPTIONAL LEVEL THROUGH TRANSCRIPTIONAL FACTOR NUCLEAR FACTOR ERYTHROID 2 (NF-E2)-RELATED FACTOR 2 (NRF2), SPECIFICITY PROTEIN 1 (SP1), TRANSCRIPTIONAL REPRESSOR BTB-AND-CNC HOMOLOGY 1 (BACH1), AND EPIGENETIC REGULATION. SEVERAL STUDIES REPORT THAT HO-1 EXPRESSION CAN BE REGULATED USING VARIOUS ANTIOXIDATIVE FACTORS AND CHEMICAL COMPOUNDS, SUGGESTING THERAPEUTIC IMPLICATIONS IN OA PATHOGENESIS AS WELL AS IN THE WIDER CONTEXT OF JOINT DISEASE. HERE, WE REVIEW THE PROTECTIVE ROLE OF HO-1 IN OA WITH A FOCUS ON THE REGULATORY MECHANISMS THAT MEDIATE HO-1 ACTIVITY. 2021 9 3355 20 HISTONE EXTRACTION FROM HUMAN ARTICULAR CARTILAGE FOR THE STUDY OF EPIGENETIC REGULATION IN OSTEOARTHRITIS. OSTEOARTHRITIS (OA) IS A CHRONIC DISEASE THAT AFFECTS ARTICULAR CARTILAGE, CAUSING ITS DEGENERATION. ALTHOUGH OA IS ONE OF THE MOST PREVALENT PATHOLOGIES GLOBALLY, THERE ARE NO DEFINITIVE TREATMENTS AVAILABLE. RECENTLY, RESEARCH HAS FOCUSED ON ELUCIDATING THE COMPLEX INTERPLAY THAT TAKES PLACE BETWEEN INFLAMMATORY PROCESSES AND EPIGENETIC REGULATION, SHOWING THAT HISTONE POST-TRANSLATIONAL MODIFICATIONS (PTMS) CAN EXERT A PRONOUNCED EFFECT ON THE EXPRESSION OF OA-RELATED GENES. OA CHONDROCYTES ENHANCE THE PRODUCTION OF INTERLEUKIN 1BETA (IL-1BETA) AND INTERLEUKIN 8 (IL-8), WHICH ARE EPIGENETICALLY REGULATED. THESE CYTOKINES UPREGULATE THE SYNTHESIS OF MATRIX METALLOPROTEINASES (MMPS) AND AGGRECANASES, WHICH PROMOTE THE EXTRACELLULAR MATRIX (ECM) DESTRUCTION. THIS MOTIVATES THE STUDY OF HISTONE PTMS TO INVESTIGATE THE EPIGENETIC REGULATION OF PROINFLAMMATORY MOLECULES, BUT THE ABSENCE OF SPECIFIC PROTOCOLS TO EXTRACT HISTONES FROM HUMAN ARTICULAR CARTILAGE HAS COMPLICATED THIS TASK. THE LACK OF EFFECTIVE METHODS CAN BE EXPLAINED BY THE STRUCTURAL COMPLEXITY AND LOW CELLULARITY OF THIS TISSUE, WHICH ARE RESPONSIBLE FOR THE BIOMECHANICAL PROPERTIES THAT ALLOW THE MOVEMENT OF THE JOINT BUT ALSO COMPLICATE HISTONE ISOLATION. HERE, WE PROVIDE A HISTONE EXTRACTION PROCEDURE SPECIFICALLY ADAPTED FOR CRYOPRESERVED HUMAN ARTICULAR CARTILAGE THAT CAN BE USEFUL TO UNDERSTAND EPIGENETIC REGULATION IN OA AND ACCELERATE THE SEARCH FOR NOVEL STRATEGIES. 2022 10 4679 31 NEW MOLECULAR TARGETS FOR THE TREATMENT OF OSTEOARTHRITIS. OSTEOARTHRITIS (OA) IS A CHRONIC DEGENERATIVE JOINT DISORDER CHARACTERIZED BY DESTRUCTION OF THE ARTICULAR CARTILAGE, SUBCHONDRAL BONE ALTERATIONS AND SYNOVITIS. CURRENT TREATMENTS ARE FOCUSED ON SYMPTOMATIC RELIEF BUT THEY LACK EFFICACY TO CONTROL THE PROGRESSION OF THIS DISEASE WHICH IS A LEADING CAUSE OF DISABILITY. THEREFORE, THE DEVELOPMENT OF EFFECTIVE DISEASE-MODIFYING DRUGS IS URGENTLY NEEDED. DIFFERENT INITIATIVES ARE IN PROGRESS TO DEFINE THE MOLECULAR MECHANISMS INVOLVED IN THE INITIATION AND PROGRESSION OF OA. THESE STUDIES SUPPORT THE THERAPEUTIC POTENTIAL OF PATHWAYS RELEVANT IN JOINT METABOLISM SUCH AS WNT/BETA-CATENIN, DISCOIDIN DOMAIN RECEPTOR 2 OR PROTEINASE-ACTIVATED RECEPTOR 2. THE DYSREGULATION IN CARTILAGE CATABOLISM AND SUBCHONDRAL BONE REMODELING COULD BE IMPROVED BY SELECTIVE INHIBITORS OF MATRIX METALLOPROTEINASES, AGGRECANASES AND OTHER PROTEASES. ANOTHER APPROACH WOULD FAVOR THE ACTIVITY OF ANABOLIC PROCESSES BY USING GROWTH FACTORS OR REGULATORY MOLECULES. RECENT STUDIES HAVE ALSO REVEALED THE ROLE OF OXIDATIVE STRESS AND SYNOVITIS IN THE PROGRESSION OF THIS DISEASE, SUPPORTING THE DEVELOPMENT OF A NUMBER OF INHIBITORY STRATEGIES. NOVEL TARGETS IN OA ARE REPRESENTED BY GENES INVOLVED IN OA PATHOPHYSIOLOGY DISCOVERED USING GENE NETWORK, EPIGENETIC AND MICRORNA APPROACHES. FURTHER INSIGHTS INTO THE MOLECULAR MECHANISMS INVOLVED IN OA INITIATION AND PROGRESSION MAY LEAD TO THE DEVELOPMENT OF NEW THERAPIES ABLE TO CONTROL JOINT DESTRUCTION AND REPAIR. 2010 11 6218 28 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 12 2823 32 FLAVONOIDS AS EPIGENETIC MODULATORS FOR PROSTATE CANCER PREVENTION. PROSTATE CANCER (PCA) IS A MULTIFACTORIAL DISEASE WITH AN UNCLEAR ETIOLOGY. DUE TO ITS HIGH PREVALENCE, LONG LATENCY, AND SLOW PROGRESSION, PCA IS AN IDEAL TARGET FOR CHEMOPREVENTION STRATEGIES. MANY RESEARCH STUDIES HAVE HIGHLIGHTED THE POSITIVE EFFECTS OF NATURAL FLAVONOIDS ON CHRONIC DISEASES, INCLUDING PCA. DIFFERENT CLASSES OF DIETARY FLAVONOIDS EXHIBIT ANTI-OXIDATIVE, ANTI-INFLAMMATORY, ANTI-MUTAGENIC, ANTI-AGING, CARDIOPROTECTIVE, ANTI-VIRAL/BACTERIAL AND ANTI-CARCINOGENIC PROPERTIES. WE OVERVIEWED THE MOST RECENT EVIDENCE OF THE ANTITUMORAL EFFECTS EXERTED BY DIETARY FLAVONOIDS, WITH A SPECIAL FOCUS ON THEIR EPIGENETIC ACTION IN PCA. EPIGENETIC ALTERATIONS HAVE BEEN IDENTIFIED AS KEY INITIATING EVENTS IN SEVERAL KINDS OF CANCER. MANY DIETARY FLAVONOIDS HAVE BEEN FOUND TO REVERSE DNA ABERRATIONS THAT PROMOTE NEOPLASTIC TRANSFORMATION, PARTICULARLY FOR PCA. THE EPIGENETIC TARGETS OF THE ACTIONS OF FLAVONOIDS INCLUDE ONCOGENES AND TUMOR SUPPRESSOR GENES, INDIRECTLY CONTROLLED THROUGH THE REGULATION OF EPIGENETIC ENZYMES SUCH AS DNA METHYLTRANSFERASE (DNMT), HISTONE ACETYLTRANSFERASE (HAT), AND HISTONE DEACETYLASE (HDAC). IN ADDITION, FLAVONOIDS WERE FOUND CAPABLE OF RESTORING MIRNA AND LNCRNA EXPRESSION THAT IS ALTERED DURING DISEASES. THE OPTIMIZATION OF THE USE OF FLAVONOIDS AS NATURAL EPIGENETIC MODULATORS FOR CHEMOPREVENTION AND AS A POSSIBLE TREATMENT OF PCA AND OTHER KINDS OF CANCERS COULD REPRESENT A PROMISING AND VALID STRATEGY TO INHIBIT CARCINOGENESIS AND FIGHT CANCER. 2020 13 757 30 CARTILAGE REPAIR BY MESENCHYMAL STEM CELLS: CLINICAL TRIAL UPDATE AND PERSPECTIVES. OSTEOARTHRITIS IS A DEGENERATIVE DISEASE OF JOINTS WITH DESTRUCTION OF ARTICULAR CARTILAGE ASSOCIATED WITH SUBCHONDRAL BONE HYPERTROPHY AND INFLAMMATION. OA IS THE LEADING CAUSE OF JOINT PAIN RESULTING IN SIGNIFICANT WORSENING OF THE QUALITY-OF-LIFE IN THE ELDERLY. NUMEROUS EFFORTS HAVE BEEN SPENT TO OVERCOME THE INHERENTLY POOR HEALING ABILITY OF ARTICULAR CARTILAGE. MESENCHYMAL STEM CELLS (MSCS) HAVE BEEN IN THE LIMELIGHT OF CELL-BASED THERAPIES TO PROMOTE CARTILAGE REPAIR. DESPITE PROGRESSIVE ADVANCEMENTS IN MSC MANIPULATION AND THE INTRODUCTION OF VARIOUS BIOACTIVE SCAFFOLDS AND GROWTH FACTORS IN PRECLINICAL STUDIES, CURRENT CLINICAL TRIALS ARE STILL AT EARLY STAGES WITH PRELIMINARY AIMS TO EVALUATE SAFETY, FEASIBILITY AND EFFICACY. THIS REVIEW SUMMARISES RECENTLY REPORTED MSC-BASED CLINICAL TRIALS AND DISCUSSES NEW RESEARCH DIRECTIONS WITH PARTICULAR FOCUS ON THE POTENTIAL APPLICATION OF MSC-DERIVED EXTRACELLULAR VEHICLES, MIRNAS AND ADVANCED GENE EDITING TECHNIQUES WHICH MAY SHED LIGHT ON THE DEVELOPMENT OF NOVEL TREATMENT STRATEGIES. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: THIS REVIEW SUMMARISES RECENT MSC-RELATED CLINICAL RESEARCH THAT FOCUSES ON CARTILAGE REPAIR. WE ALSO PROPOSE A NOVEL POSSIBLE TRANSLATIONAL DIRECTION FOR HYALINE CARTILAGE FORMATION AND A NEW PARADIGM MAKING USE OF EXTRA-CELLULAR SIGNALLING AND EPIGENETIC REGULATION IN THE APPLICATION OF MSCS FOR CARTILAGE REPAIR. 2017 14 5109 36 POLYPHENOL-RELATED EPIGENETIC MODIFICATIONS IN OSTEOARTHRITIS: CURRENT THERAPEUTIC PERSPECTIVES. THE HYALINE CARTILAGE IS AN AVASCULAR, ANEURAL AND ALYMPHATIC TISSUE WITH A LIMITED ABILITY TO REPAIR ITSELF. WHEN THE CARTILAGE IS EXPOSED TO SOME KIND OF INJURY, IT USUALLY TRIGGERS OSTEOARTHRITIS (OA), A PREVALENT AND DEGENERATIVE JOINT DISEASE CLOSELY RELATED TO AGING. OA IS BOTH COMPLEX AND MULTIFACTORIAL, AND IS THE MOST COMMON FORM OF ARTHRITIS, BEING POSITIONED AS A MAJOR CAUSE OF PAIN AND DYSFUNCTION IN THE WORLD. IN ADDITION, HIGH OA PREVALENCE CAN GREATLY AFFECT WORK CAPACITY, MAKING THIS DISEASE A SIGNIFICANT SOCIAL PROBLEM, THEREFORE, ITS PREVENTION AND TREATMENT BECOMES A PRIORITY. AT THIS TIME, THERE ARE NUMEROUS THERAPEUTIC STRATEGIES AVAILABLE TO IMPROVE HYALINE CARTILAGE REPAIR BY USING CHONDROCYTES OR MESENCHYMAL CELLS, BUT NEITHER IS EFFECTIVE ENOUGH TO GENERATE FUNCTIONAL AND DURABLE TISSUE REPARATION OVER TIME. IN OA, CHONDROCYTES HAVE AN ABERRANT GENE EXPRESSION AND PHENOTYPE, RESULTING IN A LOSS OF BALANCE BETWEEN ANABOLIC AND CATABOLIC PROCESSES. ENVIRONMENTAL INFLUENCES SUCH AS RADIATION, INFECTION, SMOKING, NUTRIENTS, TOXINS AND STRESS CAN AFFECT GENE EXPRESSION PATTERNS, WHICH MAY CONSTITUTE RISK FACTORS FOR VARIOUS CHRONIC AND DEGENERATIVE DISEASES, SUCH AS OA. IN ADDITION, CONSIDERABLE EVIDENCE SHOWS THAT EPIGENETIC MECHANISMS PLAY AN IMPORTANT ROLE IN OA CHONDROGENESIS AND PATHOGENESIS. NATURAL PLANT-DERIVED PRODUCTS SUCH AS POLYPHENOLS, WHICH ARE SECONDARY METABOLITES CONSIDERED TO HAVE POTENTIAL ACTIVITY TO BLOCK INFLAMMATION IN SEVERAL DEGENERATIVE DISEASES, CAN STIMULATE EPIGENETIC MODIFICATIONS, AND MAY PROVIDE NEW THERAPEUTIC TARGETS AND COST-EFFECTIVE TREATMENTS. THIS REVIEW AIMS TO PRESENT VARIOUS POLYPHENOLBASED THERAPIES CURRENTLY USED FOR THE TREATMENT OF SEVERAL PROGRESSIVE DISEASES, INCLUDING OA. 2016 15 3800 34 INTERPLAY OF INFLAMMATORY MEDIATORS WITH EPIGENETICS AND CARTILAGE MODIFICATIONS IN OSTEOARTHRITIS. OSTEOARTHRITIS (OA), A DEGENERATIVE DISEASE OF DIARTHRODIAL JOINTS, IS INFLUENCED BY MECHANICAL AND INFLAMMATORY FACTORS WITH AGING, OBESITY, CHRONIC INJURIES, AND SECONDARY DISEASES THOUGHT TO BE MAJOR FACTORS DRIVING THE PROCESS OF ARTICULAR CARTILAGE DEGENERATION. CHONDROCYTES, THE CELLULAR COMPONENT OF CARTILAGE, RESIDE IN AN AVASCULAR ENVIRONMENT AND NORMALLY HAVE LIMITED POTENTIAL TO REPLICATE. HOWEVER, EXTRINSIC FACTORS SUCH AS INJURY TO THE JOINT OR INTRINSIC ALTERATIONS TO THE CHONDROCYTES THEMSELVES CAN LEAD TO AN ALTERED PHENOTYPE AND DEVELOPMENT OF OA. SYNOVIAL INFLAMMATION IS ALSO A PIVOTAL ELEMENT OF THE OSTEOARTHRITIC, DEGENERATIVE PROCESS: INFLUX OF PRO-INFLAMMATORY CYTOKINES AND PRODUCTION OF MATRIX METALLOPROTEINASES ACCELERATE ADVANCED CELLULAR PROCESSES SUCH AS SYNOVITIS AND CARTILAGE DAMAGE. AS WELL AS A GENETIC INPUT, RECENT DATA HAVE HIGHLIGHTED EPIGENETIC FACTORS AS CONTRIBUTING TO DISEASE. STUDIES CONDUCTED OVER THE LAST DECADE HAVE FOCUSED ON THREE KEY ASPECTS IN OA; INFLAMMATION AND THE IMMUNE RESPONSE, GENOME-WIDE ASSOCIATION STUDIES THAT HAVE IDENTIFIED IMPORTANT GENES UNDERGOING EPIGENETIC MODIFICATIONS, AND FINALLY HOW CHONDROCYTES TRANSFORM IN THEIR FUNCTION DURING DEVELOPMENT AND DISEASE. DATA HIGHLIGHTED HERE HAVE IDENTIFIED CRITICAL INFLAMMATORY GENES INVOLVED IN OA AND HOW THESE FACTORS IMPACT CHONDROCYTE HYPERTROPHY IN THE DISEASE. THIS REVIEW ALSO ADDRESSES KEY INFLAMMATORY FACTORS IN SYNOVIAL INFLAMMATION, EPIGENETICS, AND CHONDROCYTE FATE, AND HOW AGENTS THAT INHIBIT EPIGENETIC MECHANISMS LIKE DNA METHYLATION AND HISTONE MODIFICATIONS COULD AID IN DEVELOPMENT OF LONG-TERM TREATMENT STRATEGIES FOR THE DISEASE. 2018 16 6546 24 TRANSCRIPTOMIC AND EPIGENETIC PROFILING OF FIBROBLASTS IN IDIOPATHIC PULMONARY FIBROSIS. IDIOPATHIC PULMONARY FIBROSIS (IPF), A DEVASTATING, FIBROPROLIFERATIVE, CHRONIC LUNG DISORDER, IS ASSOCIATED WITH EXPANSION OF FIBROBLASTS/MYOFIBROBLASTS, WHICH LEADS TO EXCESSIVE PRODUCTION AND DEPOSITION OF EXTRACELLULAR MATRIX. IPF IS TYPICALLY CLINICALLY IDENTIFIED AS END-STAGE LUNG DISEASE, AFTER FIBROTIC PROCESSES ARE WELL-ESTABLISHED AND ADVANCED. FIBROBLASTS HAVE BEEN SHOWN TO BE CRITICALLY IMPORTANT IN THE DEVELOPMENT AND PROGRESSION OF IPF. WE HYPOTHESIZE THAT DIFFERENTIAL CHROMATIN ACCESS CAN DRIVE GENETIC DIFFERENCES IN IPF FIBROBLASTS RELATIVE TO HEALTHY FIBROBLASTS. TO THIS END, WE PERFORMED ASSAY OF TRANSPOSASE-ACCESSIBLE CHROMATIN SEQUENCING TO IDENTIFY DIFFERENTIALLY ACCESSIBLE REGIONS WITHIN THE GENOMES OF FIBROBLASTS FROM HEALTHY AND IPF LUNGS. MULTIPLE MOTIFS WERE IDENTIFIED TO BE ENRICHED IN IPF FIBROBLASTS COMPARED WITH HEALTHY FIBROBLASTS, INCLUDING BINDING MOTIFS FOR TWIST1 AND FOXA1. RNA SEQUENCING IDENTIFIED 93 GENES THAT COULD BE ANNOTATED TO DIFFERENTIALLY ACCESSIBLE REGIONS. PATHWAY ANALYSIS OF THE ANNOTATED GENES IDENTIFIED CELLULAR ADHESION, CYTOSKELETAL ANCHORING, AND CELL DIFFERENTIATION AS IMPORTANT BIOLOGICAL PROCESSES. IN ADDITION, SINGLE NUCLEOTIDE POLYMORPHISM ANALYSIS SHOWED THAT LINKAGE DISEQUILIBRIUM BLOCKS OF IPF RISK SINGLE NUCLEOTIDE POLYMORPHISMS WITH IPF-ACCESSIBLE REGIONS THAT HAVE BEEN IDENTIFIED TO BE LOCATED IN GENES THAT ARE IMPORTANT IN IPF, INCLUDING MUC5B, TERT, AND TOLLIP. VALIDATION STUDIES IN ISOLATED LUNG TISSUE CONFIRMED INCREASED EXPRESSION FOR TWIST1 AND FOXA1 IN ADDITION TO REVEALING SHANK2 AND CSPR2 AS NOVEL TARGETS. THUS, MODULATION OF DIFFERENTIAL CHROMATIN ACCESS MAY BE AN IMPORTANT MECHANISM IN THE PATHOGENESIS OF LUNG FIBROSIS. 2022 17 5968 25 TERPENOID TREATMENT IN OSTEOPOROSIS: THIS IS WHERE WE HAVE COME IN RESEARCH. LOWER BONE RESISTANCE TO LOAD IS DUE TO THE IMBALANCE OF BONE HOMEOSTASIS, WHERE EXCESSIVE BONE RESORPTION, COMPARED WITH BONE FORMATION, DETERMINES A PROGRESSIVE OSTEOPENIA, LEADING TO A HIGH RISK OF FRACTURES AND CONSEQUENT PAIN AND FUNCTIONAL LIMITATIONS. TERPENOIDS, WITH THEIR ACTIVITIES AGAINST BONE RESORPTION, HAVE RECENTLY RECEIVED INCREASED ATTENTION FROM RESEARCHERS. THEY ARE POTENTIALLY MORE SUITABLE FOR LONG-TERM USE COMPARED WITH TRADITIONAL THERAPEUTICS. IN THIS REVIEW OF THE LITERATURE OF THE PAST 5 YEARS, WE PROVIDE COMPREHENSIVE INFORMATION ON TERPENOIDS, WITH THEIR ANTI-OSTEOPOROTIC EFFECTS, HIGHLIGHTING MOLECULAR MECHANISMS THAT ARE OFTEN IN EPIGENETIC KEY AND A POSSIBLE PHARMACOLOGICAL USE IN OSTEOPOROSIS PREVENTION AND TREATMENT. 2021 18 2824 23 FLAVONOIDS IN BONE EROSIVE DISEASES: PERSPECTIVES IN OSTEOPOROSIS TREATMENT. IMBALANCE OF BONE HOMEOSTASIS, WITH EXCESSIVE BONE RESORPTION COMPARED WITH BONE FORMATION, LEADS TO THE DEVELOPMENT OF PROGRESSIVE OSTEOPENIA LEADING TO LOWER BONE RESISTANCE TO LOAD, WITH CONSEQUENT PAIN AND FUNCTIONAL LIMITATIONS. PHYTOCHEMICALS WITH THERAPEUTIC AND PREVENTIVE EFFECTS AGAINST BONE RESORPTION HAVE RECENTLY RECEIVED INCREASING ATTENTION SINCE THEY ARE POTENTIALLY MORE SUITABLE FOR LONG-TERM USE THAN TRADITIONAL THERAPEUTIC CHEMICAL COMPOUNDS. IN THIS SYSTEMATIC REVIEW OF THE LITERATURE OF THE PAST 5 YEARS, COMPREHENSIVE INFORMATION IS PROVIDED ON FLAVONOIDS WITH POTENTIAL ANTIRESORPTION AND PRO-OSTEOGENIC EFFECTS. IT AIMS TO HIGHLIGHT THE MOLECULAR MECHANISMS OF THESE MOLECULES, OFTEN EPIGENETIC, AND THEIR POSSIBLE PHARMACOLOGICAL USE, WHICH IS OF GREAT IMPORTANCE FOR THE PREVENTION AND TREATMENT OF OSTEOPOROSIS (OP). 2021 19 3514 33 IDIOPATHIC PULMONARY FIBROSIS: PATHOGENESIS AND THERAPEUTIC APPROACHES. IDIOPATHIC PULMONARY FIBROSIS (IPF), ALSO TERMED CRYPTOGENIC FIBROSING ALVEOLITIS, IS A CLINICOPATHOLOGICAL SYNDROME CHARACTERISED BY COUGH, EXERTIONAL DYSPNEOA, BASILAR CRACKLES, A RESTRICTIVE DEFECT ON PULMONARY FUNCTION TESTS, HONEYCOMBING ON HIGH-RESOLUTION, THIN-SECTION COMPUTED TOMOGRAPHIC SCANS AND THE HISTOLOGICAL DIAGNOSIS OF USUAL INTERSTITIAL PNEUMONIA ON LUNG BIOPSY. THE COURSE IS USUALLY INDOLENT BUT INEXORABLE. MOST PATIENTS DIE OF PROGRESSIVE RESPIRATORY FAILURE WITHIN 3-8 YEARS OF THE ONSET OF SYMPTOMS. CURRENT THERAPIES ARE OF UNPROVEN BENEFIT. ALTHOUGH THE PATHOGENESIS OF IPF HAS NOT BEEN ELUCIDATED, EARLY CONCEPTS FOCUSED ON LUNG INJURY LEADING TO A CYCLE OF CHRONIC ALVEOLAR INFLAMMATION EVENTUATING IN FIBROSIS AND DESTRUCTION OF THE LUNG ARCHITECTURE. ANTI-INFLAMMATORY THERAPIES EMPLOYING CORTICOSTEROIDS OR IMMUNOSUPPRESSIVE OR CYTOTOXIC AGENTS HAVE BEEN DISAPPOINTING. MORE RECENT HYPOTHESES ACKNOWLEDGE THAT SEQUENTIAL ALVEOLAR EPITHELIAL CELL INJURY IS LIKELY TO BE A KEY EVENT IN THE PATHOGENESIS OF IPF, BUT THE CARDINAL EVENT IS AN ABERRANT HOST RESPONSE TO WOUND HEALING. IN THIS CONTEXT, ABNORMAL EPITHELIAL-MESENCHYMAL INTERACTIONS, ALTERED FIBROBLAST PHENOTYPES, EXAGGERATED FIBROBLAST PROLIFERATION, AND EXCESSIVE DEPOSITION OF COLLAGEN AND EXTRACELLULAR MATRIX ARE PIVOTAL TO THE FIBROTIC PROCESS. SEVERAL CLINICAL TRIALS ARE CURRENTLY UNDERWAY OR IN THE PLANNING STAGES, AND INCLUDE DRUGS SUCH AS INTERFERON-GAMMA 1B, PIRFENIDONE, ACETYLCYSTEINE, ETANERCEPT (A TUMOR NECROSIS FACTOR-ALPHA ANTAGONIST), BOSENTAN (AN ENDOTHELIN-1 RECEPTOR ANTAGONIST) AND ZILEUTON (A 5-LYPOXYGENASE INHIBITOR). FUTURE THERAPEUTIC STRATEGIES SHOULD BE FOCUSED ON ALVEOLAR EPITHELIAL CELLS AIMED AT ENHANCING RE-EPITHELIALISATION AND ON FIBROBLASTIC/MYOFIBROBLASTIC FOCI, WHICH PLAY AN ESSENTIAL ROLE IN THE DEVELOPMENT OF IPF. STEM CELL PROGENITORS OF THE ALVEOLAR EPITHELIAL CELLS AND GENETIC AND EPIGENETIC THERAPIES ARE ATTRACTIVE FUTURE APPROACHES FOR THIS AND OTHER FIBROTIC LUNG DISORDERS. 2004 20 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