1 4347 111 MIR-140 ATTENUATES THE PROGRESSION OF EARLY-STAGE OSTEOARTHRITIS BY RETARDING CHONDROCYTE SENESCENCE. OSTEOARTHRITIS (OA) IS A MAJOR CAUSE OF JOINT PAIN AND DISABILITY, AND CHONDROCYTE SENESCENCE IS A KEY PATHOLOGICAL PROCESS IN OA AND MAY BE A TARGET OF NEW THERAPEUTICS. MICRORNA-140 (MIR-140) PLAYS A PROTECTIVE ROLE IN OA, BUT LITTLE IS KNOWN ABOUT ITS EPIGENETIC EFFECT ON CHONDROCYTE SENESCENCE. IN THIS STUDY, WE FIRST VALIDATED THE FEATURES OF CHONDROCYTE SENESCENCE CHARACTERIZED BY INCREASED CELL CYCLE ARREST IN THE G0/G1 PHASE AND THE EXPRESSION OF SENESCENCE-ASSOCIATED BETA-GALACTOSIDASE (SA-BETAGAL), P16(INK4A), P21, P53, AND GAMMAH2AX IN HUMAN KNEE OA. THEN, WE REVEALED IN INTERLEUKIN 1BETA (IL-1BETA)-INDUCED OA CHONDROCYTES IN VITRO THAT PRETRANSFECTION WITH MIR-140 EFFECTIVELY INHIBITED THE EXPRESSION OF SA-BETAGAL, P16(INK4A), P21, P53, AND GAMMAH2AX. FURTHERMORE, IN VIVO RESULTS FROM TRAUMA-INDUCED EARLY-STAGE OA RATS SHOWED THAT INTRA-ARTICULARLY INJECTED MIR-140 COULD RAPIDLY REACH THE CHONDROCYTE CYTOPLASM AND INDUCE MOLECULAR CHANGES SIMILAR TO THE IN VITRO RESULTS, RESULTING IN A NOTICEABLE ALLEVIATION OF OA PROGRESSION. FINALLY, BIOINFORMATICS ANALYSIS PREDICTED THE POTENTIAL TARGETS OF MIR-140 AND A MECHANISTIC NETWORK BY WHICH MIR-140 REGULATES CHONDROCYTE SENESCENCE. COLLECTIVELY, MIR-140 CAN EFFECTIVELY ATTENUATE THE PROGRESSION OF EARLY-STAGE OA BY RETARDING CHONDROCYTE SENESCENCE, CONTRIBUTING NEW EVIDENCE OF THE INVOLVEMENT OF MIR-MEDIATED EPIGENETIC REGULATION OF CHONDROCYTE SENESCENCE IN OA PATHOGENESIS. 2020 2 6218 27 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 3 4880 21 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 4 5695 41 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 5 484 27 ARTICULAR CARTILAGE CHANGES IN MATURING ATHLETES: NEW TARGETS FOR JOINT REJUVENATION. CONTEXT: ARTICULAR CARTILAGE HAS A UNIQUE FUNCTIONAL ARCHITECTURE CAPABLE OF PROVIDING A LIFETIME OF PAIN-FREE JOINT MOTION. THIS TISSUE, HOWEVER, UNDERGOES SUBSTANTIAL AGE-RELATED PHYSIOLOGIC, MECHANICAL, BIOCHEMICAL, AND FUNCTIONAL CHANGES THAT REDUCE ITS ABILITY TO OVERCOME THE EFFECTS OF MECHANICAL STRESS AND INJURY. MANY FACTORS AFFECT JOINT FUNCTION IN THE MATURING ATHLETE-FROM CHONDROCYTE SURVIVAL AND METABOLISM TO STRUCTURAL COMPOSITION AND GENETIC/EPIGENETIC FACTORS GOVERNING CARTILAGE AND SYNOVIUM. AN EVALUATION OF AGE-RELATED CHANGES FOR JOINT HOMEOSTASIS AND RISK FOR OSTEOARTHRITIS IS IMPORTANT TO THE DEVELOPMENT OF NEW STRATEGIES TO REJUVENATE AGING JOINTS. OBJECTIVE: THIS REVIEW SUMMARIZES THE CURRENT LITERATURE ON THE BIOCHEMICAL, CELLULAR, AND PHYSIOLOGIC CHANGES OCCURRING IN AGING ARTICULAR CARTILAGE. DATA SOURCES: PUBMED (1969-2013) AND PUBLISHED BOOKS IN SPORTS HEALTH, CARTILAGE BIOLOGY, AND AGING. STUDY SELECTION: KEYWORDS INCLUDED AGING, ATHLETE, ARTICULAR CARTILAGE, EPIGENETICS, AND FUNCTIONAL PERFORMANCE WITH AGE. STUDY DESIGN: SYSTEMATIC REVIEW. LEVEL OF EVIDENCE: LEVEL 3. DATA EXTRACTION: TO BE INCLUDED, RESEARCH QUESTIONS ADDRESSED THE EFFECT OF AGE-RELATED CHANGES ON PERFORMANCE, ARTICULAR CARTILAGE BIOLOGY, MOLECULAR MECHANISM, AND MORPHOLOGY. RESULTS: THE MATURE ATHLETE FACES CHALLENGES IN MAINTAINING CARTILAGE HEALTH AND JOINT FUNCTION DUE TO AGE-RELATED CHANGES TO ARTICULAR CARTILAGE BIOLOGY, MORPHOLOGY, AND PHYSIOLOGY. THESE CHANGES INCLUDE CHONDROCYTE LOSS AND A DECLINE IN METABOLIC RESPONSE, ALTERATIONS TO MATRIX AND SYNOVIAL TISSUE COMPOSITION, AND DYSREGULATION OF REPARATIVE RESPONSES. CONCLUSION: ALTHOUGH PHYSICAL DECLINE HAS BEEN REGARDED AS A NORMAL PART OF AGING, MANY INDIVIDUALS MAINTAIN OVERALL FITNESS AND ENJOY TARGETED IMPROVEMENT TO THEIR ATHLETIC CAPACITY THROUGHOUT LIFE. HEALTHY ARTICULAR CARTILAGE AND JOINTS ARE NEEDED TO MAINTAIN ATHLETIC PERFORMANCE AND GENERAL ACTIVITIES. GENETIC AND POTENTIALLY REVERSIBLE EPIGENETIC FACTORS INFLUENCE CARTILAGE PHYSIOLOGY AND ITS RESPONSE TO MECHANICAL AND INJURIOUS STIMULI. IMPROVED UNDERSTANDINGS OF THE PHYSICAL AND MOLECULAR CHANGES TO ARTICULAR CARTILAGE WITH AGING ARE IMPORTANT TO DEVELOP SUCCESSFUL STRATEGIES FOR JOINT REJUVENATION. 2014 6 5145 31 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 7 1878 28 EMERGING ROLES OF LONG NONCODING RNA IN CHONDROGENESIS, OSTEOGENESIS, AND OSTEOARTHRITIS. OSTEOARTHRITIS (OA) IS THE MOST PREVALENT AGE-RELATED DEBILITATING JOINT DISEASE, AND IS CHARACTERIZED PRIMARILY BY ARTICULAR CARTILAGE DEGRADATION AND SUBCHONDRAL BONE LESIONS. IT IS ALSO THE LEADING CAUSE OF CHRONIC MORBIDITY IN OLDER POPULATIONS. THE ETIOLOGY OF OA IS MULTIFACTORIAL, WITH THE UNDERLYING REGULATORY MECHANISMS REMAINING LARGELY UNKNOWN. LONG NONCODING RNA (LNCRNA) IS A GROUP OF NONCODING RNAS DEFINED AS BEING >200 NUCLEOTIDES IN LENGTH. INCREASING EVIDENCE DEMONSTRATES THAT MANY LNCRNAS SERVE AS CRITICAL REGULATORS OF CHONDROGENESIS AND BONE AND CARTILAGE HOMEOSTASIS, THEREBY INFLUENCING OA DEVELOPMENT. IN THIS REVIEW, WE HIGHLIGHT THE CURRENT UNDERSTANDING CONCERNING LNCRNAS, INCLUDING THEIR PHYSICAL FEATURES, BIOLOGICAL FUNCTIONS, AND POTENTIAL ROLES IN CHONDROGENESIS, OSTEOGENESIS, AND OA. THIS INFORMATION MAY SHED NEW LIGHT ON THE EPIGENETIC REGULATION OF CARTILAGE AND SUBSTANTIATE LNCRNAS AS NOVEL THERAPEUTIC TARGETS IN OA. 2019 8 3355 33 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 9 3800 27 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 10 814 31 CHANGES IN SMALL NONCODING RNA EXPRESSION DURING CHONDROCYTE SENESCENCE. OBJECTIVE: OSTEOARTHRITIS (OA) IS CHARACTERIZED BY THE CHRONIC AND PROGRESSIVE DETERIORATION OF ARTICULAR CARTILAGE. CHONDROCYTE SENESCENCE COULD LEAD TO A SHIFT IN THE BALANCE BETWEEN EXTRACELLULAR MATRIX (ECM) COMPONENT SYNTHESIS AND DEGRADATION. SMALL NONCODING RNAS (SNCRNAS), INCLUDING MICRORNAS (MIRNAS), P-ELEMENT-INDUCED WIMPY TESTIS-(PIWI-) INTERACTING RNAS (PIRNAS), SMALL NUCLEOLAR RNAS (SNORNAS), SMALL NUCLEAR RNAS (SNRNAS), AND REPEAT-ASSOCIATED SIRNAS (RASIRNAS), ARE A CLASS OF IMPORTANT EPIGENETIC MOLECULES. WE AIMED TO GAIN INSIGHTS INTO THE CHANGES AND ROLES OF SNCRNA IN CHONDROCYTE SENESCENCE. DESIGN: HEALTHY MOUSE POSTNATAL CHONDROCYTES WERE ISOLATED, AND A REPLICATIVE AGING MODEL WAS CONSTRUCTED. WE USED SMALL RNA SEQUENCING (SMALL RNA-SEQ) TO GENERATE EXTENSIVE SMALL RNA DATA. WE IDENTIFIED DIFFERENTIALLY EXPRESSED SNCRNAS AND PERFORMED TISSUE-SPECIFIC ANALYSIS USING REAL-TIME QUANTITATIVE POLYMERASE CHAIN REACTION (QRT-PCR). BETA-GALACTOSIDASE STAINING WAS USED TO DETECT CHONDROCYTE SENESCENCE. THE RESULTS SHOWED THAT THE EXPRESSION PROFILES OF SNCRNA IN PASSAGE 5 CHONDROCYTES WERE SIGNIFICANTLY DIFFERENT FROM THOSE IN PASSAGE 0 CHONDROCYTES. THE EXPRESSION OF SNCRNA WAS TISSUE SPECIFIC. WE FOUND THAT 40 MIRNAS WERE UPREGULATED AND 70 MIRNAS WERE DOWNREGULATED DURING CHONDROCYTE SENESCENCE, AND THAT MIR-132-5P EXPRESSION INHIBITION PREVENTED CHONDROCYTE SENESCENCE. WE FOUND THAT 8 PIRNAS WERE UPREGULATED AND 17 PIRNAS WERE DOWNREGULATED DURING CHONDROCYTE SENESCENCE, AND THAT PIRNA PIR_025576 OVEREXPRESSION DELAYED CHONDROCYTE SENESCENCE. WE FOUND THAT 24 SNORNAS WERE UPREGULATED AND 28 SNORNAS WERE DOWNREGULATED DURING CHONDROCYTE SENESCENCE, AND THAT SNORNA ENSMUSG00000087935 OVEREXPRESSION DELAYED CHONDROCYTE SENESCENCE. WE FOUND THAT 5 SNRNAS WERE UPREGULATED AND 6 SNRNAS WERE DOWNREGULATED DURING CHONDROCYTE SENESCENCE, AND THAT SNRNA ENSMUSG00000064682 OVEREXPRESSION DELAYED CHONDROCYTE SENESCENCE. WE FOUND THAT 1 RASIRNA WAS UPREGULATED AND 4 RASIRNAS WERE DOWNREGULATED DURING CHONDROCYTE SENESCENCE. CONCLUSIONS: THESE FINDINGS MIGHT PROVIDE NOVEL INSIGHTS INTO OA PATHOGENESIS AND CONTRIBUTE TO THE DEVELOPMENT OF CANDIDATES FOR TARGETED THERAPEUTICS IN OA. 2022 11 5796 32 STAT3 PROMOTES A YOUTHFUL EPIGENETIC STATE IN ARTICULAR CHONDROCYTES. EPIGENETIC MECHANISMS GUIDING ARTICULAR CARTILAGE REGENERATION AND AGE-RELATED DISEASE SUCH AS OSTEOARTHRITIS (OA) ARE POORLY UNDERSTOOD. STAT3 IS A CRITICAL AGE-PATTERNED TRANSCRIPTION FACTOR HIGHLY ACTIVE IN FETAL AND OA CHONDROCYTES, BUT THE CONTEXT-SPECIFIC ROLE OF STAT3 IN REGULATING THE EPIGENOME OF CARTILAGE CELLS REMAIN ELUSIVE. IN THIS STUDY, DNA METHYLATION PROFILING WAS PERFORMED ACROSS HUMAN CHONDROCYTE ONTOGENY TO BUILD AN EPIGENETIC CLOCK AND ESTABLISH AN ASSOCIATION BETWEEN CPG METHYLATION AND HUMAN CHONDROCYTE AGE. EXPOSURE OF ADULT CHONDROCYTES TO A SMALL MOLECULE STAT3 AGONIST DECREASED DNA METHYLATION, WHILE GENETIC ABLATION OF STAT3 IN FETAL CHONDROCYTES INDUCED GLOBAL HYPERMETHYLATION. CUT&RUN ASSAY AND SUBSEQUENT TRANSCRIPTIONAL VALIDATION REVEALED DNA METHYLTRANSFERASE 3 BETA (DNMT3B) AS ONE OF THE PUTATIVE STAT3 TARGETS IN CHONDROCYTE DEVELOPMENT AND OA. FUNCTIONAL ASSESSMENT OF HUMAN OA CHONDROCYTES SHOWED THE ACQUISITION OF PROGENITOR-LIKE IMMATURE PHENOTYPE BY A SIGNIFICANT SUBSET OF CELLS. FINALLY, CONDITIONAL DELETION OF STAT3 IN CARTILAGE CELLS INCREASED DNMT3B EXPRESSION IN ARTICULAR CHONDROCYTES IN THE KNEE JOINT IN VIVO AND RESULTED IN A MORE PROMINENT OA PROGRESSION IN A POST-TRAUMATIC OA (PTOA) MOUSE MODEL INDUCED BY DESTABILIZATION OF THE MEDIAL MENISCUS (DMM). TAKEN TOGETHER THESE DATA REVEAL A NOVEL ROLE FOR STAT3 IN REGULATING DNA METHYLATION IN CARTILAGE DEVELOPMENT AND DISEASE. OUR FINDINGS ALSO SUGGEST THAT ELEVATED LEVELS OF ACTIVE STAT3 IN OA CHONDROCYTES MAY INDICATE AN INTRINSIC ATTEMPT OF THE TISSUE TO REGENERATE BY PROMOTING A PROGENITOR-LIKE PHENOTYPE. HOWEVER, IT IS LIKELY THAT CHRONIC ACTIVATION OF THIS PATHWAY, INDUCED BY IL-6 CYTOKINES, IS DETRIMENTAL AND LEADS TO TISSUE DEGENERATION. 2023 12 4296 43 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 13 5052 29 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 14 757 26 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 15 6741 20 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 16 296 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 17 4679 36 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 18 1547 28 DNA METHYLATION IN OSTEOARTHRITIS. OSTEOARTHRITIS (OA) IS A PREVALENT DISEASE OF ARTICULAR JOINTS AND PRIMARILY CHARACTERIZED BY DEGRADATION AND CALCIFICATION OF ARTICULAR CARTILAGE. PRESENTLY, NO EFFECTIVE TREATMENT OTHER THAN PAIN RELIEF EXISTS AND PATIENTS ULTIMATELY NEED TO UNDERGO REPLACEMENT SURGERY OF THE AFFECTED JOINT. DURING DISEASE PROGRESSION ARTICULAR CHONDROCYTES, THE SINGLE CELL TYPE PRESENT IN ARTICULAR CARTILAGE, SHOW ALTERED TRANSCRIPTIONAL PROFILES AND UNDERGO PHENOTYPIC CHANGES THAT RESEMBLE THE TERMINAL DIFFERENTIATION ROUTE APPARENT IN GROWTH PLATE CHONDROCYTES. HENCE, GIVEN ITS PROMINENT FUNCTION IN BOTH REGULATING GENE EXPRESSION AND MAINTAINING CELLULAR PHENOTYPES, DNA METHYLATION OF CPG DINUCLEOTIDES IS INTENSIVELY STUDIED IN THE CONTEXT OF OA. AN INCREASING NUMBER OF STUDIES HAVE BEEN PUBLISHED THAT EMPLOYED A TARGETED APPROACH ON GENES KNOWN TO PLAY A ROLE IN OA PATHOPHYSIOLOGY. AS OF SUCH, IT HAS BECOME CLEAR THAT OA RESPONSIVE DNA METHYLATION CHANGES SEEM TO MEDIATE DISEASE ASSOCIATED ABERRANT GENE EXPRESSION. FURTHERMORE, ESTABLISHED OA SUSCEPTIBILITY ALLELES SUCH AS GDF5 AND DIO2 APPEAR TO CONFER OA RISK VIA DNA METHYLATION AND RESPECTIVE PATHOPHYSIOLOGICAL EXPRESSION CHANGES. IN MORE RECENT YEARS, GENOME WIDE PROFILING OF DNA METHYLATION IN OA AFFECTED ARTICULAR CARTILAGE HAS EMERGED AS A POWERFUL TOOL TO ADDRESS THE EPIGENETIC CHANGES IN THEIR ENTIRETY, WHICH HAS RESULTED IN THE IDENTIFICATION OF PUTATIVE PATIENT SUBGROUPS AS WELL AS GENERIC OA ASSOCIATED PATHWAYS. 2015 19 1257 24 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 20 5109 35 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