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 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 3 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 4 2232 34 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 5 4745 25 NOVEL INSIGHTS OF EZH2-MEDIATED EPIGENETIC MODIFICATIONS IN DEGENERATIVE MUSCULOSKELETAL DISEASES. DEGENERATIVE MUSCULOSKELETAL DISEASES (OSTEOPOROSIS, OSTEOARTHRITIS, DEGENERATIVE SPINAL DISEASE AND SARCOPENIA) ARE PATHOLOGICAL CONDITIONS THAT AFFECT THE FUNCTION AND PAIN OF TISSUES SUCH AS BONE, CARTILAGE, AND MUSCLES, AND ARE CLOSELY ASSOCIATED WITH AGEING AND LONG-TERM DEGENERATION. ENHANCER OF ZESTE HOMOLOG 2 (EZH2), AN IMPORTANT EPIGENETIC REGULATOR, REGULATES GENE EXPRESSION MAINLY THROUGH THE PRC2-DEPENDENT TRIMETHYLATION OF HISTONE H3 AT LYSINE 27 (H3K27ME3). INCREASING EVIDENCE SUGGESTS THAT EZH2 IS INVOLVED IN SEVERAL BIOLOGICAL PROCESSES CLOSELY RELATED TO DEGENERATIVE MUSCULOSKELETAL DISEASES, SUCH AS OSTEOGENIC-ADIPOGENIC DIFFERENTIATION OF BONE MARROW MESENCHYMAL STEM CELLS, OSTEOCLAST ACTIVATION, CHONDROCYTE FUNCTIONAL STATUS, AND SATELLITE CELL PROLIFERATION AND DIFFERENTIATION, MAINLY THROUGH EPIGENETIC REGULATION (H3K27ME3). THEREFORE, THE SYNTHESIS AND ELUCIDATION OF THE ROLE OF EZH2 IN DEGENERATIVE MUSCULOSKELETAL DISEASES HAVE ATTRACTED INCREASING ATTENTION. IN ADDITION, ALTHOUGH EZH2 INHIBITORS HAVE BEEN APPROVED FOR CLINICAL USE, WHETHER THEY CAN BE REPURPOSED FOR THE TREATMENT OF DEGENERATIVE MUSCULOSKELETAL DISEASES NEEDS TO BE CONSIDERED. HERE, WE REVIEWED THE ROLE OF EZH2 IN THE DEVELOPMENT OF DEGENERATIVE MUSCULOSKELETAL DISEASES AND BROUGHT FORWARD PROSPECTS OF ITS PHARMACOLOGICAL INHIBITORS IN THE IMPROVEMENT OF THE TREATMENT OF THE DISEASES. 2023 6 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 7 797 32 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 8 2508 23 EPIGENETICS AND OSTEOARTHRITIS. OSTEOARTHRITIS (OA) IS THE MOST COMMON FORM OF JOINT DISEASE AND THE LEADING CAUSE OF CHRONIC DISABILITY IN MIDDLE-AGED AND OLDER POPULATIONS. THE DEVELOPMENT OF DISEASE-MODIFYING THERAPY FOR OA CURRENTLY FACES MAJOR OBSTACLES LARGELY BECAUSE THE REGULATORY MECHANISMS FOR THE FUNCTION OF JOINT TISSUE CELLS REMAIN UNCLEAR. PREVIOUS STUDIES HAVE FOUND THAT THE ALTERATIONS IN GENE EXPRESSION OF SPECIFIC TRANSCRIPTION FACTORS (TFS), PRO- OR ANTI-INFLAMMATORY CYTOKINES, MATRIX PROTEINASES AND EXTRACELLULAR MATRIX (ECM) PROTEINS IN ARTICULAR CARTILAGE MAY BE INVOLVED IN THE DEVELOPMENT OF OA. HOWEVER, THE REGULATORY MECHANISMS FOR THE EXPRESSION OF THOSE GENES IN OA CHONDROCYTES ARE LARGELY UNKNOWN. THE RECENT ADVANCES IN EPIGENETIC STUDIES HAVE SHED LIGHTS ON THE IMPORTANCE OF EPIGENETIC REGULATION OF GENE EXPRESSION IN THE DEVELOPMENT OF OA. IN THIS REVIEW, WE SUMMARIZE AND DISCUSS THE RECENT STUDIES ON THE REGULATORY ROLES OF VARIOUS EPIGENETIC MECHANISMS IN THE EXPRESSION OF GENES FOR SPECIFIC TFS, CYTOKINES, ECM PROTEINS AND MATRIX PROTEINASES, AS WELL THE SIGNIFICANCE OF THESE EPIGENETIC MECHANISMS IN THE PATHOGENESIS OF OA. 2015 9 4289 31 MICRORNA IN OSTEOARTHRITIS. OSTEOARTHRITIS (OA) IS THE MOST PREVALENT DEGENERATIVE JOINT DISEASE AND IS ACCOMPANIED BY PAIN AND JOINT DYSFUNCTION. ITS CLINICAL TREATMENT TENDS TO BE UNSATISFACTORY. NOVEL TARGETS IN OA INCLUDE GENES THAT ARE INVOLVED IN OA PATHOPHYSIOLOGY AND HAVE BEEN DISCOVERED USING GENE NETWORK, EPIGENETIC AND MICRORNA (MIRNA) APPROACHES. MIRNA HAS BEEN IMPLICATED IN IMPORTANT CELLULAR PROCESSES SUCH AS LIPID METABOLISM, APOPTOSIS, DIFFERENTIATION AND ORGAN DEVELOPMENT. THE IMPORTANCE OF MIRNA REGULATION IN CELLULAR FUNCTION IS BECOMING INCREASINGLY CLEAR AS NEW MIRNA TARGETS ARE REVEALED. THE PRESENT REVIEW SUMMARIZES THE CURRENT EVIDENCE OF THE IMPORTANT ROLE PLAYED BY MIRNA IN DETERMINING THE COMPLEX GENE EXPRESSION PATTERNS OF OA CHONDROCYTES AND THEIR ROLE IN THE REGULATION OF TRANSCRIPTION, AND POSSIBLE DEMETHYLATION MECHANISMS THAT MIGHT BE APPLICABLE IN OA. IN SUMMARY, MIRNA MAY HAVE IMPORTANT DIAGNOSTIC AND THERAPEUTIC POTENTIAL, AND MIGHT PROVIDE A NOVEL MEANS OF TREATING OA. 2011 10 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 11 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 12 2309 27 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 13 5724 33 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 14 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 15 2550 31 EPIGENETICS IN OSTEOARTHRITIS: POTENTIAL OF HDAC INHIBITORS AS THERAPEUTICS. OSTEOARTHRITIS (OA) IS THE MOST COMMON JOINT DISEASE AND THE LEADING CAUSE OF CHRONIC DISABILITY IN MIDDLE-AGED AND OLDER POPULATIONS WORLDWIDE. THE DEVELOPMENT OF DISEASE MODIFYING THERAPY FOR OA IS IN ITS INFANCY LARGELY BECAUSE THE REGULATORY MECHANISMS FOR THE MOLECULAR EFFECTORS OF OA PATHOGENESIS ARE POORLY UNDERSTOOD. RECENT STUDIES IDENTIFIED EPIGENETIC EVENTS AS A CRITICAL REGULATOR OF MOLECULAR PLAYERS INVOLVED IN THE INDUCTION AND DEVELOPMENT OF OA. EPIGENETIC MECHANISMS INCLUDE DNA METHYLATION, NON-CODING RNA AND HISTONE MODIFICATIONS. THE AIM OF THIS REVIEW IS TO BRIEFLY HIGHLIGHT THE RECENT ADVANCES IN THE EPIGENETICS OF CARTILAGE AND POTENTIAL OF HDACS (HISTONE DEACETYLASES) INHIBITORS IN THE THERAPEUTIC MANAGEMENT OF OA. WE SUMMARIZE THE RECENT STUDIES UTILIZING HDAC INHIBITORS AS POTENTIAL THERAPEUTICS FOR INHIBITING DISEASE PROGRESSION AND PREVENTING THE CARTILAGE DESTRUCTION IN OA. HDACS CONTROL NORMAL CARTILAGE DEVELOPMENT AND HOMEOSTASIS AND UNDERSTANDING THE IMPACT OF HDACS INHIBITORS ON THE DISEASE PATHOGENESIS IS OF INTEREST BECAUSE OF ITS IMPORTANCE IN AFFECTING OVERALL CARTILAGE HEALTH AND HOMEOSTASIS. THESE FINDINGS ALSO SHED NEW LIGHT ON CARTILAGE DISEASE PATHOPHYSIOLOGY AND PROVIDE SUBSTANTIAL EVIDENCE THAT HDACS MAY BE POTENTIAL NOVEL THERAPEUTIC TARGETS IN OA. 2018 16 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 17 3729 35 INHIBITION OF TET1 PREVENTS THE DEVELOPMENT OF OSTEOARTHRITIS AND REVEALS THE 5HMC LANDSCAPE THAT ORCHESTRATES PATHOGENESIS. OSTEOARTHRITIS (OA) IS A DEGENERATIVE DISEASE OF THE JOINT, WHICH RESULTS IN PAIN, LOSS OF MOBILITY, AND, EVENTUALLY, JOINT REPLACEMENT. CURRENTLY, NO DISEASE-MODIFYING DRUGS EXIST, PARTLY BECAUSE OF THE MULTIPLE LEVELS AT WHICH CARTILAGE HOMEOSTASIS IS DISRUPTED. RECENT STUDIES HAVE HIGHLIGHTED THE IMPORTANCE OF EPIGENETIC DYSREGULATION IN OA, SPARKING INTEREST IN THE EPIGENETIC MODULATION FOR THIS DISEASE. IN OUR PREVIOUS WORK, WE CHARACTERIZED A FIVEFOLD INCREASE IN CYTOSINE HYDROXYMETHYLATION (5HMC), AN OXIDIZED DERIVATIVE OF CYTOSINE METHYLATION (5MC) ASSOCIATED WITH GENE ACTIVATION, ACCUMULATING AT OA-ASSOCIATED GENES. TO TEST THE ROLE OF 5HMC IN OA, HERE, WE USED A MOUSE MODEL OF SURGICALLY INDUCED OA AND FOUND THAT OA ONSET WAS ACCOMPANIED BY A GAIN OF ~40,000 DIFFERENTIALLY HYDROXYMETHYLATED SITES BEFORE THE NOTABLE HISTOLOGICAL APPEARANCE OF DISEASE. WE DEMONSTRATED THAT TEN-ELEVEN-TRANSLOCATION ENZYME 1 (TET1) MEDIATES THE 5HMC DEPOSITION BECAUSE 98% OF SITES ENRICHED FOR 5HMC IN OA WERE LOST IN TET1(-/-) MICE. LOSS OF TET1-MEDIATED 5HMC PROTECTED THE TET1(-/-) MICE FROM OA DEVELOPMENT, INCLUDING DEGENERATION OF THE CARTILAGE SURFACE AND OSTEOPHYTE FORMATION, BY DIRECTLY PREVENTING THE ACTIVATION OF MULTIPLE OA PATHWAYS. LOSS OF TET1 IN HUMAN OA CHONDROCYTES REDUCED THE EXPRESSION OF THE MATRIX METALLOPROTEINASES MMP3 AND MMP13 AND MULTIPLE INFLAMMATORY CYTOKINES. INTRA-ARTICULAR INJECTIONS OF A DIOXYGENASES INHIBITOR, 2-HYDROXYGLUTARATE, ON MICE AFTER SURGICAL INDUCTION OF OA STALLED DISEASE PROGRESSION. TREATMENT OF HUMAN OA CHONDROCYTES WITH THE SAME INHIBITOR ALSO PHENOCOPIED TET1 LOSS. COLLECTIVELY, THESE DATA DEMONSTRATE THAT TET1-MEDIATED 5HMC DEPOSITION REGULATES MULTIPLE OA PATHWAYS AND CAN BE MODULATED FOR THERAPEUTIC INTERVENTION. 2020 18 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 19 476 35 ARSENIC INDUCES FIBROGENIC CHANGES IN HUMAN KIDNEY EPITHELIAL CELLS POTENTIALLY THROUGH EPIGENETIC ALTERATIONS IN DNA METHYLATION. ARSENIC CONTAMINATION IS A SIGNIFICANT PUBLIC HEALTH ISSUE, AND KIDNEY IS ONE OF THE TARGET ORGAN FOR ARSENIC-INDUCED ADVERSE EFFECTS. RENAL FIBROSIS IS A WELL-KNOWN PATHOLOGICAL STAGE FREQUENTLY OBSERVED IN PROGRESSIVE CHRONIC KIDNEY DISEASE (CKD). EPIDEMIOLOGICAL STUDIES IMPLICATE ARSENIC EXPOSURE TO CKD, BUT THE ROLE OF ARSENIC IN KIDNEY FIBROSIS AND THE UNDERLYING MECHANISM IS STILL UNCLEAR. IT IS IN THIS CONTEXT THAT THE CURRENT STUDY EVALUATED THE EFFECTS OF LONG-TERM ARSENIC EXPOSURE ON THE CELLULAR RESPONSE IN MORPHOLOGY, AND MARKER GENES EXPRESSION WITH RESPECT TO FIBROSIS USING HUMAN KIDNEY 2 (HK-2) EPITHELIAL CELLS. RESULTS OF THIS STUDY REVEALED THAT IN ADDITION TO INCREASED GROWTH, HK-2 CELLS UNDERWENT PHENOTYPIC, BIOCHEMICAL AND MOLECULAR CHANGES INDICATIVE OF EPITHELIAL-MESENCHYMAL TRANSITION (EMT) IN RESPONSE TO THE EXPOSURE TO ARSENIC. MOST IMPORTANTLY, THE ARSENIC-EXPOSED CELLS ACQUIRED THE PATHOGENIC FEATURES OF FIBROSIS AS SUPPORTED BY INCREASED EXPRESSION OF MARKERS FOR FIBROSIS, SUCH AS COLLAGEN I, FIBRONECTIN, TRANSFORMING GROWTH FACTOR BETA, AND ALPHA-SMOOTH MUSCLE ACTIN. UPREGULATION OF FIBROSIS ASSOCIATED SIGNALING MOLECULES SUCH AS TISSUE INHIBITOR OF METALLOPROTEINASES-3 AND MATRIX METALLOPROTEINASE-2 AS WELL AS ACTIVATION OF AKT WAS ALSO OBSERVED. ADDITIONALLY, THE EXPRESSION OF EPIGENETIC GENES (DNA METHYLTRANSFERASES 3A AND 3B; METHYL-CPG BINDING DOMAIN 4) WAS INCREASED IN ARSENIC-EXPOSED CELLS. TREATMENT WITH DNA METHYLATION INHIBITOR 5-AZA-2'-DC REVERSED THE EMT PROPERTIES AND RESTORED THE LEVEL OF PHOSPHO-AKT. TOGETHER, THESE DATA FOR THE FIRST TIME SUGGEST THAT LONG-TERM EXPOSURE TO ARSENIC CAN INCREASE THE RISK OF KIDNEY FIBROSIS. ADDITIONALLY, OUR DATA SUGGEST THAT THE ARSENIC-INDUCED FIBROTIC CHANGES ARE, AT LEAST IN PART, MEDIATED BY DNA METHYLATION AND THEREFORE POTENTIALLY CAN BE REVERSED BY EPIGENETIC THERAPEUTICS. 2019 20 3322 27 HISTONE ACETYLTRANSFERASE P300 INDUCES DE NOVO SUPER-ENHANCERS TO DRIVE CELLULAR SENESCENCE. ACCUMULATION OF SENESCENT CELLS DURING AGING CONTRIBUTES TO CHRONIC INFLAMMATION AND AGE-RELATED DISEASES. WHILE SENESCENCE IS ASSOCIATED WITH PROFOUND ALTERATIONS OF THE EPIGENOME, A SYSTEMATIC VIEW OF EPIGENETIC FACTORS IN REGULATING SENESCENCE IS LACKING. HERE, WE CURATED A LIBRARY OF SHORT HAIRPIN RNAS FOR TARGETED SILENCING OF ALL KNOWN EPIGENETIC PROTEINS AND PERFORMED A HIGH-THROUGHPUT SCREEN TO IDENTIFY KEY CANDIDATES WHOSE DOWNREGULATION CAN DELAY REPLICATIVE SENESCENCE OF PRIMARY HUMAN CELLS. THIS SCREEN IDENTIFIED MULTIPLE NEW PLAYERS INCLUDING THE HISTONE ACETYLTRANSFERASE P300 THAT WAS FOUND TO BE A PRIMARY DRIVER OF THE SENESCENT PHENOTYPE. P300, BUT NOT THE PARALOGOUS CBP, INDUCES A DYNAMIC HYPER-ACETYLATED CHROMATIN STATE AND PROMOTES THE FORMATION OF ACTIVE ENHANCER ELEMENTS IN THE NON-CODING GENOME, LEADING TO A SENESCENCE-SPECIFIC GENE EXPRESSION PROGRAM. OUR WORK ILLUSTRATES A CAUSAL ROLE OF HISTONE ACETYLTRANSFERASES AND ACETYLATION IN SENESCENCE AND SUGGESTS P300 AS A POTENTIAL THERAPEUTIC TARGET FOR SENESCENCE AND AGE-RELATED DISEASES. 2019