1  3943 121 LNCRNA ENST00000563492 PROMOTING THE OSTEOGENESIS-ANGIOGENESIS COUPLING PROCESS IN BONE MESENCHYMAL STEM CELLS (BMSCS) BY FUNCTIONS AS A CERNA FOR MIR-205-5P. PAIN, PHYSICAL DYSFUNCTION, AND MENTAL DISORDERS CAUSED BY BONE NONUNION BRING GREAT BURDEN TO PATIENTS. BONE MESENCHYMAL STEM CELLS (BMSCS) ISOLATED FROM BONE NONUNION PATIENTS WITH POOR PROLIFERATION AND OSTEOGENIC ABILITY ARE COMPARED WITH THAT FROM NORMAL BONE-HEALING PATIENTS. LONG NONCODING RNAS (LNCRNAS) ARE A CLASS OF RNAS THAT ARE MORE THAN 200 NUCLEOTIDES IN LENGTH, LACK AN OPEN-READING FRAME ENCODING A PROTEIN, AND HAVE LITTLE OR NO PROTEIN-CODING FUNCTION, AND COULD REGULATE GENE EXPRESSION, WHICH IS INVOLVED IN THE REGULATION OF IMPORTANT LIFE ACTIVITIES, SUCH AS GROWTH, DEVELOPMENT, AGING, AND DEATH AT EPIGENETIC, TRANSCRIPTIONAL, AND POST-TRANSCRIPTIONAL LEVELS. IN THIS STUDY, WE INTENDED TO INVESTIGATE THE DIFFERENCE OF LNCRNA EXPRESSION BETWEEN PATIENTS WITH NONUNION AND NORMAL FRACTURE HEALING. OUR RESULT FOUND THAT LNCRNA ENST00000563492 WAS DOWNREGULATED IN BONE NONUNION TISSUES. LNCRNA ENST00000563492 PROMOTES OSTEOGENIC DIFFERENTIATION OF BMSCS THROUGH UPREGULATING THE EXPRESSION OF CDH11. ON THE OTHER HAND, LNCRNA ENST0000563492 COULD IMPROVE THE OSTEOGENESIS-ANGIOGENESIS COUPLING PROCESS THROUGH ENHANCING THE EXPRESSION OF VEGF DURING OSTEOGENIC DIFFERENTIATION OF BMSCS. LNCRNA ENST00000563492 FUNCTIONS AS A CERNA FOR MIR-205-5P THAT WAS TARGETING CDH11 AND VEGF. LNCRNA ENST00000563492 COULD PROMOTE THE OSTEOGENESIS OF BMSCS IN VIVO. OUR RESULT INDICATED THAT LNCRNA ENST00000563492 MAY BE A NEW TARGET FOR BONE NONUNION.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
2  1663  45 DOWNREGULATION OF DNA METHYLTRANSFERASE-3A AMELIORATES THE OSTEOGENIC DIFFERENTIATION ABILITY OF ADIPOSE-DERIVED STEM CELLS IN DIABETIC OSTEOPOROSIS VIA WNT/BETA-CATENIN SIGNALING PATHWAY. BACKGROUND: DIABETES-RELATED OSTEOPOROSIS (DOP) IS A CHRONIC DISEASE CAUSED BY THE HIGH GLUCOSE ENVIRONMENT THAT INDUCES A METABOLIC DISORDER OF OSTEOCYTES AND OSTEOBLAST-ASSOCIATED MESENCHYMAL STEM CELLS. THE PROCESSES OF BONE DEFECT REPAIR AND REGENERATION BECOME EXTREMELY DIFFICULT WITH DOP. ADIPOSE-DERIVED STEM CELLS (ASCS), AS SEED CELLS IN BONE TISSUE ENGINEERING TECHNOLOGY, PROVIDE A PROMISING THERAPEUTIC APPROACH FOR BONE REGENERATION IN DOP PATIENTS. THE OSTEOGENIC ABILITY OF ASCS IS LOWER IN A DOP MODEL THAN THAT OF CONTROL ASCS. DNA METHYLATION, AS A MECHANISM OF EPIGENETIC REGULATION, MAY BE INVOLVED IN DNA METHYLATION OF VARIOUS GENES, THEREBY PARTICIPATING IN BIOLOGICAL BEHAVIORS OF VARIOUS CELLS. EMERGING EVIDENCE SUGGESTS THAT INCREASED DNA METHYLATION LEVELS ARE ASSOCIATED WITH ACTIVATION OF WNT/BETA-CATENIN SIGNALING PATHWAY. THE PURPOSE OF THIS STUDY WAS TO INVESTIGATE THE INFLUENCE OF THE DIABETIC ENVIRONMENT ON THE OSTEOGENIC POTENTIAL OF ASCS, TO EXPLORE THE ROLE OF DNA METHYLATION ON OSTEOGENIC DIFFERENTIATION OF DOP-ASCS VIA WNT/BETA-CATENIN SIGNALING PATHWAY, AND TO IMPROVE THE OSTEOGENIC DIFFERENTIATION ABILITY OF ASCS WITH DOP. METHODS: DOP-ASCS AND CONTROL ASCS WERE ISOLATED FROM DOP C57BL/6 AND CONTROL MICE, RESPECTIVELY. THE MULTIPOTENCY OF DOP-ASCS WAS CONFIRMED BY ALIZARIN RED-S, OIL RED-O, AND ALCIAN BLUE STAINING. REAL-TIME POLYMERASE CHAIN REACTION (RT-PCR), IMMUNOFLUORESCENCE, AND WESTERN BLOTTING WERE USED TO ANALYZE CHANGES IN MARKERS OF OSTEOGENIC DIFFERENTIATION, DNA METHYLATION, AND WNT/BETA-CATENIN SIGNALING. ALIZARIN RED-S STAINING WAS ALSO USED TO CONFIRM CHANGES IN THE OSTEOGENIC ABILITY. DNMT SMALL INTERFERING RNA (SIRNA), SHRNA-DNMT3A, AND LVRNA-DNMT3A WERE USED TO ASSESS THE ROLE OF DNMT3A IN OSTEOGENIC DIFFERENTIATION OF CONTROL ASCS AND DOP-ASCS. MICRO-COMPUTED TOMOGRAPHY, HEMATOXYLIN AND EOSIN STAINING, AND MASSON STAINING WERE USED TO ANALYZE CHANGES IN THE OSTEOGENIC CAPABILITY WHILE DOWNREGULATING DNMT3A WITH LENTIVIRUS IN DOP MICE IN VIVO. RESULTS: THE PROLIFERATIVE ABILITY OF DOP-ASCS WAS LOWER THAN THAT OF CONTROL ASCS. DOP-ASCS SHOWED A DECREASE IN OSTEOGENIC DIFFERENTIATION CAPACITY, LOWER WNT/BETA-CATENIN SIGNALING PATHWAY ACTIVITY, AND A HIGHER LEVEL OF DNMT3A THAN CONTROL ASCS. WHEN DNMT3A WAS DOWNREGULATED BY SIRNA AND SHRNA, OSTEOGENIC-RELATED FACTORS RUNT-RELATED TRANSCRIPTION FACTOR 2 AND OSTEOPONTIN, AND ACTIVITY OF WNT/BETA-CATENIN SIGNALING PATHWAY WERE INCREASED, WHICH RESCUED THE POOR OSTEOGENIC POTENTIAL OF DOP-ASCS. WHEN DNMT3A WAS UPREGULATED BY LVRNA-DNMT3A, THE OSTEOGENIC ABILITY WAS INHIBITED. THE SAME RESULTS WERE OBTAINED IN VIVO. CONCLUSIONS: DNMT3A SILENCING RESCUES THE NEGATIVE EFFECTS OF DOP ON ASCS AND PROVIDES A POSSIBLE APPROACH FOR BONE TISSUE REGENERATION IN PATIENTS WITH DIABETIC OSTEOPOROSIS.	2022	

3  6658  33 UPREGULATED LNCRNA H19 SPONGES MIR-106A-5P AND CONTRIBUTES TO ALDOSTERONE-INDUCED VASCULAR CALCIFICATION VIA ACTIVATING THE RUNX2-DEPENDENT PATHWAY. BACKGROUND: EXCESS ALDOSTERONE IS IMPLICATED IN VASCULAR CALCIFICATION (VC), BUT THE MECHANISM BY WHICH ALDOSTERONE-MR (MINERALOCORTICOID RECEPTOR) COMPLEX PROMOTES VC IS UNCLEAR. EMERGING EVIDENCE INDICATES THAT LONG-NONCODING RNA H19 (H19) PLAYS A CRITICAL ROLE IN VC. WE EXAMINED WHETHER ALDOSTERONE-INDUCED OSTEOGENIC DIFFERENTIATION OF VASCULAR SMOOTH MUSCLE CELLS (VSMCS) THROUGH H19 EPIGENETIC MODIFICATION OF RUNX2 (RUNT-RELATED TRANSCRIPTION FACTOR-2) IN A MR-DEPENDENT MANNER. METHODS: WE INDUCED IN VIVO RAT MODEL OF CHRONIC KIDNEY DISEASE USING A HIGH ADENINE AND PHOSPHATE DIET TO EXPLORE THE RELATIONSHIP AMONG ALDOSTERONE, MR, H19, AND VC. WE ALSO CULTURED HUMAN AORTIC VSMCS TO EXPLORE THE ROLES OF H19 IN ALDOSTERONE-MR COMPLEX-INDUCED OSTEOGENIC DIFFERENTIATION AND CALCIFICATION OF VSMCS. RESULTS: H19 AND RUNX2 WERE SIGNIFICANTLY INCREASED IN ALDOSTERONE-INDUCED VSMC OSTEOGENIC DIFFERENTIATION AND VC, BOTH IN VITRO AND IN VIVO, WHICH WERE SIGNIFICANTLY BLOCKED BY THE MR ANTAGONIST SPIRONOLACTONE. MECHANISTICALLY, OUR FINDINGS REVEAL THAT THE ALDOSTERONE-ACTIVATED MR BOUND TO H19 PROMOTER AND INCREASED ITS TRANSCRIPTIONAL ACTIVITY, AS DETERMINED BY CHROMATIN IMMUNOPRECIPITATION, ELECTROPHORETIC MOBILITY SHIFT ASSAY, AND LUCIFERASE REPORTER ASSAY. SILENCING H19 INCREASED MICRORNA-106A-5P (MIR-106A-5P) EXPRESSION, WHICH SUBSEQUENTLY INHIBITED ALDOSTERONE-INDUCED RUNX2 EXPRESSION AT THE POSTTRANSCRIPTIONAL LEVEL. IMPORTANTLY, WE OBSERVED A DIRECT INTERACTION BETWEEN H19 AND MIR-106A-5P, AND DOWNREGULATION OF MIR-106A-5P EFFICIENTLY REVERSED THE SUPPRESSION OF RUNX2 INDUCED BY H19 SILENCING. CONCLUSIONS: OUR STUDY CLARIFIES A NOVEL MECHANISM BY WHICH UPREGULATION OF H19 CONTRIBUTES TO ALDOSTERONE-MR COMPLEX-PROMOTED RUNX2-DEPENDENT VSMC OSTEOGENIC DIFFERENTIATION AND VC THROUGH SPONGING MIR-106A-5P. THESE FINDINGS HIGHLIGHT A POTENTIAL THERAPEUTIC TARGET FOR ALDOSTERONE-INDUCED VC.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
4  3205  46 HDAC8, A POTENTIAL THERAPEUTIC TARGET, REGULATES PROLIFERATION AND DIFFERENTIATION OF BONE MARROW STROMAL CELLS IN FIBROUS DYSPLASIA. FIBROUS DYSPLASIA (FD) IS A DISEASE OF POSTNATAL SKELETAL STEM CELLS CAUSED BY ACTIVATING MUTATIONS OF GUANINE NUCLEOTIDE-BINDING PROTEIN ALPHA-STIMULATING ACTIVITY POLYPEPTIDE (GNAS). FD IS CHARACTERIZED BY HIGH PROLIFERATION AND OSTEOGENESIS DISORDER OF BONE MARROW STROMAL CELLS (BMSCS), RESULTING IN BONE PAIN, DEFORMITIES, AND FRACTURES. THE CAMP-CREB PATHWAY, WHICH IS ACTIVATED BY GNAS MUTATIONS, IS KNOWN TO BE CLOSELY ASSOCIATED WITH THE OCCURRENCE OF FD. HOWEVER, SO FAR THERE IS NO AVAILABLE TARGETED THERAPEUTIC STRATEGY FOR FD, AS A CRITICAL ISSUE THAT REMAINS LARGELY UNKNOWN IS HOW THIS PATHWAY IS INVOLVED IN FD. OUR PREVIOUS STUDY REVEALED THAT HISTONE DEACETYLASE 8 (HDAC8) INHIBITED THE OSTEOGENIC DIFFERENTIATION OF BMSCS VIA EPIGENETIC REGULATION. HERE, COMPARED WITH NORMAL BMSCS, FD BMSCS EXHIBITED SIGNIFICANTLY HIGH PROLIFERATION AND WEAK OSTEOGENIC CAPACITY IN RESPONSE TO HDAC8 UPREGULATION AND TUMOR PROTEIN 53 (TP53) DOWNREGULATION. MOREOVER, INHIBITION OF CAMP REDUCED HDAC8 EXPRESSION, INCREASED TP53 EXPRESSION AND RESULTED IN THE IMPROVEMENT OF FD PHENOTYPE. IMPORTANTLY, HDAC8 INHIBITION PREVENTED CAMP-INDUCED CELL PHENOTYPE AND PROMOTED OSTEOGENESIS IN NUDE MICE THAT WERE IMPLANTED WITH FD BMSCS. MECHANISTICALLY, HDAC8 WAS IDENTIFIED AS A TRANSCRIPTIONAL TARGET GENE OF CREB1 AND ITS TRANSCRIPTION WAS DIRECTLY ACTIVATED BY CREB1 IN FD BMSCS. IN SUMMARY, OUR STUDY REVEALS THAT HDAC8 ASSOCIATES WITH FD PHENOTYPE AND DEMONSTRATES THE MECHANISMS REGULATED BY CAMP-CREB1-HDAC8 PATHWAY. THESE RESULTS PROVIDE INSIGHTS INTO THE MOLECULAR REGULATION OF FD PATHOGENESIS, AND OFFER NOVEL CLUES THAT SMALL MOLECULE INHIBITORS TARGETING HDAC8 ARE PROMISING CLINICAL TREATMENT FOR FD. STEM CELLS TRANSLATIONAL MEDICINE 2019;8:148&14.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
5  5716  33 SIRT6 PROTECTS VASCULAR SMOOTH MUSCLE CELLS FROM OSTEOGENIC TRANSDIFFERENTIATION VIA RUNX2 IN CHRONIC KIDNEY DISEASE. VASCULAR CALCIFICATION (VC) IS REGARDED AS AN IMPORTANT PATHOLOGICAL CHANGE LACKING EFFECTIVE TREATMENT AND ASSOCIATED WITH HIGH MORTALITY. SIRTUIN 6 (SIRT6) IS A MEMBER OF THE SIRTUIN FAMILY, A CLASS III HISTONE DEACETYLASE AND A KEY EPIGENETIC REGULATOR. SIRT6 HAS A PROTECTIVE ROLE IN PATIENTS WITH CHRONIC KIDNEY DISEASE (CKD). HOWEVER, THE EXACT ROLE AND MOLECULAR MECHANISM OF SIRT6 IN VC IN PATIENTS WITH CKD REMAIN UNCLEAR. HERE, WE DEMONSTRATED THAT SIRT6 WAS MARKEDLY DOWNREGULATED IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) AND IN THE RADIAL ARTERY TISSUE OF PATIENTS WITH CKD WITH VC. SIRT6-TRANSGENIC (SIRT6-TG) MICE SHOWED ALLEVIATED VC, WHILE VASCULAR SMOOTH MUSCLE CELL-SPECIFIC (VSMC-SPECIFIC) SIRT6 KNOCKED-DOWN MICE SHOWED SEVERE VC IN CKD. SIRT6 SUPPRESSED THE OSTEOGENIC TRANSDIFFERENTIATION OF VSMCS VIA REGULATION OF RUNT-RELATED TRANSCRIPTION FACTOR 2 (RUNX2). COIMMUNOPRECIPITATION (CO-IP) AND IMMUNOPRECIPITATION (IP) ASSAYS CONFIRMED THAT SIRT6 BOUND TO RUNX2. MOREOVER, RUNX2 WAS DEACETYLATED BY SIRT6 AND FURTHER PROMOTED NUCLEAR EXPORT VIA EXPORTIN 1 (XPO1), WHICH IN TURN CAUSED DEGRADATION OF RUNX2 THROUGH THE UBIQUITIN-PROTEASOME SYSTEM. THESE RESULTS DEMONSTRATED THAT SIRT6 PREVENTED VC BY SUPPRESSING THE OSTEOGENIC TRANSDIFFERENTIATION OF VSMCS, AND AS SUCH TARGETING SIRT6 MAY BE AN APPEALING THERAPEUTIC TARGET FOR VC IN CKD.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
6  6768  37 ZOLEDRONIC ACID EPIGENETICALLY ALLEVIATES HIGH-GLUCOSE-SUPPRESSED OSTEOGENIC DIFFERENTIATION OF MC3T3-E1 CELLS. OBJECTIVE: DUE TO THE IMPACT OF EXCESSIVE GLUCOSE ON OSTEOGENIC DIFFERENTIATION, DIABETIC OSTEOPATHY FREQUENTLY RESULTS IN SKELETAL FRAGILITY, OSTEOPOROSIS, AND BONE PAIN. ZOLEDRONIC ACID, A BISPHOSPHONATE (BP) THAT EFFECTIVELY INHIBITS OSTEOCLASTIC BONE RESORPTION IS GIVEN YEARLY TO IMPROVE BONE MINERAL DENSITY (BMD) IN PATIENTS WITH OSTEOPOROSIS. HOWEVER, THE DETAILED MOLECULAR MECHANISMS REMAINED UNCLEAR. THIS STUDY INVESTIGATES THE POSSIBLE PATHWAYS BY WHICH ZOLEDRONIC ACID REGULATES OSTEOGENESIS WHEN BLOOD GLUCOSE LEVELS ARE HIGH. MATERIALS AND METHODS: MC3T3-E1 CELLS WERE TREATED WITH ONE MM ZOLEDRONIC ACID OR NOT IN A STANDARD OR HIGH GLUCOSE CULTURE MEDIUM. A QUANTITATIVE POLYMERASE CHAIN REACTION (QPCR) ASSAY WAS UTILIZED TO ASSESS THE EXPRESSION OF THE TARGET CANDIDATE GENES, INCLUDING RUNX2, MALAT1, MIR-133, MIR-20A, AND MIR-204. RESULTS: IN A HIGH-GLUCOSE CONDITION, ZOLEDRONIC ACID TREATMENT SIGNIFICANTLY LOWERED MALAT1 (P < 0.0001) AND MIR-20A (P < 0.0001) EXPRESSION. CONVERSELY, IN A HIGH-GLUCOSE CONDITION, RUNX2, MIR-133, AND MIR-204 EXPRESSIONS WERE FOUND TO BE SIGNIFICANTLY INCREASED IN THE ZOLEDRONIC ACID TREATMENT GROUP AS COMPARED TO NO TREATMENT (ALL P < 0.0001). CONCLUSIONS: IN CONCLUSION, UNDER A HIGH-GLUCOSE ENVIRONMENT, ZOLEDRONIC ACID CAN MODULATE THE EXPRESSION OF THE RUNX2 TRANSCRIPTION FACTOR THROUGH EPIGENETIC REGULATION.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
7   916  32 CHRONIC HIGH GLUCOSE AND INSULIN STIMULATE BONE-MARROW STROMAL CELLS ADIPOGENIC DIFFERENTIATION IN YOUNG SPONTANEOUSLY HYPERTENSIVE RATS. WE EVALUATED WHETHER GENETIC PREDISPOSITION IS SUFFICIENT TO INDUCE CHANGES DUE TO CHRONIC HIGH GLUCOSE (HG; 25 MMOL/L) IN THE PRESENCE OR ABSENCE OF INSULIN (HGI; 10 MUG/ML) ON OSTEOGENIC DIFFERENTIATION AND MARKERS IN BONE-MARROW MESENCHYMAL STEM CELLS (BMSCS) FROM YOUNG WISTAR (WBMSCS) AND SPONTANEOUS HYPERTENSIVE RATS (SBMSCS) WITHOUT HYPERTENSION. HG SUPPRESSED OSTEOGENIC DIFFERENTIATION IN BOTH THE STRAINS, OBSERVED BY MINERALIZATION INHIBITION AND DECREASED LEVELS OF THE OSTEOGENIC MARKERS RUNX2, OSTERIX, OSTEOPONTIN, AND BONE SIALOPROTEIN, COMPARED TO OSTEOGENIC MEDIUM (OM) CELLS. IN WBMSCS, THE EFFECTS OF HG WERE ASSOCIATED WITH THE DOWN REGULATION OF ERK1/2 AND UP REGULATION OF P38 ACTIVITIES; HOWEVER, HGI DID NOT REVERT THE EFFECTS OF HG ON MAPK ACTIVITIES. MOREOVER, HG DID NOT AFFECT MAPK SIGNALING IN SBMSCS COMPARED TO THAT IN OM. HGI INCREASED MINERALIZATION IN WBMSCS COMPARED TO THAT IN OM, BUT NOT IN SBMSCS. HIGH EXPRESSION OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA AND GLUCOSE TRANSPORTER TYPE 4 IN OM COULD BE RELATED WITH THE PREDISPOSITION TO ADIPOGENIC DIFFERENTIATION NOTED IN SBMSCS AND WAS CONFIRMED BY EMERGENCE OF ADIPOCYTE-LIKE CELLS BY HGI TREATMENT. DOWNREGULATION OF P38 AND UPREGULATION OF JNK ACTIVITIES WERE OBSERVED IN BOTH BMSCS TREATED WITH HGI COMPARED TO THOSE TREATED BY HG. MA (OSMOTIC CONTROL) ALSO SUPPRESSED OSTEOGENIC DIFFERENTIATION IN BOTH THE STRAINS. IN CONCLUSION, WE DEMONSTRATED THAT SBMSCS FROM YOUNG SPONTANEOUS HYPERTENSIVE RATS, WITHOUT HYPERTENSION BUT WITH GENETIC AND EPIGENETIC PREDISPOSITION, EXHIBITED DECREASED OSTEOBLASTIC DIFFERENTIATION UNDER HG AND HGI DID NOT REVERT THE EFFECTS OF HG IN SBMSCS BUT INCREASED ADIPOGENIC DIFFERENTIATION.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
8  3295  36 HIGH PHOSPHATE-INDUCED DOWNREGULATION OF PPARGAMMA CONTRIBUTES TO CKD-ASSOCIATED VASCULAR CALCIFICATION. MEDIAL ARTERIAL CALCIFICATION ASSOCIATED WITH HYPERPHOSPHATEMIA IS A MAIN CAUSE OF CARDIOVASCULAR MORTALITY IN PATIENTS WITH CHRONIC KIDNEY DISEASE (CKD), BUT THE MECHANISMS UNDERLYING HIGH PHOSPHATE-INDUCED VASCULAR CALCIFICATION REMAIN LARGELY UNKNOWN. HERE, WE OBSERVED A SIGNIFICANT DECREASE IN THE EXPRESSION OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA (PPARGAMMA) IN CALCIFIED ARTERIES BOTH IN CKD PATIENTS AND IN A MOUSE MODEL OF CKD WITH HYPERPHOSPHATEMIA. IN VITRO, HIGH PHOSPHATE TREATMENT LED TO A DECREASED EXPRESSION OF PPARGAMMA IN MOUSE VASCULAR SMOOTH MUSCLE CELLS (VMSCS), ACCOMPANIED BY APPARENT OSTEOGENIC DIFFERENTIATION AND CALCIFICATION. PRETREATMENT WITH PPARGAMMA AGONIST ROSIGLITAZONE SIGNIFICANTLY REVERSED HIGH PHOSPHATE-INDUCED VSMCS CALCIFICATION. FURTHER INVESTIGATION SHOWED THAT METHYL-CPG BINDING PROTEIN 2 (MECP2)-MEDIATED EPIGENETIC REPRESSION WAS INVOLVED IN HIGH PHOSPHATE-INDUCED PPARGAMMA DOWNREGULATION. MOREOVER, THE EXPRESSION OF KLOTHO THAT HAS THE ABILITY TO INHIBIT VASCULAR CALCIFICATION BY REGULATING PHOSPHATE UPTAKE DECREASED WITH THE PPARGAMMA REDUCTION IN VSMCS AFTER HIGH PHOSPHATE TREATMENT, AND ROSIGLITAZONE FAILED TO INHIBIT HIGH PHOSPHATE-INDUCED CALCIFICATION IN VSMCS WITH KNOCKDOWN OF KLOTHO OR IN AORTIC RINGS FROM KLOTHO-DEFICIENT (KL/KL) MICE. FINALLY, AN IN VIVO STUDY DEMONSTRATED THAT ORAL ADMINISTRATION OF ROSIGLITAZONE COULD INCREASE KLOTHO EXPRESSION AND PROTECT AGAINST HIGH PHOSPHATE-INDUCED VASCULAR CALCIFICATION IN CKD MICE. THESE FINDINGS SUGGEST THAT THE INHIBITION OF PPARGAMMA EXPRESSION MAY CONTRIBUTE TO THE PATHOGENESIS OF HIGH PHOSPHATE-INDUCED VASCULAR CALCIFICATION, WHICH MAY PROVIDE A NEW THERAPEUTIC TARGET FOR VASCULAR CALCIFICATION IN CKD PATIENTS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
9  3526  30 IL-6 AND SIL-6R INDUCES STAT3-DEPENDENT DIFFERENTIATION OF HUMAN VSMCS INTO OSTEOBLAST-LIKE CELLS THROUGH JMJD2B-MEDIATED HISTONE DEMETHYLATION OF RUNX2. INFLAMMATION AND VASCULAR CALCIFICATION ARE INDEPENDENT RISK FACTORS OF CARDIOVASCULAR EVENTS. VASCULAR SMOOTH MUSCLE CELLS (VSMCS) EXHIBIT OSTEOBLAST-LIKE CHARACTERISTICS IN RESPONSE TO VARIOUS STIMULI SUCH AS OXIDIZED CHOLESTEROL AND INFLAMMATION. HOWEVER THE PRECISE MECHANISM OF TRANSCRIPTIONAL REGULATION OF VSMCS BY INFLAMMATORY STIMULI REMAINS UNCLEAR. WE INVESTIGATED THE PROCESS AND MECHANISMS OF INFLAMMATORY CYTOKINE-INDUCED TRANSFORMATION OF HUMAN VSMCS (HVSMCS) INTO OSTEOBLAST-LIKE CELLS, WITH A SPECIAL FOCUS ON EPIGENETIC CHANGES. OUR RESULTS DEMONSTRATED: (1) INTERLEUKIN-6 (IL-6)/SOLUBLE INTERLEUKIN-6 RECEPTOR (SIL-6R) INDUCED TRANSFORMATION OF HVSMCS INTO AN OSTEOBLAST PHENOTYPE, WITH SUBSEQUENT VASCULAR CALCIFICATION, BASED ON THE RESULTS OF ALIZARIN RED S STAINING AND O-CRESOLPHTHALEIN COMPLEXONE METHOD; (2) IL-6/SIL-6R ACCELERATED THE EXPRESSION OF RUNT-RELATED TRANSCRIPTION FACTOR 2 (RUNX2) BASED ON THE RESULTS OF QUANTITATIVE REAL-TIME POLYMERASE CHAIN REACTION; (3) KNOCKDOWN OF SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION (STAT) 3 REDUCED IL-6/SIL-6R-INDUCED RUNX2 MRNA EXPRESSION AND OSTEOBLAST TRANSDIFFERENTIATION OF HVSMCS; (4) CHROMATIN IMMUNOPRECIPITATION (CHIP) COUPLED WITH PCR (CHIP-PCR) IDENTIFIED A STAT-BINDING SITE IN RUNX2 PROMOTER REGION CONTAINING TRIMETHYLATED HISTONE 3 LYSINE 9 (H3K9ME3), A TRANSCRIPTIONAL REPRESSOR, AND H3K4ME3, A TRANSCRIPTIONAL ENHANCER. STIMULATION WITH IL-6/SIL-6R SUPPRESSED H3K9ME3 BUT NOT H3K4ME3 THROUGH THE RECRUITMENT OF JUMONJI DOMAIN-CONTAINING PROTEIN (JMJD) 2B, A HISTONE LYSINE DEMETHYLASE, AT THE STAT-BINDING SITE IN RUNX2 PROMOTER REGION; (5) IL-6/SIL-6R-INDUCED RUNX2 GENE EXPRESSION WAS INHIBITED IN HVSMCS PRETREATED WITH JIB04, JMJD2 INHIBITOR, AND THE INHIBITORY EFFECT WAS JIB04 DOSE-DEPENDENT. OUR RESULTS INDICATE THAT THE IL-6/STAT3/JMJD2B PATHWAY REGULATES HVSMCS DIFFERENTIATION INTO OSTEOBLAST-LIKE CELLS, WHICH SUGGEST ITS PATHOGENIC ROLE IN VASCULAR CALCIFICATION ASSOCIATED WITH CHRONIC INFLAMMATION.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
10  3654  30 INDOXYL SULFATE ACCELERATES VASCULAR SMOOTH MUSCLE CELL CALCIFICATION VIA MICRORNA-29B DEPENDENT REGULATION OF WNT/BETA-CATENIN SIGNALING. VASCULAR CALCIFICATION (VC) IS A VERY COMMON PHENOMENON IN PATIENTS WITH CHRONIC KIDNEY DISEASE(CKD) AND IT INCREASES THE INCIDENCE OF CARDIOVASCULAR DISEASE AND LEADS TO HIGH MORTALITY IN CKD PATIENTS. IT HAS BEEN REPORTED THAT SOME MICRORNAS (MIRS) PLAY ROLES IN VASCULAR CALCIFICATION AS AN EPIGENETIC REGULATOR. INDOXYL SULFATE (IS) IS A PROTEIN-BOUND UREMIC TOXIN WHICH HAS BEEN PROVEN AS ONE OF THE MAJOR RISK FACTORS OF CARDIOVASCULAR DISEASE IN CKD. HERE WE INVESTIGATED WHETHER MICRORNA-29B (MIR-29B) IS INVOLVED IN IS-INDUCED VASCULAR CALCIFICATION. WE FOUND THAT VASCULAR MIR-29B WAS DOWN-REGULATED IN RADIAL ARTERIES OF PATIENTS WITH END-STAGE RENAL DISEASE. CONSISTENTLY, IS ALSO DECREASED MIR-29B EXPRESSION IN HUMAN AORTIC SMOOTH MUSCLE CELLS (HASMCS) AND POTENTIATED THEIR CALCIFICATION. MIR-29B MIMICS SIGNIFICANTLY SUPPRESSED, WHILE MIR-29B ANTI-MIR MARKEDLY ENHANCED, IS-INDUCED RUNT-RELATED TRANSCRIPTION FACTOR 2 AND OSTEOPONTIN EXPRESSION. THE EXPRESSION OF WNT7B/BETA-CATENIN IN RADIAL ARTERIES WAS HIGHER IN END STAGE RENAL DISEASE THAN IN CONTROL GROUP, AND IS INCREASED WNT7B/BETA-CATENIN EXPRESSION IN HASMCS AS EARLY AS 3DAYS AFTER STIMULATION. FURTHERMORE, MIR-29B MIMICS POTENTLY REPRESSED WNT7B/BETA-CATENIN PROTEIN EXPRESSION IN HASMCS, WHEREAS MIR-29B ANTI-MIR INCREASED THEIR EXPRESSION, INDICATING MIR-29B INDEED NEGATIVELY REGULATES WNT7B/BETA-CATENIN SIGNALING. DICKKOPF-1 PROTEIN, THE WNT/BETA-CATENIN SIGNALING INHIBITOR, SUPPRESSED ANTI-MIR-29B-ENHANCED HASMCS CALCIFICATION. OUR DATA THUS INDICATE THAT MIR-29B DOWNREGULATION AND WNT/BETA-CATENIN SIGNALING ACTIVATION MAY BE THE KEY MECHANISM OF IS INDUCED VASCULAR CALCIFICATION IN CHRONIC KIDNEY DISEASE.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
11  3306  31 HIGH-PHOSPHATE-INDUCED CALCIFICATION IS RELATED TO SM22ALPHA PROMOTER METHYLATION IN VASCULAR SMOOTH MUSCLE CELLS. HYPERPHOSPHATEMIA IS CLOSELY RELATED TO VASCULAR CALCIFICATION IN PATIENTS WITH CHRONIC KIDNEY DISEASE. VASCULAR SMOOTH MUSCLE CELLS (VSMCS) EXPOSED TO HIGH PHOSPHATE CONCENTRATIONS IN VITRO UNDERGO PHENOTYPIC TRANSITION TO OSTEOBLAST-LIKE CELLS. MECHANISMS UNDERLYING THIS TRANSDIFFERENTIATION ARE NOT CLEAR. IN THIS STUDY WE USED TWO IN VITRO MODELS, HUMAN AORTIC SMOOTH MUSCLE CELLS AND RAT AORTIC RINGS, TO INVESTIGATE THE PHENOTYPIC TRANSITION OF VSMCS INDUCED BY HIGH PHOSPHATE. WE FOUND THAT HIGH PHOSPHATE CONCENTRATION (3.3 MMOL/L) IN THE MEDIUM WAS ASSOCIATED WITH INCREASED DNA METHYLTRANSFERASE ACTIVITY AND METHYLATION OF THE PROMOTER REGION OF SM22ALPHA. THIS WAS ACCOMPANIED BY LOSS OF THE SMOOTH MUSCLE CELL-SPECIFIC PROTEIN SM22ALPHA, GAIN OF THE OSTEOBLAST TRANSCRIPTION FACTOR CBFA1, AND INCREASED ALKALINE PHOSPHATASE ACTIVITY WITH THE SUBSEQUENT IN VITRO CALCIFICATION. THE ADDITION OF A DEMETHYLATING AGENT (PROCAINE) TO THE HIGH-PHOSPHATE MEDIUM REDUCED DNA METHYLTRANSFERASE ACTIVITY AND PREVENTED METHYLATION OF THE SM22ALPHA PROMOTER, WHICH WAS ACCOMPANIED BY AN INCREASE IN SM22ALPHA EXPRESSION AND LESS CALCIFICATION. ADDITIONALLY, DOWNREGULATION OF SM22ALPHA, EITHER BY SIRNA OR BY A METHYL GROUP DONOR (S-ADENOSYL METHIONINE), RESULTED IN OVEREXPRESSION OF CBFA1. IN CONCLUSION, WE DEMONSTRATE THAT METHYLATION OF SM22ALPHA PROMOTER IS AN IMPORTANT EVENT IN VASCULAR SMOOTH MUSCLE CELL CALCIFICATION AND THAT HIGH PHOSPHATE INDUCES THIS EPIGENETIC MODIFICATION. THESE FINDINGS UNCOVER A NEW INSIGHT INTO MECHANISMS BY WHICH HIGH PHOSPHATE CONCENTRATION PROMOTES VASCULAR CALCIFICATION.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
12  4867  25 OSSIFYING FIBROMA TUMOR STEM CELLS ARE MAINTAINED BY EPIGENETIC REGULATION OF A TSP1/TGF-BETA/SMAD3 AUTOCRINE LOOP. ABNORMAL STEM CELL FUNCTION MAKES A KNOWN CONTRIBUTION TO MANY MALIGNANT TUMORS, BUT THE ROLE OF STEM CELLS IN BENIGN TUMORS IS NOT WELL UNDERSTOOD. HERE, WE SHOW THAT OSSIFYING FIBROMA (OF) CONTAINS A STEM CELL POPULATION THAT RESEMBLES MESENCHYMAL STEM CELLS (OFMSCS) AND IS CAPABLE OF GENERATING OF-LIKE TUMOR XENOGRAFTS. MECHANISTICALLY, OFMSCS SHOW ENHANCED TGF-BETA SIGNALING THAT INDUCES ABERRANT PROLIFERATION AND DEFICIENT OSTEOGENESIS VIA NOTCH AND BMP SIGNALING PATHWAYS, RESPECTIVELY. THE ELEVATED TGF-BETA ACTIVITY IS TIGHTLY REGULATED BY JHDM1D-MEDIATED EPIGENETIC REGULATION OF THROMBOSPONDIN-1 (TSP1), FORMING A JHDM1D/TSP1/TGF-BETA/SMAD3 AUTOCRINE LOOP. INHIBITION OF TGF-BETA SIGNALING IN OFMSCS CAN RESCUE THEIR ABNORMAL OSTEOGENIC DIFFERENTIATION AND ELEVATED PROLIFERATION RATE. FURTHERMORE, CHRONIC ACTIVATION OF TGF-BETA CAN CONVERT NORMAL MSCS INTO OF-LIKE MSCS VIA ESTABLISHMENT OF THIS JHDM1D/TSP1/TGF-BETA/SMAD3 AUTOCRINE LOOP. THESE RESULTS REVEAL THAT EPIGENETIC REGULATION OF TGF-BETA SIGNALING IN MSCS GOVERNS THE BENIGN TUMOR PHENOTYPE IN OF AND HIGHLIGHT TGF-BETA SIGNALING AS A CANDIDATE THERAPEUTIC TARGET.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
13  3944  38 LNCRNA H19-EZH2 INTERACTION PROMOTES LIVER FIBROSIS VIA REPROGRAMMING H3K27ME3 PROFILES. LIVER FIBROSIS IS A WOUND-HEALING PROCESS CHARACTERIZED BY EXCESS FORMATION OF EXTRACELLULAR MATRIX (ECM) FROM ACTIVATED HEPATIC STELLATE CELLS (HSCS). PREVIOUS STUDIES SHOW THAT BOTH EZH2, AN EPIGENETIC REGULATOR THAT CATALYZES LYSINE 27 TRIMETHYLATION ON HISTONE 3 (H3K27ME3), AND LONG NON-CODING RNA H19 ARE HIGHLY CORRELATED WITH FIBROGENESIS. IN THE CURRENT STUDY, WE INVESTIGATED THE UNDERLYING MECHANISMS. VARIOUS MODELS OF LIVER FIBROSIS INCLUDING MDR2(-/-), BILE DUCT LIGATION (BDL) AND CCL(4) MICE WERE ADAPTED. WE FOUND THAT EZH2 WAS MARKEDLY UPREGULATED AND CORRELATED WITH H19 AND FIBROTIC MARKERS EXPRESSION IN THESE MODELS. ADMINISTRATION OF EZH2 INHIBITOR 3-DZNEP CAUSED SIGNIFICANT PROTECTIVE EFFECTS IN THESE MODELS. FURTHERMORE, TREATMENT WITH 3-DZNEP OR GSK126 SIGNIFICANTLY INHIBITED PRIMARY HSC ACTIVATION AND PROLIFERATION IN TGF-BETA-TREATED HSCS AND H19-OVEREXPREESING LX2 CELLS IN VIVO. USING RNA-PULL DOWN ASSAY COMBINED WITH RNA IMMUNOPRECIPITATION, WE DEMONSTRATED THAT H19 COULD DIRECTLY BIND TO EZH2. INTEGRATED ANALYSIS OF RNA-SEQUENCING (RNA-SEQ) AND CHROMATIN IMMUNOPRECIPITATION SEQUENCING (CHIP-SEQ) FURTHER REVEALED THAT H19 REGULATED THE REPROGRAMMING OF EZH2-MEDIATED H3K27ME3 PROFILES, WHICH EPIGENETICALLY PROMOTED SEVERAL PATHWAYS FAVORING HSCS ACTIVATION AND PROLIFERATION, INCLUDING EPITHELIAL-MESENCHYMAL TRANSITION AND WNT/BETA-CATENIN SIGNALING. IN CONCLUSION, HIGHLY EXPRESSED H19 IN CHRONIC LIVER DISEASES PROMOTES FIBROGENESIS BY REPROGRAMMING EZH2-MEDIATED EPIGENETIC REGULATION OF HSCS ACTIVATION. TARGETING THE H19-EZH2 INTERACTION MAY SERVE AS A NOVEL THERAPEUTIC APPROACH FOR LIVER FIBROSIS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
14  4076  32 MATERNAL HIGH-FAT DIET MODIFIES EPIGENETIC MARKS H3K27ME3 AND H3K27AC IN BONE TO REGULATE OFFSPRING OSTEOBLASTOGENESIS IN MICE. STUDIES FROM BOTH HUMANS AND ANIMAL MODELS INDICATED THAT MATERNAL CHRONIC POOR-QUALITY DIET, ESPECIALLY A HIGH FAT DIET (HFD), IS SIGNIFICANTLY ASSOCIATED WITH REDUCED BONE DENSITY AND CHILDHOOD FRACTURES IN OFFSPRING. WHEN PREVIOUSLY STUDIED IN A RAT MODEL, OUR DATA SUGGESTED THAT MATERNAL HFD CHANGES EPIGENETIC MARKS SUCH AS DNA METHYLATION AND HISTONE MODIFICATIONS TO CONTROL OSTEOBLAST METABOLISM. IN MOUSE EMBRYONIC AND POSTNATAL OFFSPRING BONE SAMPLES, A CHIP-SEQUENCING (CHIP-SEQ)-BASED GENOME-WIDE METHOD WAS USED TO LOCATE THE REPRESSIVE HISTONE MARK H3K27ME3 (MEDIATED VIA THE POLYCOMB HISTONE METHYLTRANSFERASE, EZH2) AND EXPRESSIVE HISTONE MARK H3K27AC (P300/CBP MEDIATED) THROUGHOUT THE GENOME. USING ISOLATED MOUSE EMBRYONIC CELLS FROM FOETAL CALVARIA (OSTEOBLAST-LIKE CELLS), H3K27ME3 CHIP-SEQ SHOWED THAT 147 GENE BODIES AND 26 GENE PROMOTERS IN HFD EMBRYOTIC SAMPLES HAD A GREATER THAN TWOFOLD INCREASE IN H3K27ME PEAKS COMPARED TO CONTROLS. AMONG THE HFD SAMPLES, PTHLH AND COL2A1 THAT ARE IMPORTANT GENES PLAYING ROLES DURING CHONDRO- AND OSTEOGENESIS HAD SIGNIFICANTLY ENRICHED LEVELS OF H3K27ME3. THEIR DECREASED MRNA EXPRESSION WAS CONFIRMED BY REAL-TIME PCR AND STANDARD CHIP ANALYSIS, INDICATING A STRONG ASSOCIATION WITH EZH2 MEDIATED H3K27ME3 EPIGENETIC CHANGES. USING EMBRYONIC CALVARIA OSTEOBLASTIC CELLS AND OFFSPRING BONE SAMPLES, H3K27AC CHIP-SEQ ANALYSIS SHOWED THAT OSTEOBLAST INHIBITOR GENES TNFAIP3 AND TWIST1 HAD SIGNIFICANTLY ENRICHED PEAKS OF H3K27AC IN HFD SAMPLES COMPARED TO CONTROLS. THEIR INCREASED GENE EXPRESSION AND ASSOCIATION WITH H3K27AC WERE ALSO CONFIRMED BY REAL-TIME PCR AND STANDARD CHIP ANALYSIS. THESE FINDINGS INDICATE THAT CHRONIC MATERNAL HFD CHANGES HISTONE TRIMETHYLATION AND ACETYLATION EPIGENETIC MARKS TO REGULATE EXPRESSION OF GENES CONTROLLING OSTEOBLASTOGENESIS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
15  3388  25 HOMOCYSTEINE INDUCES PODOCYTE APOPTOSIS BY REGULATING MIR-1929-5P EXPRESSION THROUGH C-MYC, DNMT1 AND EZH2. CHRONIC KIDNEY DISEASE (CKD) IS A COMMON AND COMPLEX DISEASE IN KIDNEYS WHICH HAS BEEN ASSOCIATED WITH AN INCREASED RISK OF RENAL CELL CARCINOMA. ELEVATED HOMOCYSTEINE (HCY) LEVELS ARE KNOWN TO INFLUENCE THE DEVELOPMENT AND PROGRESSION OF CKD BY REGULATING PODOCYTE INJURY AND APOPTOSIS. TO INVESTIGATE THE MOLECULAR MECHANISMS TRIGGERED IN PODOCYTES BY HCY, WE USED CBS(+/-) MICE AND OBSERVED THAT HIGHER HCY LEVELS INCREASED THE APOPTOSIS RATE OF PODOCYTES WITH ACCOMPANYING GLOMERULAR DAMAGE. HCY-INDUCED PODOCYTE INJURY AND APOPTOSIS IN CBS(+/-) MICE WAS REGULATED BY INHIBITION OF MICRORNA (MIR)-1929-5P EXPRESSION. OVEREXPRESSION OF MIR-1929-5P IN PODOCYTES INHIBITED APOPTOSIS BY UPREGULATING BCL-2. FURTHERMORE, THE EXPRESSION OF MIR-1929-5P WAS REGULATED BY EPIGENETIC MODIFICATIONS OF ITS PROMOTER. HCY UPREGULATED DNA METHYLTRANSFERASE 1 (DNMT1) AND ENHANCER OF ZESTE HOMOLOG 2 (EZH2) LEVELS, RESULTING IN INCREASED DNA METHYLATION AND H3K27ME3 LEVELS ON THE MIR-1929-5P PROMOTER. ADDITIONALLY, WE OBSERVED THAT C-MYC RECRUITED DNMT1 AND EZH2 TO THE MIR-1929-5P PROMOTER AND SUPPRESSED THE EXPRESSION OF MIR-1929-5P. IN SUMMARY, WE DEMONSTRATED THAT HCY PROMOTES PODOCYTE APOPTOSIS THROUGH THE REGULATION OF THE EPIGENETIC MODIFIERS DNMT1 AND EZH2, WHICH ARE RECRUITED BY C-MYC TO THE PROMOTER OF MIR-1929-5P TO SILENCE MIR-1929-5P EXPRESSION.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
16  6232  34 THE LONG NONCODING RNA MEG3 REGULATES MYOBLAST PLASTICITY AND MUSCLE REGENERATION THROUGH EPITHELIAL-MESENCHYMAL TRANSITION. FORMATION OF SKELETAL MUSCLE IS AMONG THE MOST STRIKING EXAMPLES OF CELLULAR PLASTICITY IN ANIMAL TISSUE DEVELOPMENT, AND WHILE MUSCLE PROGENITOR CELLS ARE REPROGRAMMED BY EPITHELIAL-MESENCHYMAL TRANSITION (EMT) TO MIGRATE DURING EMBRYONIC DEVELOPMENT, THE REGULATION OF EMT IN POST-NATAL MYOGENESIS REMAINS POORLY UNDERSTOOD. HERE, WE DEMONSTRATE THAT THE LONG NONCODING RNA (LNCRNA) MEG3 REGULATES EMT IN MYOBLAST DIFFERENTIATION AND SKELETAL MUSCLE REGENERATION. CHRONIC INHIBITION OF MEG3 IN C2C12 MYOBLASTS INDUCED EMT, AND SUPPRESSED CELL STATE TRANSITIONS REQUIRED FOR DIFFERENTIATION. FURTHERMORE, ADENOVIRAL MEG3 KNOCKDOWN COMPROMISED MUSCLE REGENERATION, WHICH WAS ACCOMPANIED BY ABNORMAL MESENCHYMAL GENE EXPRESSION AND INTERSTITIAL CELL PROLIFERATION. TRANSCRIPTOMIC AND PATHWAY ANALYSES OF MEG3-DEPLETED C2C12 MYOBLASTS AND INJURED SKELETAL MUSCLE REVEALED A SIGNIFICANT DYSREGULATION OF EMT-RELATED GENES, AND IDENTIFIED TGFBETA AS A KEY UPSTREAM REGULATOR. IMPORTANTLY, INHIBITION OF TGFBETAR1 AND ITS DOWNSTREAM EFFECTORS, AND THE EMT TRANSCRIPTION FACTOR SNAI2, RESTORED MANY ASPECTS OF MYOGENIC DIFFERENTIATION IN MEG3-DEPLETED MYOBLASTS IN VITRO WE FURTHER DEMONSTRATE THAT REDUCTION OF MEG3-DEPENDENT EZH2 ACTIVITY RESULTS IN EPIGENETIC ALTERATIONS ASSOCIATED WITH TGFBETA ACTIVATION. THUS, MEG3 REGULATES MYOBLAST IDENTITY TO FACILITATE PROGRESSION INTO DIFFERENTIATION.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
17  1728  37 DYSREGULATION OF MICRORNAS IN HYPERTROPHY AND OSSIFICATION OF LIGAMENTUM FLAVUM: NEW ADVANCES, CHALLENGES, AND POTENTIAL DIRECTIONS. PATHOLOGICAL CHANGES IN THE LIGAMENTUM FLAVUM (LF) CAN BE DEFINED AS A PROCESS OF CHRONIC PROGRESSIVE ABERRATIONS IN THE NATURE AND STRUCTURE OF LIGAMENTOUS TISSUES CHARACTERIZED BY INCREASED THICKNESS, REDUCED ELASTICITY, LOCAL CALCIFICATION, OR AGGRAVATED OSSIFICATION, WHICH MAY CAUSE SEVERE MYELOPATHY, RADICULOPATHY, OR BOTH. HYPERTROPHY OF LIGAMENTUM FLAVUM (HLF) AND OSSIFICATION OF LIGAMENTUM FLAVUM (OLF) ARE CLINICALLY COMMON ENTITIES. THOUGH ACCUMULATED EVIDENCE HAS INDICATED BOTH GENETIC AND ENVIRONMENTAL FACTORS COULD CONTRIBUTE TO THE INITIATION AND PROGRESSION OF HLF/OLF, THE DEFINITE PATHOGENESIS REMAINS FULLY UNCLEAR. MICRORNAS (MIRNAS), ONE OF THE IMPORTANT EPIGENETIC MODIFICATIONS, ARE SHORT SINGLE-STRANDED RNA MOLECULES THAT REGULATE PROTEIN-CODING GENE EXPRESSION AT POSTTRANSCRIPTIONAL LEVEL, WHICH CAN DISCLOSE THE MECHANISM UNDERLYING DISEASES, IDENTIFY VALUABLE BIOMARKERS, AND EXPLORE POTENTIAL THERAPEUTIC TARGETS. CONSIDERING THAT MIRNAS PLAY A CENTRAL ROLE IN REGULATING GENE EXPRESSION, WE SUMMARIZED CURRENT STUDIES FROM THE POINT OF VIEW OF MIRNA-RELATED MOLECULAR REGULATION NETWORKS IN HLF/OLF. EXPLORATORY STUDIES REVEALED A VARIETY OF MIRNA EXPRESSION PROFILES AND IDENTIFIED A BATTERY OF UPREGULATED AND DOWNREGULATED MIRNAS IN OLF/HLF PATIENTS THROUGH MICROARRAY DATASETS OR TRANSCRIPTOME SEQUENCING. EXPERIMENTAL STUDIES VALIDATED THE ROLES OF SPECIFIC MIRNAS (E.G., MIR-132-3P, MIR-199B-5P IN OLF, MIR-155, AND MIR-21 IN HLF) IN REGULATING FIBROSIS OR OSTEOGENESIS DIFFERENTIATION OF LF CELLS AND RELATED TARGET GENES OR MOLECULAR SIGNALING PATHWAYS. FINALLY, WE DISCUSSED THE PERSPECTIVES AND CHALLENGES OF MIRNA-BASED MOLECULAR MECHANISM, DIAGNOSTIC BIOMARKERS, AND THERAPEUTIC TARGETS OF HLF/OLF.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
18  3655  31 INDOXYL SULFATE ENHANCE THE HYPERMETHYLATION OF KLOTHO AND PROMOTE THE PROCESS OF VASCULAR CALCIFICATION IN CHRONIC KIDNEY DISEASE. CHRONIC KIDNEY DISEASE (CKD) IS A STATE OF KLOTHO DEFICIENCY. THE KLOTHO EXPRESSION MAY BE SUPPRESSED DUE TO DNA HYPERMETHYLATION IN CANCER CELLS SO WE HAVE INVESTIGATED THE EFFECTS AND POSSIBLE MECHANISMS BY WHICH KLOTHO EXPRESSION IS REGULATED IN HUMAN AORTIC SMOOTH MUSCLE CELLS (HASMCS). THE VASCULAR KLOTHO HYPERMETHYLATION IN RADIAL ARTERIES OF PATIENTS WITH END-STAGE RENAL DISEASE WAS DESCRIBED. CULTURED HASMCS AND 5/6-NEPHRECTOMIZED SPRAGUE DAWLEY (SD) RATS TREATED WITH INDOXYL SULFATE (IS) WERE USED AS IN VITRO AND IN VIVO MODELS, RESPECTIVELY. IS INCREASED CPG HYPERMETHYLATION OF THE KLOTHO GENE AND DECREASED KLOTHO EXPRESSION IN HASMCS, AND POTENTIATED HASMCS CALCIFICATION. THE EXPRESSION OF DNA METHYLTRANSFERASE (DNMT) 1 AND 3A IN HASMCS TREATED WITH IS WAS SIGNIFICANTLY INCREASED AND SPECIFIC INHIBITION OF DNA METHYLTRANSFERASE 1 BY 5-AZA-2'-DEOXYCYTIDINE(5AZA-2DC) CAUSED DEMETHYLATION OF THE KLOTHO GENE AND INCREASED KLOTHO EXPRESSION. IN RATS, INJECTION OF IS POTENTIATED VASCULAR CALCIFICATION, INCREASED CPG HYPERMETHYLATION OF THE KLOTHO GENE AND DECREASED KLOTHO EXPRESSION IN THE AORTIC MEDIAL LAYER AND ALL OF THESE CHANGES COULD BE REVERTED BY 5AZA-2DC TREATMENT. TRANSCRIPTIONAL SUPPRESSION OF VASCULAR KLOTHO GENE EXPRESSION BY IS AND EPIGENETIC MODIFICATION OF KLOTHO BY IS MAY BE AN IMPORTANT PATHOLOGICAL MECHANISM OF VASCULAR CALCIFICATION IN CKD.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
19  2223  35 EPIGENETIC MODIFICATIONS IN SPINAL LIGAMENT AGING. SPINAL STENOSIS IS A COMMON DEGENERATIVE SPINE DISORDER IN THE AGED POPULATION AND THE SPINAL LIGAMENT AGING IS A MAIN CONTRIBUTOR TO THIS CHRONIC DISEASE. HOWEVER, THE UNDERLYING MECHANISMS OF SPINAL LIGAMENT AGING REMAIN UNCLEAR. EPIGENETICS IS THE STUDY OF HERITABLE AND REVERSIBLE CHANGES IN THE FUNCTION OF A GENE OR GENOME THAT OCCUR WITHOUT ANY ALTERATION IN THE PRIMARY DNA SEQUENCE. EPIGENETIC ALTERATIONS HAVE BEEN DEMONSTRATED TO PLAY CRUCIAL ROLES IN AGE-RELATED DISEASES AND CONDITIONS, AND THEY ARE RECENTLY STUDIED AS BIOMARKERS AND THERAPEUTIC TARGETS IN THE FIELD OF CANCER RESEARCH. THE MAIN EPIGENETIC MODIFICATIONS, INCLUDING DNA METHYLATION ALTERATION, HISTONE MODIFICATIONS AS WELL AS DYSREGULATED NONCODING RNA MODULATION, HAVE ALL BEEN IMPLICATED IN SPINAL LIGAMENT AGING DISEASES. DNA METHYLATION MODULATES THE EXPRESSION OF CRITICAL GENES INCLUDING WNT5A, GDNF, ACSM5, MIR-497 AND MIR-195 DURING SPINAL LIGAMENT DEGENERATION. HISTONE MODIFICATIONS WIDELY AFFECT GENE EXPRESSION AND OBVIOUS HISTONE MODIFICATION ABNORMALITIES HAVE BEEN FOUND IN SPINAL LIGAMENT AGING. MICRORNAS (MIRNAS), LONG NONCODING RNAS (LNCRNAS) AND CIRCULAR RNAS (CIRCRNAS) EXERT CRUCIAL REGULATING EFFECTS ON SPINAL LIGAMENT AGING CONDITIONS VIA TARGETING VARIOUS OSTEOGENIC OR FIBROGENIC DIFFERENTIATION RELATED GENES. TO OUR KNOWLEDGE, THERE IS NO SYSTEMATIC REVIEW YET TO SUMMARIZE THE INVOLVEMENT OF EPIGENETIC MECHANISMS OF SPINAL LIGAMENT AGING IN DEGENERATIVE SPINAL DISEASES. IN THIS STUDY, WE SYSTEMATICALLY DISCUSSED THE DIFFERENT EPIGENETIC MODIFICATIONS AND THEIR POTENTIAL FUNCTIONS IN SPINAL LIGAMENT AGING PROCESS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
20  1878  30 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