1 484 153 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 2 5109 44 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 3 3800 45 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 4 2309 35 EPIGENETIC REGULATION OF CHONDROCYTES AND SUBCHONDRAL BONE IN OSTEOARTHRITIS. THE AIM OF THIS REVIEW IS TO PROVIDE AN UPDATED REVIEW OF THE EPIGENETIC FACTORS INVOLVED IN THE ONSET AND DEVELOPMENT OF OSTEOARTHRITIS (OA). OA IS A PREVALENT DEGENERATIVE JOINT DISEASE CHARACTERIZED BY CHRONIC INFLAMMATION, ECTOPIC BONE FORMATION WITHIN THE JOINT, AND PHYSICAL AND PROTEOLYTIC CARTILAGE DEGRADATION WHICH RESULT IN CHRONIC PAIN AND LOSS OF MOBILITY. AT PRESENT, NO DISEASE-MODIFYING THERAPEUTICS EXIST FOR THE PREVENTION OR TREATMENT OF THE DISEASE. RESEARCH HAS IDENTIFIED SEVERAL OA RISK FACTORS INCLUDING MECHANICAL STRESSORS, PHYSICAL ACTIVITY, OBESITY, TRAUMATIC JOINT INJURY, GENETIC PREDISPOSITION, AND AGE. RECENTLY, THERE HAS BEEN INCREASED INTEREST IN IDENTIFYING EPIGENETIC FACTORS INVOLVED IN THE PATHOGENESIS OF OA. IN THIS REVIEW, WE DETAIL SEVERAL OF THESE EPIGENETIC MODIFICATIONS WITH KNOWN FUNCTIONS IN THE ONSET AND PROGRESSION OF THE DISEASE. WE ALSO REVIEW CURRENT THERAPEUTICS TARGETING ABERRANT EPIGENETIC REGULATION AS POTENTIAL OPTIONS FOR PREVENTIVE OR THERAPEUTIC TREATMENT. 2022 5 296 39 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 3829 28 INVOLVEMENT OF EPIGENETICS IN OSTEOARTHRITIS. OSTEOARTHRITIS (OA) IS THE MOST PREVALENT CHRONIC AGE-RELATED ARTHRITIC DISEASE THAT MAINLY AFFECTS THE DIARTHRODIAL JOINTS. NEVERTHELESS, THERE IS NO TREATMENT CURRENTLY AVAILABLE THAT CAN EFFECTIVELY REDUCE SYMPTOMS OR SLOW DOWN OR STOP DISEASE PROGRESSION. THE LACK OF DISEASE-MODIFYING THERAPIES COULD BE EXPLAINED BY THE COMPLEX PATHOGENESIS OF OA, WHICH IS STILL NOT COMPLETELY UNDERSTOOD. INTERTWINED EPIGENETIC MECHANISMS SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS, AND NONCODING RNAS (NCRNAS) HAVE BEEN INDICATED AS IMPORTANT CELLULAR TOOLS TO MAINTAIN TISSUE HOMEOSTASIS UPON ENVIRONMENTAL CHALLENGES. THE CURRENT REVIEW ILLUSTRATES THAT DYSFUNCTIONAL EPIGENETIC CONTROL MECHANISMS IN THE ARTICULAR CARTILAGE LIKELY PLAY AN IMPORTANT ROLE IN DRIVING OA PATHOPHYSIOLOGY. 2017 7 2460 34 EPIGENETIC THERAPIES FOR OSTEOARTHRITIS. OSTEOARTHRITIS (OA) IS AN AGE-ASSOCIATED DISEASE CHARACTERIZED BY CHRONIC JOINT PAIN RESULTING FROM DEGRADATION OF ARTICULAR CARTILAGE, INFLAMMATION OF THE SYNOVIAL LINING, AND CHANGES TO THE SUBCHONDRAL BONE. DESPITE THE WIDE PREVALENCE, NO FDA-APPROVED DISEASE-MODIFYING DRUGS EXIST. RECENT EVIDENCE HAS DEMONSTRATED THAT EPIGENETIC DYSREGULATION OF MULTIPLE MOLECULAR PATHWAYS UNDERLIES OA PATHOGENESIS, PROVIDING A NEW MECHANISTIC AND THERAPEUTIC AXIS WITH THE ADVANTAGE OF TARGETING MULTIPLE DEREGULATED PATHWAYS SIMULTANEOUSLY. IN THIS REVIEW, WE FOCUS ON THE EPIGENETIC REGULATORS THAT HAVE BEEN IMPLICATED IN OA, THEIR INDIVIDUAL ROLES, AND POTENTIAL CROSSTALK. FINALLY, WE DISCUSS THE PHARMACOLOGICAL MOLECULES THAT CAN MODULATE THEIR ACTIVITIES AND DISCUSS THE POTENTIAL ADVANTAGES AND CHALLENGES ASSOCIATED WITH EPIGENOME-BASED THERAPEUTICS FOR OA. 2020 8 4776 39 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 9 5724 40 SKELETAL MUSCLE WASTING AND ITS RELATIONSHIP WITH OSTEOARTHRITIS: A MINI-REVIEW OF MECHANISMS AND CURRENT INTERVENTIONS. PURPOSE OF REVIEW: OSTEOARTHRITIS (OA) IS A SUBSET OF JOINT DISORDERS RESULTING IN DEGENERATION OF SYNOVIAL JOINTS. THIS LEADS TO PAIN, DISABILITY AND LOSS OF INDEPENDENCE. KNEE AND HIP OA ARE EXTREMELY PREVALENT, AND THEIR OCCURRENCE INCREASES WITH AGEING. SIMILARLY, LOSS OF MUSCLE MASS AND FUNCTION, SARCOPENIA, OCCURS DURING AGEING. RECENT FINDINGS: LITTLE IS KNOWN ABOUT THE IMPACT OF MUSCLE WASTING ON OA PROGRESSION; NEVERTHELESS, IT HAS BEEN SUGGESTED THAT MUSCLE WASTING DIRECTLY AFFECTS THE STABILITY OF THE JOINTS AND LOSS OF MOBILITY LEADS TO GRADUAL DEGENERATION OF ARTICULAR CARTILAGE. THE MOLECULAR MECHANISMS UNDERLYING MUSCLE WASTING IN OA ARE NOT WELL UNDERSTOOD; HOWEVER, THESE ARE PROBABLY RELATED TO CHANGES IN GENE EXPRESSION, AS WELL AS EPIGENETIC MODIFICATIONS. IT IS BECOMING CLEAR THAT SKELETAL MUSCLE WASTING PLAYS AN IMPORTANT ROLE IN OA DEVELOPMENT AND/OR PROGRESSION. HERE, WE DISCUSS MECHANISMS, CURRENT INTERVENTIONS, SUCH AS EXERCISE, AND POTENTIALLY NOVEL APPROACHES, SUCH AS MODULATION OF MICRORNAS, AIMING AT AMELIORATING OA SYMPTOMS THROUGH MAINTAINING MUSCLE MASS AND FUNCTION. 2019 10 4679 38 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 11 797 37 CELLULAR SENESCENCE IN OSTEOARTHRITIS PATHOLOGY. CELLULAR SENESCENCE IS A STATE OF STABLE PROLIFERATION ARREST OF CELLS. THE SENESCENCE PATHWAY HAS MANY BENEFICIAL EFFECTS AND IS SEEN TO BE ACTIVATED IN DAMAGED/STRESSED CELLS, AS WELL AS DURING EMBRYONIC DEVELOPMENT AND WOUND HEALING. HOWEVER, THE PERSISTENCE AND ACCUMULATION OF SENESCENT CELLS IN VARIOUS TISSUES CAN ALSO IMPAIR FUNCTION AND HAVE BEEN IMPLICATED IN THE PATHOGENESIS OF MANY AGE-RELATED DISEASES. OSTEOARTHRITIS (OA), A SEVERELY DEBILITATING CHRONIC CONDITION CHARACTERIZED BY PROGRESSIVE TISSUE REMODELING AND LOSS OF JOINT FUNCTION, IS THE MOST PREVALENT DISEASE OF THE SYNOVIAL JOINTS, AND INCREASING AGE IS THE PRIMARY OA RISK FACTOR. THE PROFILE OF INFLAMMATORY AND CATABOLIC MEDIATORS PRESENT DURING THE PATHOGENESIS OF OA IS STRIKINGLY SIMILAR TO THE SECRETORY PROFILE OBSERVED IN 'CLASSICAL' SENESCENT CELLS. DURING OA, CHONDROCYTES (THE SOLE CELL TYPE PRESENT WITHIN ARTICULAR CARTILAGE) EXHIBIT INCREASED LEVELS OF VARIOUS SENESCENCE MARKERS, SUCH AS SENESCENCE-ASSOCIATED BETA-GALACTOSIDASE (SABETAGAL) ACTIVITY, TELOMERE ATTRITION, AND ACCUMULATION OF P16INK4A. THIS SUGGESTS THE HYPOTHESIS THAT SENESCENCE OF CELLS WITHIN JOINT TISSUES MAY PLAY A PATHOLOGICAL ROLE IN THE CAUSATION OF OA. IN THIS REVIEW, WE DISCUSS THE MECHANISMS BY WHICH SENESCENT CELLS MAY PREDISPOSE SYNOVIAL JOINTS TO THE DEVELOPMENT AND/OR PROGRESSION OF OA, AS WELL AS TOUCHING UPON VARIOUS EPIGENETIC ALTERATIONS ASSOCIATED WITH BOTH OA AND SENESCENCE. 2017 12 6218 35 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 13 1047 31 CLINICAL EFFECT AND BIOLOGICAL MECHANISM OF EXERCISE FOR RHEUMATOID ARTHRITIS: A MINI REVIEW. RHEUMATOID ARTHRITIS (RA) IS A COMMON SYSTEMATIC, CHRONIC INFLAMMATORY, AUTOIMMUNE, AND POLYARTICULAR DISEASE, CAUSING A RANGE OF CLINICAL MANIFESTATIONS, INCLUDING JOINT SWELLING, REDNESS, PAIN, STIFFNESS, FATIGUE, DECREASED QUALITY OF LIFE, PROGRESSIVE DISABILITY, CARDIOVASCULAR PROBLEMS, AND OTHER COMORBIDITIES. STRONG EVIDENCE HAS SHOWN THAT EXERCISE IS EFFECTIVE FOR RA TREATMENT IN VARIOUS CLINICAL DOMAINS. EXERCISE TRAINING FOR RELATIVELY LONGER PERIODS (E.G., >/= 12 WEEKS) CAN DECREASE DISEASE ACTIVITY OF RA. HOWEVER, THE MECHANISM UNDERLYING THE EFFECTIVENESS OF EXERCISE IN REDUCING RA DISEASE ACTIVITY REMAINS UNCLEAR. THIS REVIEW FIRST SUMMARIZES AND HIGHLIGHTS THE EFFECTIVENESS OF EXERCISE IN RA TREATMENT. THEN, WE INTEGRATE CURRENT EVIDENCE AND PROPOSE BIOLOGICAL MECHANISMS RESPONSIBLE FOR THE POTENTIAL EFFECTS OF EXERCISE ON IMMUNE CELLS AND IMMUNITY, INFLAMMATORY RESPONSE, MATRIX METALLOPROTEINASES, OXIDATIVE STRESS, AND EPIGENETIC REGULATION. HOWEVER, A LARGE BODY OF EVIDENCE WAS OBTAINED FROM THE NON-RA POPULATIONS. FUTURE STUDIES ARE NEEDED TO FURTHER EXAMINE THE PROPOSED BIOLOGICAL MECHANISMS RESPONSIBLE FOR THE EFFECTIVENESS OF EXERCISE IN DECREASING DISEASE ACTIVITY IN RA POPULATIONS. SUCH KNOWLEDGE WILL CONTRIBUTE TO THE BASIC SCIENCE AND STRENGTHEN THE SCIENTIFIC BASIS OF THE PRESCRIPTION OF EXERCISE THERAPY FOR RA IN THE CLINICAL ROUTINE. 2022 14 757 31 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 1547 31 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 16 3020 39 GENETICS AND EPIGENETICS OF OSTEOARTHRITIS. OSTEOARTHRITIS (OA) IS A COMMON AGE-RELATED DISEASE THAT AFFECTS THE TISSUES OF THE SYNOVIAL JOINT, LEADING TO LOSS OF FUNCTION AND PAIN. IT IMPACTS ON BOTH PATIENT MORBIDITY AND MORTALITY. IT IS A COMPLEX, POLYGENIC DISEASE THAT LACKS ANY LARGE-EFFECT SUSCEPTIBILITY LOCI. INSTEAD, OA SUSCEPTIBILITY ALLELES INDIVIDUALLY CONTRIBUTE ONLY MODESTLY TO THE OVERALL DISEASE RISK, MAKING THEIR IDENTIFICATION CHALLENGING. DESPITE THIS, BREAKTHROUGHS HAVE OCCURRED WITH COMPELLING ASSOCIATIONS SO FAR REPORTED TO POLYMORPHISMS WITHIN THE GENES GDF5 AND MCF2L AND TO THE GENOMIC REGION 7Q22. THE LATTER TWO HAVE EMERGED FROM GENOME-WIDE ASSOCIATION SCANS, WHICH ARE LIKELY TO YIELD MORE HITS IN THE NEAR FUTURE. AS FOR MANY COMPLEX DISEASES, IT IS NOW APPARENT THAT EPIGENETIC EFFECTS ARE ALSO IMPORTANT MEDIATORS OF DISEASE BIOLOGY, WITH DNA METHYLATION, HISTONE MODIFICATIONS AND NON-CODING RNAS ALL HAVING A ROLE. AT PRESENT, MUCH OF THE EPIGENETIC FOCUS HAS BEEN ON CARTILAGE, THE TISSUE AT THE CENTER OF THE OA DISEASE PROCESS. IF WE ARE TO GET CLOSE TO A QUALITATIVE AND QUANTITATIVE UNDERSTANDING OF THE IMPACT OF EPIGENETICS ON OA, THEN IN FUTURE THE OTHER TISSUES OF THE JOINT WILL ALSO NEED TO BE INVESTIGATED. ONE OF THE MORE EXCITING INSIGHTS TO HAVE EMERGED RECENTLY IS THE FACT THAT EPIGENETIC EFFECTS CAN IMPACT ON OA GENETIC EFFECTS AND THIS MAY BE A PARTICULARLY FRUITFUL AVENUE FOR INTEGRATING BOTH AS WE MOVE TOWARD A CLEARER UNDERSTANDING OF THE PATHOPHYSIOLOGY OF THIS INTRIGUING DISEASE. 2012 17 2232 37 EPIGENETIC MODIFICATIONS OF MIRNAS IN OSTEOARTHRITIS: A SYSTEMATIC REVIEW ON THEIR METHYLATION LEVELS AND EFFECTS ON CHONDROCYTES, EXTRACELLULAR MATRIX AND JOINT INFLAMMATION. OSTEOARTHRITIS (OA) IS A JOINT DISORDER CHARACTERIZED BY PROGRESSIVE DEGENERATION OF CARTILAGE EXTRACELLULAR MATRIX (ECM), CHONDROCYTE HYPERTROPHY AND APOPTOSIS AND INFLAMMATION. THE CURRENT TREATMENTS MAINLY CONCERN PAIN CONTROL AND REDUCTION OF INFLAMMATION, BUT NO THERAPEUTIC STRATEGY HAS BEEN IDENTIFIED AS A DISEASE-MODIFYING TREATMENT. THEREFORE, IDENTIFYING SPECIFIC BIOMARKERS USEFUL TO PREVENT, TREAT OR DISTINGUISH THE STAGES OF OA DISEASE HAS BECOME AN IMMEDIATE NEED OF CLINICAL PRACTICE. THE ROLE OF MICRORNAS (MIRNAS) IN OA HAS BEEN INVESTIGATED IN THE LAST DECADE, AND INCREASING EVIDENCE HAS EMERGED THAT THE INFLUENCE OF THE ENVIRONMENT ON GENE EXPRESSION THROUGH EPIGENETIC PROCESSES CONTRIBUTES TO THE DEVELOPMENT, PROGRESSION AND AGGRESSIVENESS OF OA, IN PARTICULAR ACTING ON THE MICROENVIRONMENT MODULATIONS. THE EFFECTS OF EPIGENETIC REGULATION, PARTICULARLY DIFFERENT MIRNA METHYLATION DURING OA DISEASE, WERE HIGHLIGHTED IN THE PRESENT SYSTEMATIC REVIEW. THE EVIDENCE ARISING FROM THIS STUDY OF THE LITERATURE CONDUCTED IN THREE DATABASES (PUBMED, SCOPUS, WEB OF SCIENCE) SUGGESTED THAT MIRNA METHYLATION STATE ALREADY STRONGLY IMPACTS OA PROGRESSION, DRIVING CHONDROCYTES AND SYNOVIOCYTE PROLIFERATION, APOPTOSIS, INFLAMMATION AND ECM DEPOSITION. HOWEVER, THE POSSIBILITY OF UNDERSTANDING THE MECHANISM BY WHICH DIFFERENT EPIGENETIC MODIFICATIONS OF MIRNA OR PRE-MIRNA SEQUENCES DRIVE THE AGGRESSIVENESS OF OA COULD BE THE NEW FOCUS OF FUTURE INVESTIGATIONS. 2023 18 1258 34 CURRENT UNDERSTANDING OF OSTEOARTHRITIS PATHOGENESIS AND RELEVANT NEW APPROACHES. OSTEOARTHRITIS (OA) IS THE MOST COMMON DEGENERATIVE JOINT DISEASE THAT CAUSES PAINFUL SWELLING AND PERMANENT DAMAGE TO THE JOINTS IN THE BODY. THE MOLECULAR MECHANISMS OF OA ARE CURRENTLY UNKNOWN. OA IS A HETEROGENEOUS DISEASE THAT AFFECTS THE ENTIRE JOINT, AND MULTIPLE TISSUES ARE ALTERED DURING OA DEVELOPMENT. TO BETTER UNDERSTAND THE PATHOLOGICAL MECHANISMS OF OA, NEW APPROACHES, METHODS, AND TECHNIQUES NEED TO BE USED TO UNDERSTAND OA PATHOGENESIS. IN THIS REVIEW, WE FIRST FOCUS ON THE EPIGENETIC REGULATION OF OA, WITH A PARTICULAR FOCUS ON DNA METHYLATION, HISTONE MODIFICATION, AND MICRORNA REGULATION, FOLLOWED BY A SUMMARY OF SEVERAL KEY MEDIATORS IN OA-ASSOCIATED PAIN. WE THEN INTRODUCE SEVERAL INNOVATIVE TECHNIQUES THAT HAVE BEEN AND WILL CONTINUE TO BE USED IN THE FIELDS OF OA AND OA-ASSOCIATED PAIN, SUCH AS CRISPR, SCRNA SEQUENCING, AND LINEAGE TRACING. NEXT, WE DISCUSS THE TIMELY UPDATES CONCERNING CELL DEATH REGULATION IN OA PATHOLOGY, INCLUDING PYROPTOSIS, FERROPTOSIS, AND AUTOPHAGY, AS WELL AS THEIR INDIVIDUAL ROLES IN OA AND POTENTIAL MOLECULAR TARGETS IN TREATING OA. FINALLY, OUR REVIEW HIGHLIGHTS NEW DIRECTIONS ON THE ROLE OF THE SYNOVIAL LYMPHATIC SYSTEM IN OA. AN IMPROVED UNDERSTANDING OF OA PATHOGENESIS WILL AID IN THE DEVELOPMENT OF MORE SPECIFIC AND EFFECTIVE THERAPEUTIC INTERVENTIONS FOR OA. 2022 19 6102 33 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 20 410 27 ANALYSIS OF GENETICS AND DNA METHYLATION IN OSTEOARTHRITIS: WHAT HAVE WE LEARNT ABOUT THE DISEASE? OSTEOARTHRITIS (OA) IS A CHRONIC MUSCULOSKELETAL DISEASE CHARACTERISED BY THE DESTRUCTION OF ARTICULAR CARTILAGE, SYNOVIAL INFLAMMATION AND BONE REMODELLING. DISEASE AETIOLOGY IS COMPLEX AND HIGHLY HERITABLE, WITH GENETIC VARIATION ESTIMATED TO CONTRIBUTE TO 50% OF OA OCCURRENCE. EPIGENETIC ALTERATIONS, INCLUDING DNA METHYLATION CHANGES, HAVE ALSO BEEN IMPLICATED IN OA PATHOPHYSIOLOGY. THIS REVIEW EXAMINES WHAT GENETIC AND DNA METHYLATION STUDIES HAVE TAUGHT US ABOUT THE GENES AND PATHWAYS INVOLVED IN OA PATHOLOGY. THE INFLUENCE OF DNA METHYLATION ON THE MOLECULAR MECHANISMS UNDERLYING OA GENETIC RISK AND THE CONSEQUENCE OF THIS INTERACTION ON DISEASE SUSCEPTIBILITY AND PENETRANCE ARE ALSO DISCUSSED. 2017