tokyo medical and dental university grants for excellent ... · osteoclast as mdsc (myeloid-derived...
TRANSCRIPT
Tokyo Medical and Dental UniversityGrants for Excellent Graduate Schools Symposium
February 17th~18th, 2014Tokyo Medical and Dental University
http://www.tmd.ac.jp/cmn/gcoe/index.html
卓越した大学院拠点形成支援補助金国際シンポジウム
Molecular mechanism in bone and tooth,its clinical implication
February 17th~18th, 2014
2014.2.17(Mon)
9:00 − 9:10 PresidentAddress Takashi Ohyama
Openingremark Atsushi Okawa
Session 1 Chairpersons : Bjorn R. Olsen, Atsushi Okawa
9:10 − 10:25 Henry M. Kronenberg Flexibilityintheosteoblastlineage
10:25 − 11:40 Shu Takeda Controlofbonemetabolismviaorgancrosstalk
Session 2 Chairpersons : Benjamin A. Alman, Shohei Kasugai
12:30 − 13:45 Akira Yamaguchi Bonedestructionbyoralcancer
13:45 − 15:00 Hiroshi Takayanagi Forefrontofosteoimmunology
15:00 − 15:30 PosterSession,CoffeeBreak
Session 3 Chairpersons : Ichiro Nishimura, Ichiro Sekiya
15:30 − 16:45 Vicki Rosen Regenerativepotentialofthekneemeniscus
16:45 − 18:00 Hiroshi Asahara Combinatorialapproachtoidentifygeneregulationofinflammatory signalsatRNAlevel
18:30 − Reception
2014.2.18(Tue)
Session 4 Chairpersons : Henry M. Kronenberg, Keiji Moriyama
9:00 − 10:15 Bjorn R. Olsen Craniofacialdysmorphogenesisandinfantilehemangioma– theantraxtoxinreceptorconnection
10:15 − 11:30 Ichiro Sekiya Cartilageandmeniscusregenerationwithsynovialstemcells
Session 5 Chairpersons : Vicki Rosen, Takeshi Muneta
12:20 − 13:35 Benjamin A. Alman Fracturerepairandbeta-catenininaginganddisease: implicationsforanapproachtotherapy
13:35 − 14:50 Ichiro Nishimura OsteoclastasMDSC(myeloid-derivedsuppressorcell)anditsrolein ONJandtumorbonemetastasis
14:50 − 14:55 ClosingRemark Atsushi Okawa
C O N T E N T SHenry M. Kronenberg………………………………………………………… 1Flexibilityintheosteoblastlineage
Shu Takeda …………………………………………………………………… 5Controlofbonemetabolismviaorgancrosstalk
Akira Yamaguchi……………………………………………………………… 9Bonedestructionbyoralcancer
Hiroshi Takayanagi………………………………………………………… 13Forefrontofosteoimmunology
Vicki Rosen ………………………………………………………………… 17Regenerativepotentialofthekneemeniscus
Hiroshi Asahara …………………………………………………………… 21CombinatorialapproachtoidentifygeneregulationofinflammatorysignalsatRNAlevel
Bjorn R. Olsen ……………………………………………………………… 25Craniofacialdysmorphogenesisandinfantilehemangioma–theantraxtoxinreceptorconnection
Ichiro Sekiya………………………………………………………………… 29Cartilageandmeniscusregenerationwithsynovialstemcells
Benjamin A. Alman………………………………………………………… 33Fracturerepairandbeta-catenininaginganddisease:implicationsforanapproachtotherapy
Ichiro Nishimura…………………………………………………………… 37OsteoclastasMDSC(myeloid-derivedsuppressorcell)anditsroleinONJandtumorbonemetastasis
Poster Session……………………………………………………………… 42
1
Flexibility in the osteoblast lineage
Henry M. Kronenberg, M.D.
ProfessorandDirectorEndocrineUnit,MassachusettsGeneralHospitalandHarvardMedicalSchool
Theclassicview,basedprimarilyonstudiesofcellsinculture,isthatmesenchymalprogenitorsinthebonemarrow(called“mesenchymalstemcells”bysomeinvestigators)havethepotentialtodifferentiateintoosteoblasts,chondrocytes,andadipocytes.OsteoblastprecursorsfirstexpressRunx2,thenosterix,andthenothertranscriptionfactorsthatdirectthesecellsfirsttoproliferateandthendifferentiateintomatureosteoblasts.Thefatesofosteoblastsincludetheirdyingbyapoptosisor,instead,becomingosteocytesorinactiveboneliningcells.Invivostudiesusingcrerecombinase,controlledbyvariouspromotersandsometimesrequiringtamoxifenadministrationforactivation(throughactivationofacrerecombinaselinkedtotheligandbindingdomainofamutatedestrogenreceptor)(creERt),haveallowedthemarkingandgeneticmanipulationofcellsintheskeletalsystematvariousstagesofdifferentiationandatspecifictimes.Thesestudieshavedemonstratedunanticipatedflexibilityinthelineageprogramjustoutlined.
Herewewillshowthat,afterosteoblastprecursorsexpressosterixinvivoinmice,removalofβ-cateninexpressionfromthesecellssteersmanyofthesepre-osteoblastsintotheadipocytelineage.Wealsoshowthatmanyosterix-expressingcellsbecomestromalcellsthatsupporthematopoiesis.FurtherweshowthatinactiveboneliningcellscanbereactivatedtoparticipateinboneformationasmatureosteoblastsafterPTHadministration.Finally,weshowthatcollagenII-creERtcanmarkstemcellsthatsubsequentlycanbecomeosteoblasts,chondrocytes,oradipocytesandcontinuetodosoformonthsafteroneadministrationoftamoxifen.Thispromotercanbeactivatedbytamoxifentogeneratemarkedosteoblastsseveralmonthsafterbirth.WhenPTHisgiventothesemice,thenumberofosteoblastprecursorsincreasesintheseveraldaysafterPTHadministration,asindicatedbycountingofthecellsmarkedasexpressingthecollagenIIpromoter.Thus,boththenumberandthefateofearlycellsoftheosteoblastlineagecanbemanipulatedtoservethechangingneedsoftheorganism.
2
Henry M. Kronenberg
CURRICULUM VITAE
Education
1962-1966 B.A.HistoryandLiteratureHarvardCollege1966-1970 M.D.MedicineColumbiaUniversity
Position
1984-1997 Director,EndocrineClinicalLaboratories MassachusettsGeneralHospital1985- MedicalAdministrativeCommitteeMassachusetts GeneralHospital1985-1987 InterimChief,ThyroidUnitMassachusettsGeneral Hospital1986-1989 Director,EndocrineDivisionMassachusetts GeneralHospital1997-2000 Co-Chair,AcademicCouncil,Department ofMedicineMassachusettsGeneralHospital1998-2007 Director,EndocrineDivisionMassachusetts GeneralHospital2007 Chair,CartilageBiologyandPathology ConferenceGordonResearchConferences2009-2010 Director,EndocrineDivisionMassachusetts GeneralHospital2013- Director,EndocrineDivisionMassachusetts GeneralHospital
Award and Honors
2000 VanWyckLectureshipUniversityofNorthCarolina2002 R.L.CreussLecturerMcGillUniversity,Montreal2002 NovartisLecturerCanadianSocietyofEndocrinology& Metabolism2002 5thAnnualJohnG.Haddad,JrDistinguished MemorialLecturer UniversityofPennsylvaniaSchoolofMedicine2003 TransoceanicLecturePrize EuropeanFederationofEndocrineSocieties2003 WilliamF.NeumanAward TheAmericanSocietyforBoneandMineralResearch (ASBMR)2006 LouisV.AvioliMemorialLecturer TheAmericanSocietyforBoneandMineralResearch (ASBMR)2011 Michael&IreneKarlVisitingProfessor WashingtonUniversitySchoolofMedicine2011 2ndIainMacIntyreMemorialLecturer 4thNewYorkSkeletalBiologyandMedicineConference2011 GideonA.RodanAwardforExcellenceinMentoring TheAmericanSocietyforBoneandMineralResearch (ASBMR)2012 TheNinthTorstenN.WieselDistinguishedLecturer HospitalforSpecialSurgery,NewYork,NewYork2012 TriennialInternationalPrize AustrianBoneandMineralSociety2013 JohnBaxterMemorialLecturer
Publications
KobayashiT,LuJ,CobbBS,RoddaSJ,McmahonAP,1.SchipaniE,MerkenschlagerM,Kronenberg,HM.Dicer-dependentpathwaysregulatechondrocyteproliferationanddifferentiation.PNAS2008,105:1949-1954.PMCID:PMC2538863MakKK,KronenbergHM,ChuangPT,MackemS,Yang2.Y.IndianhedgehogsignalsindependentlyofPTHrPtopromotechondrocytehypertrophy.Development2008;135:1947-56.OnoN,NakashimaK,RittlingSR,SchipaniE,HayataT,3.EzuraY,SomaK,DenhardtDT,KronenbergHM,NodaM.Osteopontinnegativelyregulatesparathyroidhormonereceptorsignalinginosteoblasts.JBC2008;283:19400-19409.ProvotS,NachtrabG,ParuchJ,ChenAP,SilvaA,4.KronenbergHM.A-RafandB-RafaredispensablefornormalendochondralbonedevelopmentandPTHrPsuppressesERKactivationinhypertrophicchondrocytes.MolCellBiol.2008;28:344-357.PMCID:PMC2223319WuJY,PurtonLE,RoddaS,ChenM,WeinsteinLS,5.McMahonAP,ScaddenDT,KronenbergHM.OsteoblasticregulationofBlymphopoiesisismediatedbyGsx03B1-dependentsignalingpathways.PNAS2008;105:16976-16981.PMCID:PMC2579363AdamsGB,AlleyIR,ChugUI,ChabnerKT,JeansonNT,6.LoCelsoC,MarstersES,ChenM,WeinsteinLS,LinCP,KronenbergHM,ScaddenDT.HaematopoieticstemcellsdependonGalpha(s)-mediatedsignalingtoengraftbonemarrow.Nature2009;459(7243):103-7.PMCID:PMC2761017BaiXH,WangDW,KongL,ZhangY,LuanY,KobayashiT,7.KronenbergH,YuXP,LiuCJ.ADAMTS-7,adirecttargetofPTHrP,adverselyregulatesendochondralbonegrowthbyassociatingwithandinactivatingGEPgrowthfactor.MolCellBiol2009;29(15)4201-19.PMCID:PMC2715794ConenKL,NishimoriS,ProvotS,KronenbergHM.The8.transcriptionalcofactorLbhregulatesangiogenesisandendochondralboneformationduringfetalbonedevelopment.DevBiol20092009;332(2):348-58.PMCID:PMC2760734MicleaRL,KarperienM,BoschCAJ,vanderHorstG,van9.derValkMA,KobayashiT,KronenbergHM,RawadiG,AkcakayaP,LowikCWGM,FoddeR,WitJ-M,Robanus-MaandagECR.Adenomatouspilyposiscoli-mediatedcontrolofbeta-cateninisessentialforbothchondrogenicandosteogenicdifferentiationofskeletalprecursors.BMCDevelopmentalBiology2009;9:26.PMCID:PMC2678105TerauchiM,LiJ-Y,BediB,BaekK-H,TawfeekH,Galley10.S,GilbertL,NanesMS,ZayzafoonM,GuldbergR,LamarDL,SingerMA,LaneTF,KronenbergHM,WeitzmannMN,PacificiR.TlymphocytesamplifytheanabolicactivityofparathyroidhormonethroughWnt10bsignaling.CellMetab2009;10(3):229-40.PMCID:PMC2761855GuoJ,LiuM,YangD,BouxseinML,SaitoH,GalvinRJS,11.KuhstossSA,ThomasCC,SchipaniE,BaronR,Bringhurst
3
FR,KronenbergHM.SuppressionofWntsignalingbyDKK1attenuatesPTH-mediatedstromalcellresponseandnewboneformation.CellMetabolism2010;11:161-71.PMCID:PMC2819982.KamiyaN,KobayashiT,MochidaY,YuP,Yamauchi12.M,KronenbergH,MishinaY.WntinhibitorsDkk1andSostaredownstreamtargetsofBMPsignalingthroughtheType1Areceptor(BMPR1A)inosteoblasts.JBMR2010:25(2);200-10.PMCID:PMC3153381GuoJ,LiuM,YangD,BouxseinML,ThomasCC,Schipani13.E,BringhurstFR,KronenbergHM.PhospholipaseCsignalingviathePTH/PTHrPreceptorisessentialfornormalbonemodelingandremodeling.Endocrinology2010;151:3502-13.PMCID:PMC2940537MaesC,KobayashiT,SeligMK,TorrekensS,Roth14.SI,MackemS,CarmelietG,KronenbergHM.Osterix-expressingimmatureosteoblastprecursorsinvadegrowthcartilagealongwithbloodvessels.DevelopmentalCell2010;19:329-44.TawfeekH,BediB,LiJ-Y,AdamsJ,KobayashiT,15.WeitzmannMN,KronenbergHM,pacificiR.DisruptionofPTHreceptor1inTcellsprotectsagainstPTH-inducedboneloss.PLoSOne.2010;5(8):e12290.Publishedonline2010August.PMCID:PMC2924900HiraiT,ChaginA,KobayashiT,MackemS,Kronenberg16.H.PTH/PTHrPreceptorsignalingisrequiredformaintenanceofthegrowthplateinpostnatallife.PNAS2011;108(1):191-6.PMCID:PMC3017151MoisanA,RiveraMN,LotinunS,AkhavanfordS,Coffman17.EJ,CookEB,StoykovaS,MukherjeeS,SchoonmakerJA,BurgerA,KimWJ,KronenbergHM,BaronR,HaberDA,BardeesyN.TheWTXtumorsuppressorregulatesmesenchymalprogenitorcellfatespecification.DevCell2011;20(5):583-96.MorishitaM,OnoN,MiyaiK,NakagawaT,HanyuR,18.NagaoM,KamoiratanakulP,NotomiT,RittlingSR,DenhardtDT,KronenbergHM,EzuraY,HayataT,NakamotoT,NodaM.Osteopontindeficiencyenhancesparathyroidhormone/parathyroidhormonerelatedpeptidereceptor(PPR)signaling-inducedalterationintoothformationandodontoblasticmorphology.TissueCell2011;43(3):196-200.OnoN,NakashimaK,SchipaniE,HayataT,EzuraY,19.SomaK,KronenbergHM,NodaM.ConstitutivelyactivePTH/PTHrPreceptorspecificallyexpressedinosteoblastsenhancesboneformationinducedbybonemarrowablation.JCellPysiol2011.Doi:10.1002/jcp22986[Epubaheadofprint].PMID21866553WuJY,AarnisaloP,BastepeM,SinhaP,FulzeleK,Selig20.MK,ChenM,PoultonIJ,PurtonLE,SimsNA,WeinsteinLS,KronenbergHM.Gsαenhancescommitmentofmesenchymalprogenitorstotheosteoblastlineagebutrestrainsosteoblastdifferentiationinmice.JClinInvest2011:121(9):3492-504.PMCID:PMC3163961
Henry M. Kronenberg
HanyuR,WehbiVL,HayataT,MoriyaS,Feinstein21.TN,EzuraY,NagaoM,SaitaY,HemmiH,NotomiT,NakamotoT,SchipaniE,TakedaS,KanekoK,KurosawaH,KarsentyG,KronenbergHM,VilardagaJP,NodaM.Anabolicactionofparathyroidhormoneregulatedbytheβ2-adrenergicreceptor.ProcNatlAcadSciUSA2012;109(19):7433-8.KimSW,PajevicPD,SeligM,BarryKJ,YangJY,Shin22.CS,BaekWY,KimJE,KronenbergHM.IntermittentPTHadministrationconvertsquiescentliningcellstoactiveosteoblasts.JBoneMinerRes.2012may23[Epubaheadofprint].OhishiM,OnoW,OnoN,KhatriR,MarziaM,Baker23.EK,RootSH,WilsonTL,IwamotoY,KronenbergHM,AguilaHL,PurtonLE,SchipaniE.Anovelpopulationofcellsexpressingbothhematopoieticandmesenchymalmarkersispresentinthenormaladultbonemarrowandisaugmentedinamurinemodelofmarrowfibrosis.AmJPathol.2012;180(2):811-8.Epub2011Dec5.OnoN,NakashimaK,SchipaniE,HayataT,EzuraY,24.SomaK,KronenbergHM,NodaM.ConstitutivelyactivePTH/PTHrPreceptorspecificallyexpressedinosteoblastsenhancesboneformationinducedbybonemarrowablation.JCellPhysiol.2012;227(2):408-15.ParkD,SpencerJA,KohBI,KobayashiT,FujisakiJ,25.ClemensTL,LinCP,KronenbergHM,ScaddenDT.EndogenousbonemarrowMSCsaredynamic,fate-restrictedparticipantsinbonemaintenanceandregeneration.CellStemCell2012;10(3):259-72.SongL,LiuM,OnoN,BringhurstFR,KronenbergHM,26.GuoJ.Lostofwnt/β-cateninsignalingcausescellfateshiftofpreosteoblastsfromosteoblaststoadipocytes.JBoneMinerRes.2012;27(11):2344-58.FulzeleK,KrauseDS,PanaroniC,SainiV,BarryKJ,27.LiuX,LotinunS,BaronR,BonewaldL,FengJQ,ChenM,WeinsteinLS,WuJY,KronenbergHM,ScaddenDT,DivietiPajevicP.MyelopoiesisisregulatedbyosteocytesthroughGsα -dependentsignaling.Blood2013;121(6):930-9.GuoJ,SongL,LiuM,SegawaH,MiyamotoK,28.BringhurstFR,KronenbergHM,JüppnerH.ActivationofaNon-cAMP/PKAsignalingpathwaydownstreamofthePTH/PTHrPreceptorisessentialforasustainedhypophosphatemicresponsetoPTHinfusioninmalemice.Endocrinology2013;53(2):487-96.PozziS,FulcinitiM,YanH,ValletS,HomareE,PatelK,29.SantoL,CirsteaD,HideshimaT,SchirtzingeL,KuhstossS,AndersonKC,MunshiN,ScaddenD,KronenbergHM,RajeN.Invivoandinvitroeffectsofanovelanti-Dkk1neutralizingantibodyinmultiplemyeloma.Bone2013;53:487-496.
5
Itwasbelievedthatcytokinesandhormonesaremainregulatorsofboneremodeling.However,thisviewhasbeenchallenged.Organnetworkhasbeenshowntoplayamajorroleinhomeostasis,recently.Boneisnottheexception.
Clinically,itiswellknownthatheadtraumaacceleratesfracturehealing.Advancesinmoleculargeneticsrevealedthatneuronsandneuropeptides,includingsympatheticnervoussystem,areintimatelyinvolvedinboneremodeling.
Semaphorin3A(Sema3A)isadiffusibleaxonalchemorepellentthatplaysanimportantroleinaxonguidance.PreviousstudieshavedemonstratedthatSema3Aisanosteo-anabolicautocrineand,accordingly,Sema3A-KOmicedevelopalowbonemassduetodecreasedboneformation.However,recently,wedemonstratedthatosteoblast-specificSema3A-KOmicehadnormalbonemass,eventhoughtheexpressionofSema3Ainbonewassubstantiallydecreased.Incontrast,micelackingSema3AinneuronshadlowbonemasssimilartoSema3A-KOmice,indicatingthatneuron-derivedSema3AisresponsiblefortheboneabnormalitiesindependentofthelocaleffectofSema3Ainbone.Indeed,sensoryinnervationsoftrabecularboneweresignificantlydecreasedinneuron-specificSema3A-KO.Moreover,ablatingsensorynervesdecreasedbonemassinwild-typemice,whereasitdidnotdeterioratelowbonemassphenotypeinneuronspecificSema3A-KOmice,furtherindicatingtheessentialroleofsensorynervoussysteminnormalbonehomeostasis.Thus,wedemonstratedthatsensorynervoussystemisalsoacriticalregulatorofboneremodeling.
Inthislecture,Iwouldliketodiscussnovelregulatorsofboneremodeling.
Control of bone metabolism via organ crosstalk
Shu Takeda, M.D., Ph.D.
ProfessorDepartmentofPhysiologyandCellBiology,GraduateSchoolofMedicalandDentalSciences,TokyoMedicalandDentalUniversity
6
Shu Takeda
CURRICULUM VITAE
Education
1992 M.D.UniversityofTokyo,SchoolofMedicine2002 Ph.D.UniversityofTokyo,GraduateSchoolofMedicine
Position
1999 PostdoctralFellow,BaylorCollegeofMedicine, Houston2003 ClinicalFellow,DeptofEndocrinorogyand MetabolismMishukuHospital,Tokyo2004 AssociateProfessor(Junior),Departmentof OrthopaedicSurgery,21CenterofExcellence Program,GraduateSchool,TokyoMedicaland DentalUniversity2005-2008 AssociateProfessor(Senior),Departmentof OrthopaedicSurgery,21CenterofExcellence Program,GraduateSchool,TokyoMedicaland DentalUniversity2008 AssociateProfessor,DepartmentofOrthopaedic Surgery,21CenterofExcellenceProgram, GraduateSchool,TokyoMedicalandDental University2009- AssociateProfessor,AssociateProfessor,Section ofNephrology,EndocrinologyandMetabolism, DepartmentofInternalMedicine,Schoolof Medicine,KeioUniversity2013-present Professor,Dept.ofPhysiologyandCellBiology, GraduateSchoolofMedicalandDentalSciences, TokyoMedicalandDentalUniversity2013-present PrincipleInvestigator,CREST,JapanScienceand TechnologyAgency
Award and Honors
1997 PresidentBookAwardofAmericanSocietyforBone andMineralResearch1997 YoungInvestigatorAwardofJapaneseSocietyforBone andMineralMetabolism2000 YoungInvestigatorAwardofAmericanSocietyfor BoneandMineralResearch2007 Correspondingauthorforthepresentation:Most OutstandingAbstractAwardforthe29thAmerican SocietyforBoneandMineralResearchannualmeeting2008 ResearchAwardofJapaneseSocietyforBoneand MineralMetabolism2010 ResearchAwardofJapaneseEndocrineSociety2011 JapanSocietyforthePromotionofSciencePrize2011 BestReviewerof“Bone”2012 AcademicAwardofJapaneseSocietyforBoneand MineralMetabolism2013 MemberoftheAmericanSocietyforClinical Investigation
Publications
Elefteriou,F.,J.D.Ahn,S.Takeda,M.Starbuck,X.Yang,1.X.Liu,H.Kondo,W.G.Richards,T.W.Bannon,M.Noda,K.Clement,C.Vaisse,andG.Karsenty2005LeptinregulationofboneresorptionbythesympatheticnervoussystemandCART.Nature434 :514-20.Fukushima,N.,R.Hanada,H.Teranishi,Y.Fukue,T.2.Tachibana,H.Ishikawa,S.Takeda,Y.Takeuchi,S.Fukumoto,K.Kangawa,K.Nagata,andM.Kojima2005Ghrelindirectlyregulatesboneformation.JBoneMinerRes20 :790-8.Kondo,H.,A.Nifuji,S.Takeda,Y.Ezura,S.R.Rittling,3.D.T.Denhardt,K.Nakashima,G.Karsenty,andM.Noda2005Unloadinginducesosteoblasticcellsuppressionandosteoclasticcellactivationtoleadtobonelossviasympatheticnervoussystem.JBiolChem280 :30192-200.Takeda,S.2005Centralcontrolofboneremodeling.4.BiochemBiophysResCommun328 :697-9.Kamekura,S.,Y.Kawasaki,K.Hoshi,T.Shimoaka,H.5.Chikuda,Z.Maruyama,T.Komori,S.Sato,S.Takeda,G.Karsenty,K.Nakamura,U.I.Chung,andH.Kawaguchi2006Contributionofrunt-relatedtranscriptionfactor2tothepathogenesisofosteoarthritisinmiceafterinductionofkneejointinstability.ArthritisRheum54 :2462-70.Ito,N.,S.Fukumoto,Y.Takeuchi,S.Takeda,H.Suzuki,6.T.Yamashita,andT.Fujita2007Effectofacutechangesofserumphosphateonfibroblastgrowthfactor(FGF)23levelsinhumans.JBoneMinerMetab25 :419-22.Nakamura,T.,Y.Imai,T.Matsumoto,S.Sato,K.Takeuchi,7.K.Igarashi,Y.Harada,Y.Azuma,A.Krust,Y.Yamamoto,H.Nishina,S.Takeda,H.Takayanagi,D.Metzger,J.Kanno,K.Takaoka,T.J.Martin,P.Chambon,andS.Kato2007EstrogenpreventsbonelossviaestrogenreceptoralphaandinductionofFasligandinosteoclasts.Cell130 :811-23.Okuda,N.,S.Takeda,K.Shinomiya,T.Muneta,S.Itoh,M.8.Noda,andY.Asou2007ED-71,anovelvitaminDanalog,promotesboneformationandangiogenesisandinhibitsboneresorptionafterbonemarrowablation.Bone40 :281-92.Sato,S.,R.Hanada,A.Kimura,T.Abe,T.Matsumoto,9.M.Iwasaki,H.Inose,T.Ida,M.Mieda,Y.Takeuchi,S.Fukumoto,T.Fujita,S.Kato,K.Kangawa,M.Kojima,K.Shinomiya,andS.Takeda2007CentralcontrolofboneremodelingbyneuromedinU.NatMed13 :1234-40.Takeda,S.,10. Leptinandbone ,inLeptin ,M.C.Henson,etal.,Editors.2007,Springer.p.1059-1068.Nojiri,Y.,S.Takeda,M.Enomoto,H.Nishitsuji,T.Masuda,11.S.Sotome,andK.Shinomiya2008Co-overexpressionofGDNFandGFRalpha1inducesneuraldifferentiationinneuralprogenitorcellsincomparisontobonemarrowstromalcells.JMedDentSci55 :121-8.Sato,S.,A.Kimura,J.Ozdemir,Y.Asou,M.Miyazaki,T.12.Jinno,K.Ae,X.Liu,M.Osaki,Y.Takeuchi,S.Fukumoto,H.Kawaguchi,H.Haro,K.Shinomiya,G.Karsenty,andS.Takeda2008ThedistinctroleoftheRunxproteins
7
Shu Takeda
inchondrocytedifferentiationandintervertebraldiscdegeneration:Findingsinmurinemodelsandinhumandisease.ArthritisRheum58 :2764-75.Takeda,S.2008Centralcontrolofboneremodelling.13. JNeuroendocrinol20 :802-7.Takeda,S.andP.Ducy,14. RegulationofBoneRemodelingbyCentralandPeripheralNervousSignals ,inPrincipleofBoneBiology ,J.P.Bilezikian,L.G.Raisz,andT.J.Martin,Editors.2008,Elsevier.p.1059-1068.Takeda,S.andG.Karsenty2008Molecularbasesofthe15.sympatheticregulationofbonemass.Bone42 :837-40.Tominaga,H.,S.Maeda,M.Hayashi,S.Takeda,S.Akira,16.S.Komiya,T.Nakamura,H.Akiyama,andT.Imamura2008CCAAT/Enhancer-bindingProtein{beta}PromotesOsteoblastDifferentiationbyEnhancingRunx2ActivitywithATF4.Mol.Biol.Cell19 :5373-5386.Inose,H.,H.Ochi,A.Kimura,K.Fujita,R.Xu,S.Sato,M.17.Iwasaki,S.Sunamura,Y.Takeuchi,S.Fukumoto,K.Saito,T.Nakamura,H.Siomi,H.Ito,Y.Arai,K.-i.Shinomiya,andS.Takeda2009AmicroRNAregulatorymechanismofosteoblastdifferentiation.ProcNatlAcadSciUSA106 :20794-20799.Suzuki,D.,A.Yamada,T.Amano,R.Yasuhara,A.Kimura,18.M.Sakahara,N.Tsumaki,S.Takeda,M.Tamura,M.Nakamura,N.Wada,T.Nohno,T.Shiroishi,A.Aiba,andR.Kamijo2009EssentialmesenchymalroleofsmallGTPaseRac1ininterdigitalprogrammedcelldeathduringlimbdevelopment.DevBiol335 :396-406.Takeda,S.2009Osteoporosis:Aneuroskeletaldisease?19. IntJBiochemCellBiol41 :455-9.Itoh,T.,S.Takeda,andY.Akao2010MicroRNA-20820.modulatesBMP-2-stimulatedmousepreosteoblastdifferentiationbydirectlytargetingV-etserythroblastosisvirusE26oncogenehomolog1.JBiolChem285 :27745-52.Kimura,A.,H.Inose,F.Yano,K.Fujita,T.Ikeda,S.Sato,21.M.Iwasaki,T.Jinno,K.Ae,S.Fukumoto,Y.Takeuchi,H.Itoh,T.Imamura,H.Kawaguchi,U.I.Chung,J.F.Martin,S.Iseki,K.Shinomiya,andS.Takeda2010Runx1andRunx2cooperateduringsternalmorphogenesis.Development137 :1159-67.Nishikawa,K.,T.Nakashima,S.Takeda,M.Isogai,M.22.Hamada,A.Kimura,T.Kodama,A.Yamaguchi,M.J.Owen,S.Takahashi,andH.Takayanagi2010Mafpromotesosteoblastdifferentiationinmicebymediatingtheage-relatedswitchinmesenchymalcelldifferentiation.JClinInvest120 :3455-65.Sato,T.,D.Chida,T.Iwaya,M.Usui,M.Hatori,T.Abe,23.S.Takeda,andT.Yoda2010Non-neuronalregulationandrepertoireofcholinergicreceptorsinorgans.BioMolecularConceptsinpress .Takeda,S.,24. SkeletalRegulationofEnergyMetabolism,inBoneandDevelopmentinTopicinBoneBiology ,F.Bronner,H.Roach,andM.Farach-Carson,Editors.2010,Springer.p.267-278.
Tanaka,M.,T.Suganami,S.Sugita,Y.Shimoda,M.25.Kasahara,S.Aoe,M.Takeya,S.Takeda,Y.Kamei,andY.Ogawa2010Roleofcentralleptinsignalinginrenalmacrophageinfiltration.EndocrJ57 :61-72.Meguro,S.,M.Tomita,T.Katsuki,K.Kato,H.Oh,A.26.Ainai,R.Ito,S.Takeda,T.Kawai,Y.Atsumi,H.Itoh,andH.Hasegawa2011Plasma25-hydroxyvitamindisindependentlyassociatedwithhemoglobinconcentrationinmalesubjectswithtype2diabetesmellitus.IntJEndocrinol2011 :362981.Nagao,M.,T.N.Feinstein,Y.Ezura,T.Hayata,T.Notomi,27.Y.Saita,R.Hanyu,H.Hemmi,Y.Izu,S.Takeda,K.Wang,S.Rittling,T.Nakamoto,K.Kaneko,H.Kurosawa,G.Karsenty,D.T.Denhardt,J.-P.Vilardaga,andM.Noda2011Sympatheticcontrolofbonemassregulatedbyosteopontin.ProceedingsoftheNationalAcademyofSciences .Ogata,N.,Y.Shinoda,N.Wettschureck,S.Offermanns,28.S.Takeda,K.Nakamura,G.V.Segre,U.-i.Chung,andH.Kawaguchi2011GαqSignalinOsteoblastsIsInhibitorytotheOsteoanabolicActionofParathyroidHormone.JournalofBiologicalChemistry286 :13733-13740.Hinoi,E.,Ochi,H.,Takarada,T.,Nakatani,E.,Iezaki,T.,29.Nakajima,H.,Fujita,H.,Takahata,Y.,Hidano,S.,Kobayashi,T.,Takeda,S.,andYoneda,Y.Positiveregulationofosteoclasticdifferentiationbygrowthdifferentiationfactor15upregulatedinosteocyticcellsunderhypoxia.JBoneMinerRes27 :938-49,2012Hanyu,R.,Wehbi,V.L.,Hayata,T.,Moriya,S.,Feinstein,30.T.N.,Ezura,Y.,Nagao,M.,Saita,Y.,Hemmi,H.,Notomi,T.,Nakamoto,T.,Schipani,E.,Takeda,S.,Kaneko,K.,Kurosawa,H.,Karsenty,G.,Kronenberg,H.M.,Vilardaga,J.-P.,andNoda,M.Anabolicactionofparathyroidhormoneregulatedbytheβ2-adrenergicreceptor.ProceedingsoftheNationalAcademyofSciences109 :7433-7438,2012Fujita,K.,Iwasaki,M.,Ochi,H.,Fukuda,T.,Ma,C.,31.Miyamoto,T.,Takitani,K.,Negishi-Koga,T.,Sunamura,S.,Kodama,T.,Takayanagi,H.,Tamai,H.,Kato,S.,Arai,H.,Shinomiya,K.,Itoh,H.,Okawa,A.,andTakeda,S.VitaminEdecreasesbonemassbystimulatingosteoclastfusion.NatMed18 :589-594,2012Iwasaki,M.,Piao,J.,Kimura,A.,Sato,S.,Inose,H.,Ochi,32.H.,Asou,Y.,Shinomiya,K.,Okawa,A.,andTakeda,S.Runx2haploinsufficiencyamelioratesthedevelopmentofOssificationofthePosteriorLongitudinalLigament.PLoSONE.7 :e43372,2012Fukuda,T.,Takeda,S.,Xu,R.,Ochi,H.,Sunamura,S.,Sato,33.T.,Shibata,S.,Yoshida,Y.,Gu,Z.,Kimura,A.,Ma,C.,Xu,C.,Bando,W.,Fujita,K.,Shinomiya,K.,Hirai,T.,Asou,Y.,Enomoto,M.,Okano,H.,Okawa,A.,andItoh,H.Sema3Aregulatesbone-massaccrualthroughsensoryinnervations.Nature2013
9
Oralsquamouscellcarcinoma(OSCC)frequentlyinvadesthejaws,andthisinvasionisassociatedwithaworseprognosis.Themechanismunderlyingtheboneinvasionremainspoorlyunderstood.Wehistopathologicallyinvestigatedmandibularinvasionpatternsin97casesofprimaryOSCC,andshowedthatinallcasesvaryingamountsoffibrousconnectivetissuesintervenedbetweenthetumorcellsandthebone.ImmunohistochemistryrevealedRANKLexpressioninthefibroblasticcellsthatwereadjacenttotheosteoclastsintheareaofboneresorption.Theseresultssuggestthatthefibrousstromaisinvolvedinosteoclasticboneresorption.Toexplorethemolecularmechanism,weconductedmicroarrayanalysesusing43humanOSCCspecimens,andrevealedthatmanyofspecimensoverexpressedPTHrPmRNA,butafewoverexpressedIL-6 mRNA.ImmunohistochemicalanalysisrevealedthatIL-6wasexpressednotonlyincancercellsbutalsoinfibroblastsattumor-boneinterface.Conditionedmedia(CM)derivedfromthecultureoforalcancercelllinesstimulatedRanklexpressioninstromalcellsandosteoclastformation.AntibodiesagainstbothhumanPTHrPandmouseIL-6receptorsuppressedRankl inST2cellsandosteoclastformationinducedbyCM.XenograftsofOSCCcellsontotheperiostealregionoftheparietalboneinathymicmicepresentedsimilarhistologyandexpressionprofilesofRANKLandIL-6asobservedinbone-invasivehumanOSCCspecimens.TheseresultsindicatethatOSCCprovidesasuitablemicroenvironmentforosteoclastformationnotonlybyproducingIL-6andPTHrPbutalsobystimulatingstromalcellstosynthesizeIL-6.RecentreportsindicatedthesynthesisofRANKLbyOSCCcellsaswellasthetumorstromalcells.Indeed,HSC3andHO-1-N-1,humanOSCCcelllines,expressedRANKLandstimulatedRankl expressioninUAMS-32murineosteoblasticcellline.WediscriminatedtherolesofRANKLsynthesizedbystromalcellsandcancercellsincancer-associatedboneresorptionbyusingspecies-specificRANKLantibodiesagainstmurineRANKLandhumanRANKL,respectively.OsteoclastogenesisinducedbytheconditionedmediumofHSC3andHO-1-N-1cellsinaco-cultureofmurinebonemarrowcellsandUAMS-32cellswasinhibitedbytheadditionofantibodiesagainsteithermouseorhumanRANKL.HSC3-inducedbonedestructionwasgreatlyinhibitedbytheadministrationofanti-mouseRANKLantibodyinaxenograftmodel.HO-1-N-1-inducedbonedestructionwasinhibitedbytheadministrationofeitheranti-mouseoranti-humanRANKLantibody.BonedestructioninducedbythetransplantationofhumanRANKL-overexpressingcells(HSC3-R2)wasgreatlyinhibitedbytheinjectionofanti-humanRANKLantibody.ThepresentstudyrevealedthatRANKLproducedbybothstromalandcancercellsisinvolvedinoralcancer-inducedosteoclasticboneresorption.Theseresultsprovideimportantinformationforunderstandingthecellularandmolecularbasisofcancer-associatedbonedestructionandthemechanismofactionunderlyingRANKLantibody(denosumab)therapy.ToexplorethemoleculesthatsynthesizedbyOSCCcellsandstimulateosteoclasticboneresorption,weestablishedtwoclonalcelllines,HSC3-C13andHSC3-C17,fromthematernaloralcancercellline,HSC3.TheconditionedmediumfromHSC3-C13cellsshowedthehighestinductionofRankl expressioninthemousestromalcelllinesST2andUAMS-32ascomparedtothatinmaternalHSC3cellsandHSC3-C17cells,whichshowedsimilaractivity.TheconditionedmediumfromHSC3-C13cellssignificantlyincreasedthenumberofosteoclastsinaco-culturewithmousebonemarrowcellsandUAMS-32cells.XenografttumorsgeneratedfromtheseclonalcelllinesintotheperiostealregionoftheparietalboneinathymicmiceshowedthatHSC3-C13cellscausedextensivebonedestructionandasignificantincreaseinosteoclastnumbersascomparedtoHSC3-C17cells.GeneexpressionwascomparedbetweenHSC3-C13andHSC3-C17cellsbyusingmicroarrayanalysis,whichshowedthatCXCL2genewashighlyexpressedinHSC3-C13cellsascomparedtoHSC3-C17cells.ImmunohistochemicalstainingrevealedthelocalizationofCXCL2inhumanOSS.TheincreaseinosteoclastnumbersinducedbytheHSC3-C13-conditionedmediumwasdose-dependentlyinhibitedbyadditionofanti-humanCXCL2-neutralizingantibodyinaco-culturesystem.RecombinantCXCL2increasedtheexpressionofRankl inUAMS-32cells.TheseresultsindicatethatCXCL2isinvolvedinbonedestructioninducedbyoralcancer.ThisisthefirstreportshowingtheroleofCXCL2incancer-associatedbonedestruction.
Bone destruction by oral cancer
Akira Yamaguchi, D.D.S., Ph.D.
ProfessorDepartmentofOralPathology,GraduateSchoolofMedicalandDentalSciences,TokyoMedicalandDentalUniversity
10
Akira Yamaguchi
CURRICULUM VITAE
Education
1974 D.D.S.TokyoDentalCollege1980 Ph.D.TokyoMedicalandDentalUniversity
Position
1980-1988 AssistantProfessor,DepartmentofOralPathology, SchoolofDentistry,ShowaUniversity1985-1987 VisitingAssistantProfessor,SchoolofDentistry, WashingtonUniversity,Si.Loius,MO,USA1987-1988 VisitingAssistantProfessor,OrthopedicSurgery, SchoolofMedicine,St.LouisUniversity1988-1998 AssociateProfessor,DepartmentofOralPathology, SchoolofDentistry,ShowaUniversity1998-2004 ProfessorandChair,DepartmentofOral Pathology,UniversitySchoolofDentistry2004- ProfessorandChair,DepartmentofOralPathology GraduateSchoolofMedicalandDentalSciences TokyoMedicalandDentalUniversity2011- Councilmember,ScienceCouncilofJapan
Award and Honors
1993 TheJapaneseSocietyforBoneandMineralResearch: AcademicAward1996 TheJapaneseSocietyofPathology:PathologyResearch Award2005 TheJapanesePathologyAward
Publications
YamaguchiA,KatagiriT,IkedaT,WozneyJM,1.RosenV,WangEA,KahnAJ,SudaT,YoshikiS:Recombinanthumanbonemorphogeneticprotein-2stimulatesosteoblasticmaturationandinhibitsmyogenicdifferentiationinvitro.JCellBiol 111:681-687,1991KatagiriT,YamaguchiA,KomakiM,AbeE,TakahashiN,2.IkedaT,RosenV,WozneyJM,Fujisawa-SeharaA,SudaT:Bonemorphogeneticprotein-2convertsthedifferentiationpathwayofC2C12myoblastsintotheosteoblastlineage.JCellBiol 127:1755-1766,1994IshizuyaT,YokoseS,HoriM,NodaT,SudaT,Yoshiki3.S,YamaguchiA:Parathyroidhormoneexertsdisparateeffectsonosteoblastdifferentiationdependingonexposuretimeinratosteobllasticcells.JClinInvest 99:2961-2970,1997KomoriT,YagiH,NomuraS,YamaguchiA,SasakiK,4.DeguchiK,ShimuzuY,BronsonRT,GaoY-H,InadaM,SatoM,OkamotoR,TominagaK,KitamuraY,YoshikiS,KishimotoT:TargeteddisruptionofCbfa1resultsincompletelackofboneformationowingtothematurationarrestofosteoblasts.Cell 89:755-764,1997KintoN,IwamotoM,Enomoto-IwamotoM,NojiS,Ohuchi5.H,YoshidaH,KataokaH,WadaY,GaoY-H,TkahashiHE,YoshikiS,YamaguchiA:FibroblastsexpressingSonichedgehoginduceosteoblastdifferentiationandectopicboneformation.FEBSLetters404:319-323,1997YamaguchiA,KomoriT,SudaT:RegulationofOsteoblast6.DifferentiationMediatedbyBMPs,HedgehogsandCbfa1.EndocrineReviews21:393-411,2000YuasaT,KataokaH,KintoN,IwamotoM,Enomoto-7.IwamotoM,IemuraS,UenoN,ShibataY,KurosawaH,YamaguchiA:SonichedgehogisinvolvedinosteoblastdifferentiationbycooperatingwithBMP-2.JCell.Physiol 193:225-232,2002NobtaM,TsukazakiT,ShibataY,ChangX,MoriishiT,8.SakanoS,ShindoH,YamaguchiA:CriticalregulationofBMP-inducedosteoblasticdifferentiationbyDelta1/Jagged1-activatedNotch1signaling.JBiolChem280:15842-15848,2005LiuT,GaoY,SakamotoK,MinamizatoT,FurukawaK,9.TsukazakiT,ShibataY,BesshoK,KomoriT,YamaguchiA:BMP-2promotesdifferentiationofosteoblastsandchondroblastsinRunx2-deficientcelllines.JCellPhysiol211:728-735,2007MinamizatoT,SakamotoK,LiuT,KokuboH,KatsubeK,10.PerbalB,NakamuraS,YamaguchiA:CCN3/NOVinhibitsBMP-2-inducedosteoblastdifferentiationbyinteractingwithBMPandNotchsignalingpathways.BiochemBiophResCo354:567-573,2007IshikuroM,SakamotoK,KayamoriK,IzumoT,Yamaguchi11.A:Roleoffibrousstromainboneinvasionbygingivalsquamouscellcarcinomas.BONE43:621-627,2008KayamoriK,SakamotoK,NakashimaT,TakayanagiT,12.
11
Akira Yamaguchi
MoritaK,OmuraK,NguyenST,MikiY,IimuraT,HimenoA,AkashiT,Yamada-OkabeH,OgataE,YamaguchiA:RolesofIL-6andPTHrPinosteoclastformationassociatedwithoralcancers:ThesignificanceofIL-6synthesizedbystromalcellsinresponsetocancercells.AmerJPathol 176,968-980,2010SakamotoK,AragakiT,KawachiH,KatsubeK,MikiY,13.TakizawaT,OmuraK,MoritaK,OkadaN,YamaguchiA:Down-regulationofkeratin4andkeratin13expressioninoralsquamouscellcarcinomaandepithelialdysplasia:aclueforhistopathogenesis.Histopathol 58:531-542,2011OueE,LeeJW,SakamotoK,IimuraT,AokiK,KayamoriK,14.MichiY,YamashiroM,YamaguchiA:CXCL2synthesizedbyoralsquamouscellcarcinomaisinvolvedincancer-associatedbonedestruction.BiochemBiophResCo424:456-461,2012WatanabeT,TamamuraY,HoshinoA,MakinoY,15.NishimuraR,KamiokaH,YonedaT,AmagasaT,YamaguchiA,IimuraT:IncreasingparticipationofSclerostininpostnatalbonedevelopmentrevealedbythree-dimensionalimmunofluorescencemorphometry.BONE51:447-458,2012SakamotoK,FujiiT,KawachiH,MikiY,OmuraK,Morita16.K,KayamoriK,KhanomR,KatsubeK,YamaguchiA:ReductionofNOTCH1expressionpertainstomaturationabnormalitiesofkeratinocytesinsquamousneoplasms.LabInvest 92:688-702:2012MatsushitaY,SakamotoK,TamamuraY,ShibataY,17.MinamizatoT,KiharaT,ItoM,KatsubeK,HiraokaS,KosekiH,HaradaK,YamaguchiA:CCN3proteinparticipatesinboneregenerationasaninhibitoryfactor.JBiolChem288:19973-19985,2013SatoK,LeeJW,SakamotoK,IimuraT,KayamoriK,18.YasudaH,ShindohM,ItoM,OmuraK,YamaguchiA:RANKLsynthesizedbybothstromalcellsandcancercellsplaysacrucialroleinosteoclasticboneresorptioninducedbyoralcancer.AmerJPathol 182:1890-1899,2013
13
Thebonemarrowisoneoftheprimarylymphoidorgansthatharbortheimmunecells.Underthesemicroenvironments,bonecellsinteractnotonlywithotherbonecellsbutalsowithimmunecellsincludinghematopoieticstemcells.Thus,allthecellsinthebonemarrowarecommunicatingwitheachothertomaintainbothskeletalandimmunesystems(1,2).However,themoleculesthatmediatethecommunicationamongcellsinthebonehavebeenpoorlyidentified.Wehavetriedtoexplorethemolecularbasisforcellularcommunicationinthebonemarrowandfoundthatosteocyte-derivedRANKLplaysacrucialroleinadultosteoclastogenesis(3),osteoclast-derivedSema4Dinhibitsboneformation(4)andosteoblast-derivedSema3Afunctionsasapotentosteoprotectivecytokineinhibitingosteoclastogenesisandpromotingosteoblastogenesis(5).Assemaphorins,majoraxonguidancemolecules,haveemergedasbonecellcommunicationfactors,wearefacinganewstageofboneresearchincludingthebone,immuneandneuralsystems.WehavelongworkedontheinteractionbetweenTcellsandosteoclasts,andrecentlyfoundtheoriginofosteoclastogenicTh17cellstobeFoxp3positiveTregs(6).TherecentadvancesinosteoimmunologyfieldincludingtheconversionofTregtopathogenicTcellswillbediscussed.
1. TakayanagiH.NatRevImmunol7,292-304(2007),2. TakayanagiH.NatRevRheumatol5(12),667-76(2009),3. NakashimaT.etal.NatMed17,1231-34(2011),4. Negishi-KogaT.etal.NatMed17,1473-1480(2011),5. HayashiM.etal.Nature485,69-74(2012)6. KomatsuN.etal.NatMed,inpress
Forefront of osteoimmunology
Hiroshi Takayanagi, M.D., Ph.D.
ProfessorDepartmentofImmunology,GraduateSchoolofMedicineandFacultyofMedicine,TheUniversityofTokyo
14
Hiroshi Takayanagi
CURRICULUM VITAE
Education
1990 M.D.TheUniversityofTokyo,Tokyo,Japan2001 Ph.D.(Medicine)TheUniversityofTokyo,Tokyo,Japan
Award and Honors
2002 AmershamBiosciencesandSciencePrizeforYoung Scientists2002 NovartisJapanRheumatologyPrize2004 JapanCollegeofRheumatologyAward2004 FullerAlbrightAward,ASBMR2005 JapanSocietyforthePromotionofSciencePrize2005 JapanAcademyMedal2006 InternationalResearchPrize,AustrianSocietyforBone andMineralResearchandLudwigBoltzmannInstitute ofOsteology2008 AcademicAwardoftheMochidaMemorialFoundation2009 InouePrizeforScience2009 JSBMRDistinguishedScientistAward2011 IBMS-BONEHerbertA.FleischAward
Publications
TakayanagiHetal.1. Nature408,600-605(2000)TakayanagiHetal.2. Nature416,744-749(2002)TakayanagiHetal.3. DevCell 3,889-901(2002)KogaTetal.4. Nature428,758-763(2004)TakayanagiH.5. NatRevImmunol 7,292-304(2007)AsagiriMetal.6. Science319,624-627(2008)ShinoharaMetal.7. Cell 132,794-806(2008)Takayanagi,H8. NatRevRheumatol 5(12),667-76(2009)OkamotoKetal.9. Nature464,1381-5(2010)NakashimaTetal.10. NatMed17,1231-34(2011)Negishi-Koga,T.,etal.11. NatMed17,1473-1480(2011)Hayashi,M.,etal.12. Nature485,69-74(2012)TakayanagiHetal.13. CellMetab17(2):249-60.(2013)
17
Osteoarthritis(OA)affectsover200millionpeopleworldwide.JointsmostfrequentlyaffectedbyOAarethehands,hips,spineandknees,wherebreakdownandsubsequentlossofarticularcartilageresultsinpain,stiffnessandswellingandleadstodecreasedjointfunctionandlossofjointmobility.ThekneejointisparticularlysusceptibletoOAandmeniscalinjuriesarethemostcommonkneeinjury.Treatmentofmeniscalinjurieshasevolveddramaticallyinthepast30yearsinresponsetoanincreasedunderstandingoftheroleperformedbythemeniscuswithinthekneejoint,andtoday,surgicalproceduresareaimedatrepairingorreplacingdamagedmenisci,dependingonthesizeoftheinjuryanditslocation.Unfortunately,damagedmeniscaltissuerarelyregainsthestructuralintegrityandmechanicalstrengthofnormalmeniscus,andrecentdataindicatethatsurgicalrepairofmeniscaltearscannotreliablypreventtheprogressionofdegenerativechangesandclinicalsymptomsthatpresagethedevelopmentofkneeOA.Particularlystrikingisthelackofoptionsforreversingtheprogressivedebilitationofthekneeinyoung,healthyindividuals.
Evidencefromrecentstudieslinksthesignalingpathwaysdirectingembryonicdevelopmentwiththosethatmediateadulttissueregeneration,wheretheyinfluencethemigration,proliferationanddifferentiationoflocallyresidingtissue-specificstem/progenitorcells.Inthisway,thespecificityofthereparativeresponsegeneratedbyatissueisdependentontheactivationoftheresidenttissue-specificstem/progenitorcellpopulationandnotonthesignalsthataffecttheirbehavior.Foradultmusculoskeletaltissues,resident-specificstem/progenitorcellshavebeenidentifiedandcharacterizedinmuscle,tendonandligament,articularcartilageandbone.Asagroup,thesetissue-specificstemcellspossesssomeofthecharacteristicsofmesenchymalstemcells(MSC)butmoreimportantly,exhibitcharacteristictissue-specificidentities.Basedonthehypothesisthatcellsnecessaryformeniscalrepairarethosethatexpressacharacteristicgenesignaturethatisdefinedduringmeniscalmorphogenesiswecombinedlaser-capturemicro-dissection(LCM)ofembryonicjointtissueswiththeproductionoftissue-specificlibrariesandcomparativegenearrayanalysistouncoverthegenesignatureofmeniscusformingcellsandthesignalingpathwaysthatregulateexpressionofthesegenes.Currenteffortsareaimedatusinginformationgainedfromthestudyofmeniscusdevelopmentinmicetoquerythereparativepotentialofcellscollectedfromadultmouseandhumanmeniscus.
Regenerative potential of the knee meniscus
Vicki Rosen, Ph.D.
ProfessorDepartmentofDevelopmentalBiology,HarvardSchoolofDentalMedicine
18
Vicki Rosen
CURRICULUM VITAE
Education
1975 B.S.,Biology,StateUniversityofNewYorkatStony Brook1981 Ph.D.,CellBiologyandPhysiology,Universityof Connecticut
Position
1984-1988 StaffScientistII,BMPDiscoveryResearch, GeneticsInstitute1986-1988 PrincipalScientist,BMPDiscoveryResearch, GeneticsInstitute1988-1998 SeniorScientist,BMPDiscoveryResearch, GeneticsInstitute1998-2001 Director,TissueGrowthandRepair,Genetics Institute2001 DistinguishedResearchScientist,Genetics Institute/WyethResearch2001-2005 SeniorMemberoftheStaff,TheForsythInstitute2001-present ProfessorofDevelopmentalBiology, HarvardSchoolofDentalMedicine2005-present Chair,DepartmentofDevelopmentalBiology, HarvardSchoolofDentalMedicine
Award and Honors
2001 HonoraryMA,HarvardUniversity2008 KappaDeltaAward,co-recipient,OrthopedicResearch Society2010 MarshallUristAwardinTissueRepair,Orthopedic ResearchSociety2010 BasicScienceChair,2010ASBMRMeeting2012 Harvard-AustraliaFoundationFellowship2012 RaineMedicalResearchFoundationMedal
Publications
LanchoneyTF,OlmsteadEA,ShoreEM,GannonFA,1.RosenV,ZasloffMA,andKaplanFS.Characterizationofbonemorphogeneticprotein4receptorinfibrodysplasiaossificansprogressiva.ClinOrthopRelRes1998;346:38-45.ChenD,JiX,HarrisMA,FengJQ,KarsentyG,Celeste2.AJ,RosenV,MundyGR,andHarrisSE..Differentialrolesforbonemorphogeneticprotein(BMP)receptortypeIBandIAindifferentiationandspecificationofmesenchymalprecursorcellstoosteoblastandadipocytelineages.JCellBiol 1998;142:295-305.FuruyaK,NifujiA,RosenV,andNodaM.Effectsof3.GDF7/BMP12onproliferationandalkalinephosphataseexpressioninratosteoblasticosteosarcomaROS17/2.8cells.JCellBiochem1999;72:177-180.LeeM-H,JaavedA,KimH-J,ShinH-I,GutierrezS,Choi4.J-Y,RosenV,SteinJL,vanWijnenAJ,SteinGS,LianJB,andRyooH-M.TransientupregulationofCBFA1inresponsetobonemorphogeneticprotein-2andtransforminggrowthfactorß1inC2C12myogeniccellscoincideswithsupressionofthemyogenicphenotypebutisnotsufficientforosteoblastdifferentiation.JCellBiochem1999;73:114-125.NeuhausH,RosenV,andThiesRS.Heartspecific5.expressionofmouseBMP-10,anovelmemberoftheTGF-ßsuperfamily.MechDev1999;80:181-184.GamerLW,WolfmanNM,CelesteAJ,HattersleyG,6.HewickR,andRosenV.AnovelBMPexpressedindevelopingmouselimb,spinalcord,andtailbudisapotentmesoderminducerinXenopusembryos.DevBiol 1999;208:222-232.ValcourtU,RonziereM-C,WinklerP,RosenV,Herbage7.D,andMallein-GerinF.1999.Differenteffectsofbonemorphogeneticproteins2,4,12,and13ontheexpressionofcartilageandbonemarkersintheMC615chondrocytecellline.ExpCellRes251:264-274.LadherRHK,ChurchVL,AllenS,RobsonL,Abdelfattah8.A,BrownNA,HattersleyG,RosenV,LuytenFP,DaleL,andFrancis-WestPH.CloningandexpressionoftheWntantagonistsSfrp-2andFrzbduringchickdevelopment.DevBiol 2000;218:183-198.WestonAD,RosenV,andUnderhillTM.Regulationof9.skeletalprogenitordifferentiationbytheBMPandretinoidsignalingpathways.JCellBiol 2000;148:679-690.YiSE,DaluiskiA,PedersonR,RosenV,LyonsKM.The10.typeIBMPRIBisrequiredforchondrogenesisinthemouselimb.Development2000;127(3):621-30.DailuskiA,EngstrandT,BahamondeM,TompkinsonK,11.GamerLW,RosenV,andLyonsKM.BMP3isanegativeregulatorofbonedensity.NatureGenet2001;27:84-88.GamerLW,CoxKA,SmallC,andRosenV.Gdf11isa12.negativeregulatorofchondrogenesisandmyogenesisinthedevelopingchicklimb.DevBiol 2001;229:407-420.BanerjeeC,JavedA,ChoiJ-Y,GreenJ,RosenV,van13.
19
Vicki Rosen
WijnenAJ,SteinJL,LianJB,andSteinGS.DifferentialregulationofthetwoprincipalRunX/Cbfa1N-terminalisoformsinresponsetoBMP-2duringdevelopmentoftheosteoblastphenotype.Endocrinol 2001;142:4026-4039.SchweitzerR,ChyungJH,MurtaughLC,BrentAE,14.RosenV,OlsenEN,LassarA,andTabinCJ.AnalysisofthetendoncellfateusingScleraxis,aspecificmarkerfortendonsandligaments.Develop2001;128:3855-3886.ThomopoulosS,HattersleyG,RosenV,MertensM,Galatz15.L,WilliamsGR,andSoslowskyLJ.Thelocalizedexpressionofextracellularmatrixcomponentsinhealingtendoninsertionsites:aninsituhybridizationstudy.JOrthopRes2002;20:454-463.Gamer,LW,Nove,J,andRosen,V.ReturnoftheChalones.16.DevCell 2003;4(3):143-144.Gamer,LW,Nove,J,Levin,M,andRosen,V.BMP-3isa17.novelinhibitorofBMP-4andactivininXenopus.DevBiol 2005;285:156-168.ChenH,YongW,RenS,ShenW,HeY,CoxKA,ZhuW,18.LiW,SoonpaaM,PayneRM,FrancoD,FieldLJ,RosenV,WangY,andShouW.OverexpressionofBMP10inmyocardiumdisruptscardiacpostnatalhypertrophicgrowth.JBiolChem2006;281:27481-27491.BandyopadhyayA,TsujiK,HarfeBD,RosenV,andTabin19.CJ.GeneticanalysisoftherolesofBMP2,BMP4andBMP7inlimbpatterningandskeletogenesis.PLOSGenetics 2006;2:e216TsujiK,BandyopadhyayA,HarfeBD,CoxKA,Kakar20.S,GerstenfeldL,EinhornT,TabinCJ,andRosen,V.BMP2activity,althoughdispensableforboneformation,isrequiredfortheinitiationoffracturehealing.NatGenet .2006;38:1424-1429.TsujiK,BandyopadhyayA,HarfeBD,CoxKA,TabinCJ,21.andRosenV.BMP4isdispensableforskeletogenesisandfracturehealinginthelimb.JBoneJointSurg .2008;90(Suppl1):14-18.GamerLW,HoV,CocK,andRosenV.Expressionand22.functionofBMP3duringchicklimbdevelopment.DevDyn2008;237:1691-1698.GamerLW,CoxK,CarloJM,andRosenV.23.OverexpressionofBMP3inthedevelopingskeletonaltersendochondralboneformationresultinginspontaneousribfractures.DevDyn .2009;238:2374-2381.AlamN,St-ArnaudR,LauzierD,RosenV,andHamdyRC.24.AreendogenousBMPsnecessaryforbonehealingduringdistractionosteogenesis?ClinOrthopRelatRes .2009;467:3190-3198.TsujiK,CoxK,GamerL,GrafD,EconomidesA,and25.RosenV.ConditionaldeletionofBMP7fromthelimbskeletondoesnotaffectboneformationorfracturerepair.JOrthopRes .2010;28:384-389.StankovicKM,AdachiO,TsujiK,KristiansenAG,Adams26.JC,RosenV,andMcKennaMJ.Differencesingeneexpressionbetweentheoticcapsuleandotherbones.Hear
Res ,2010;265:83-9.PMID:20146935LoweryJW,PazinD,IntiniG,KobabuS,ChappiusV,27.CapeloLandRosenV.TheroleofBMP2signalingintheskeleton.CritrevEukaryotGeneExpr2011;21:177-185.PMID:22077155LoweryJWandRosenV.Allele-specificRNAinterference28.inFOPsilencingtheFOPgene.GeneTher2012;19:701-2.PMID:22130446GamerLW,TsujiK,CoxK,CapeloLP,LoweryJ,BeppuH,29.RosenV.“BMPR-IIisdispensableforformationofthelimbskeleton”Genesis .2011Sep:49(9):719-24.PMID:2153880KokabuS,GamerL,CoxK,LoweryJW,TsujiK,30.EconomidesA,KatagiriT,RosenV.“BMP3suppressesosteoblastdifferentiationofbonemarrowstromalcellsviainteractionwithAcvr2b.”JMolEndocrinol .2012Jan;26(1):87-94.PMID:22074949ChappuisV,GamerL,CoxK,LoweryJW,BosshardtDD31.andRosenV.PeriostealBMP2activitydrivesbonegrafthealing.Bone2012;51:800-809.PMID:22846673Pazin,DE,GamerLW,CoxKA,RosenV.“Molecular32.profilingofsynovialjoints:useamicroarrayanalysistoidentifyfactorsthatdirectthedevelopmentofthekneeandelbow.”DevDyn2012;241(11):1816-26.PMID:22972626LoweryJW,LavigneAW,KokabuS,andRosenV.33.ComparativegenomicsidentifiesthemouseBmp3promoterandanupstreamevolutionaryconservedregion(ECR)inmammals.PLoSOne2013;8:e57840PMID:23451274WhitmanM,RosenV,BrivanlouAH,GroppeJC,Sebald34.WandMuellerT.Regardingthemechanismofactionofaproposedpeptideagonistofthebonemorphogeneticproteinreceptoractivin-likekinase3.NatureMed2013;19:809-10.PMID:23836213KokabuS,NguyenT,OhteS,SatoT,KatagiriT,Yoda35.TandRosenV.TLE3,transducing-likeenhancerofsplit3,suppressesosteoblastdifferentiationofbonemarrowstromalcells.BiochemBiophysResCommun2013;438:205-10.SchminkeB,MuhammadH,BodeC,SadowskiB,Gerter36.R,GersdorffN,BurgersR,Monsonego-OrnanE,RosenV,andMiosgeN.Adiscoidindomainreceptor1knock-outmouseasanovelmodelforosteoarthritisofthetemporomandibularjoint.CellMolLifeSci 2013;Aug4PMID:23912900PazinDE,GamerLW,CapeloLP,CoxKAandRosenV.37.Genesignatureoftheembryonicmeniscus.JOrthopRes2013;Sept21PMID:24108661WuX,ChimSM,KuekV,LimBS,ChowST,ZhaoJ,Yang38.S,RosenV,TicknerJandXuJ.HtrA1isupregulatedduringRANKL-inducedosteoclastogenesis,andnegativelyregulatesosteoblastdifferentiationandBMP2-inducedSmad1/5/8,ERKandp38phosphorylation.FEBSLetters ,inpress.
21
miRNAisamemberof〜 22ntnon-cordingRNAandplayacriticalroleinthetissueororgandevelopmentandisalsoassociatedwithhumandiseases.WerecentlyfoundthatmiR-146ishighlyexpressedinrheumatoidarthritissynoviumtoregulateinflammationandthatmiR-140ishighincartilageandimportantfortissuehomeostasisagainstcartilagedegradation.Furthermore,nowwearepreparingseriesofgenomewideanalysistoexaminethemolecularmechanismsofinflammatorygeneexpressionbynon-codingRNAatthelevelofmRNAstabilityortranslation.Here,weintroduceourrecentresultsbynextgenerationsequencingtechniques,whichrevealedseriesofmiRNAsinvolvedinarthritispathogenesis.TogeneratemiRNAknockoutmiceinhigh-throughputway,weappliedTALENsystemtodeletemiRNAgeneinmicegenome,whichsuccessfullyleadsustoanalyzemiRNAfunctionsinvivo.Wealsoshowourstrategy;cellbasedcomprehensivegenescreeningtoscreennewmoleculesthatregulatesinflammatorygeneexpression.CombinationofabovemethodsmayprovidethenovelaspectofRNAregulatorysystemandshouldpromoteourunderstandingofinflammatorydiseasespathogenesis.
Combinatorial approach to identify generegulation of inflammatory signalsat RNA level
Hiroshi Asahara, M.D., Ph.D.
ProfessorDepartmentofSystemsBioMedicine,GraduateSchoolofMedicalandDentalSciences,TokyoMedicalandDentalUniversity
22
Hiroshi Asahara
CURRICULUM VITAE
Education and Position
1992 GraduatefromOkayamaUniversity,Japan1992 Resident,DepartmentofOrthopaedicSurgery, OkayamaSaiseikaiGeneralHospital,Japan1994 GraduateFellow,DepartmentofNeuroscience, InstituteofMolecularandCellularmedicine, OkayamaUniversityMedicalSchool,Japan1995 GraduateFellow,DivisionofRheumatologyand Immunology,InstituteofMedicalScience, St.UniversitySchoolofMedicine,Japan1997 AssistantProfessor,DepartmentofOrthopaedic Surgery,OkayamaUniversityMedicalSchool, Japan1997 PostdoctoralResearchFellow,DepartmentofCell Biology,HarvardMedicalSchool,MA,USA2000 StaffScientist,PeptideBiologyLaboratory,The SalkInstituteforBiologicalStudies,CA,USA2001 Scientist(PrincipalInvestigator),JST,Precursory ResearchforEmbryonicScienceandTechnology, Japan2002 AssistantProfessor,DepartmentofMolecular andExperimentalMedicine,TheScrippsResearch Institute,CA,USA2004 Head,DepartmentofRegenerativeBiologyand Medicine,NationalResearchInstituteforChild HealthandDevelopment,Japan2010 DepartmentHead,DepartmentofSystems BioMedicine,NationalResearchInstituteforChild HealthandDevelopment,Japan2011-pres. VisitingHead,DepartmentofSystemsBioMedicine, NationalResearchInstituteforChildHealthand Development,Japan2011-pres. Professor,DepartmentofSystemsBioMedicine, GraduateSchoolandFacultyofMedicine,Tokyo MedicalandDentalUniversity,Japan
Publications
NakasaT,MiyakiS,OkuboA,HashimotoM,Nishida1.K,OchiM,AsaharaH.ExpressionofmicroRNA-146inrheumatoidarthritissynovialtissue.ArthritisRheum.58(5):1284-1292.(2008)NagataY,NakasaT,MochizukiY,IshikawaM,MiyakiS,2.ShibuyaH,YamasakiK,AdachiN,AsaharaH,OchiM.Inductionofapoptosisinthesynoviumofarthriticmicebyintra-articularinjectionofdouble-strandedmicroRNA-15a.ArthritisRheum.60(9):2677-2683.(2009)MiyakiS,NakasaT,OtsukiS,GroganSP,Higashiyama3.R,InoueA,KatoY,SatoT,LotzMK,AsaharaH.MicroRNA-140isexpressedindifferentiatedhumanarticularchondrocytesandmodulatesIL-1responses.ArthritisRheum.60(9):2723-2730.(2009)ItoT,YadavN,LeeJ,FurumatsuT,YamashitaS,Yoshida4.K,TaniguchiN,HashimotoM,TsuchiyaM,OzakiT,LotzM,BedfordMT,AsaharaH.ArgininemethyltransferaseCARM1/PRMT4regulatesendochondralossification.BMCDevBiol .9:47.(2009)AbeY,OkaA,MizuguchiM,IgarashiT,IshikawaS,5.AburataniH,YokoyamaS,AsaharaH,NagaoK,YamadaM,MiyashitaT.EYA4,deletedinacasewithmiddleinterhemisphericvariantofholoprosencephaly,interactswithSIX3bothphysicallyandfunctionally.HumMutat .30(10):E946-955.(2009)KatoY,MiyakiS,YokoyamaS,OmoriS,InoueA,Horiuchi6.M,AsaharaH.Real-timefunctionalimagingformonitoringmiR-133duringmyogenicdifferentiation.IntJBiochemCellBiol .41(11):2225-2231.(2009)KumagishiK,NishidaK,YamaaiT,MomotaR,MiyakiS,7.HirohataS,NaitoI,AsaharaH,NinomiyaY,OhtsukaA.Adisintegrinandmetalloproteinasewiththrombospondinmotifs9(ADAMTS9)expressionbychondrocytesduringendochondralossification.ArchHistolCytol .72(3):175-185.(2009)YokoyamaS,ItoY,Ueno-KudohH,ShimizuH,Uchibe8.K,AlbiniS,MitsuokaK,MiyakiS,KisoM,NagaiA,HikataT,OsadaT,FukudaN,YamashitaS,HaradaD,MezzanoV,KasaiM,PuriPL,HayashizakiY,OkadoH,HashimotoM,AsaharaH.AsystemsapproachrevealsthatthemyogenesisgenomenetworkisregulatedbythetranscriptionalrepressorRP58.DevCell .17(6):836-848.(2009)ItoY,ToriuchiN,YoshitakaT,Ueno-KudohH,SatoT,9.YokoyamaS,NishidaK,AkimotoT,TakahashiM,MiyakiS,AsaharaH.TheMohawkhomeoboxgeneisacriticalregulatoroftendondifferentiation.ProcNatlAcadSciUSA.107(23):10538-10542.(2010)OtsukiS,GroganSP,MiyakiS,KinoshitaM,AsaharaH,10.LotzMK.TissueneogenesisandSTRO-1expressioninimmatureandmaturearticularcartilage.JOrthopRes .28(1):96-102.(2010)HigashiyamaR,MiyakiS,YamashitaS,YoshitakaT,11.
23
Hiroshi Asahara
LindmanG,ItoY,SashoT,TakahashiK,LotzM,AsaharaH.CorrelationbetweenMMP-13andHDAC7expressioninhumankneeosteoarthritis.ModRheumatol .20(1):11-17.(2010)MizutaniR,NakamuraK,YokoyamaS,SanbeA,Kusakawa12.S,MiyamotoY,ToriiT,AsaharaH,OkadoH,YamauchiJ,TanoueA.Developmentalexpressionofsortingnexin3inthemousecentralnervoussystem.GeneExprPatterns .11(1-2):33-40.(2010)MiyakiS,SatoT,InoueA,OtsukiS,ItoY,YokoyamaS,13.KatoY,TakemotoF,NakasaT,YamashitaS,TakadaS,LotzMK,Ueno-KudoH,AsaharaH.MicroRNA-140playsdualrolesbothincartilagedevelopmentandhomeostasis.GenesDev .24(11):1173-1185.(2010)OtsukiS,HansonSR,MiyakiS,GroganSP,KinoshitaM,14.AsaharaH,WongCH,LotzMK.ExtracellularsulfatasessupportcartilagehomeostasisbyregulationBMPandFGFsignalingpathways.ProcNatlAcadSciUSA.107(22):10202-10207.(2010)AsadaM,RauchA,ShimizuH,MaruyamaH,MiyakiS,15.ShibamoriM,KawasomeH,IshiyamaH,TuckermannJ,AsaharaH.DNAbinding-dependentglucocorticoidreceptoractivitypromotesadipogenesisviaKrüppel-likefactor15geneexpression.LabInvest .91(2):203-15.(2011)AwazawaM,UekiK,InabeK,YamauchiT,KubotaN,16.KanekoK,KobayashiM,IwaneA,SasakoT,OkazakiY,OhsugiM,TakamotoI,YamashitaS,AsaharaH,AkiraS,KasugaM,KadowakiT.AdiponectinEnhancesInsulinSensitivitybyIncreasingHepaticIRS-2ExpressionviaaMacrophage-DerivedIL-6-DependentPathway.CellMetab .13(4):401-12.(2011)WadaS,KatoY,OkutsuM,MiyakiS,SuzukiK,Yan17.Z,SchiaffinoS,AsaharaH,UshidaT,AkimotoT.TranslationalsuppressionofatrophicregulatorsbymicroRNA-23aintegratesresistancetoskeletalmuscleatrophy.JBiolChem.286(44):38456-65.(2011)MiyakiS,AsaharaH.MacroviewofmicroRNAfunction18.inosteoarthritis.NatureRevRheumatol .8(9):543-52.(2012)(Review)FukamiM,TsuchiyaT,TakadaS,KanbaraA,AsaharaH,19.IgarashiA,KamiyamaY,NishimuraG,OgataT.ComplexgenomicrearrangementintheSOX95'regioninapatientwithPierreRobinsequenceandhypoplasticleftscapula.AmJMedGenetA.158A(7):1529-34.(2012)YamashitaS,MiyakiS,KatoY,YokoyamaS,SatoT,20.BarrionuevoF,AkiyamaH,SchererG,TakadaS,AsaharaH.L-Sox5andSox6proteinsenhancechondrogenicmiR-140microRNAexpressionbystrengtheningdimericSox9activity.JBiolChem287(26),22206-22215(2012)UchibeK,ShimizuH,YokoyamaS,KubokiT,Asahara21.H.Identificationofnoveltranscription-regulatinggenesexpressedduringmurinemolardevelopment.DevDyn .241(7):1217-26.(2012)FurumatsuT,AsaharaH.Chromatinassemblyandinvitro22.
transcriptionanalysesforevaluationofindividualproteinactivitiesinmulticomponenttranscriptionalcomplexes.MethodsMolBiol .977:193-202.(2013)(Review)GibsonG,AsaharaH.microRNAsandcartilage.23. JOrthopRes .Sep;31(9):1333-44.(2013)(Review)WatanabeT,OyamaT,AsadaM,HaradaD,ItoY,24.InagawaM,SuzukiY,SuganoS,KatsubeK,KarsentyG,KomoriT,KitagawaM,AsaharaH.MAML1enhancesthetranscriptionalactivityofRunx2andplaysaroleinbonedevelopment.PLOSGenetics .9(1):e1003132.(2013)MatsukawaT,SakaiT,YonezawaT,HiraiwaH,Hamada25.T,NakashimaM,OnoY,IshizukaS,NakaharaH,LotzMK,AsaharaH,IshiguroN.MicroRNA-125bregulatestheexpressionofaggrecanase-1(ADAMTS-4)inhumanosteoarthriticchondrocytes.ArthritisResTher .15(1):R28.(2013)HasegawaA,NakaharaH,KinoshitaM,AsaharaH,Koziol26.J,LotzMK.Cellularandextracellularmatrixchangesinanteriorcruciateligamentsduringhumankneeagingandosteoarthritis.ArthritisResTher .15(1):R29(2013)RakoczyJ,Fernandez-ValverdeSL,GlazovEA,Wainwright27.EN,SatoT,TakadaS,CombesAN,KorbieDJ,MillerD,GrimmondSM,LittleMH,AsaharaH,MattickJS,TaftRJ,WilhelmD.MicroRNAs-140-5p/140-3pmodulateLeydigcellnumbersinthedevelopingmousetestis.BiolReprod .88(6):143.(2013)NakaharaH,HasegawaA,OtabeK,AyabeF,Matsukawa28.T,OnizukaN,ItoY,OzakiT,LotzMK,AsaharaH.Transcriptionfactormohawkandthepathogenesisofhumananteriorcruciateligamentdegradation.ArthritisRheum.65(8):2081-9.(2013)YoshitakaT,KawaiA,MiyakiS,NumotoK,KikutaK,29.OzakiT,LotzM,AsaharaH.AnalysisofmicroRNAsexpressionsinchondrosarcoma.JOrthopRes .inpressShimizuH,KuboA,UchibeK,HashimotoM,YokoyamaS,30.TakadaS,MitsuokaK,AsaharaH,TheAEROSystem:a3D-likeApproachforRecordingGeneExpressionPatternsintheWholeMouseEmbryo,PLOSOne .inpressTakadaS,SatoT,ItoY,YamashitaS,KatoT,Kawasumi31.M,Kanai-AzumaM,IgarashiA,KatoT,TamanoM,AsaharaH.TargetedgenedeletionofmiRNAsinmicebyTALENsystem,PLOSOne .inpressOnizukaN,ItoY,InagawaM,NakaharaH,TakadaS,32.LotzMK,ToyamaY,AsaharaH.TheMohawkhomeoboxtranscriptionfactorregulatesthedifferentiationoftendonsandvolarplates.JOrthopScience .inpressKatoT,MiyataK,SonobeM,YamashitaS,TamanoM,33.MiuraK,KanaiY,MiyamotoS,SakumaT,YamamotoT,InuiM,KikusuiT,AsaharaH*,andTakadaS*.ProductionofSryknockoutmouseusingTALENviaoocyteinjection.ScientificRep .inpress(*equallycontributedcorrespondingauthors)
25
Infantilehemangiomasarethemostcommontumorsofinfancy.Typically,theyappearwithinafewdays/weeksafterbirthandgrowrapidlyduringafewmonths(proliferativephase).Afteraboutayeartheystarttoinvolute(involutionphase)andafteraperiodofseveralmonths/years,theyarereplacedbyfibro-fattytissue.Hemangiomasaremorecommoninfemalesthaninmalesandtheyoccurmostfrequentlyintheheadandneckregionofaffectedinfants.Ourstudieshavedemonstratedthattherapidproliferationofinfantilehemangiomasiscausedbydefectsintheregulationofvascularendothelialgrowthfactorreceptor1(VEGFR1)inendothelialcellsofthetumor.WhennormalendothelialcellsarestimulatedbyVEGForactivatedbybindingtoextracellularmatrix,expressionoftheVEGFdecoyreceptorVEGFR1isstimulatedandVEGFR2-dependentsignalingconstrained.Incontrast,hemangiomaendothelialcellsintheirproliferativephaseexhibitconstitutivelowlevelsofVEGFR1expressionandhighlevelsofVEGF-dependentVEGFR2signaltransduction.Thisisaconsequenceofdefectsthatresultinlocallossoffunctionofacellsurfaceintegrin-likereceptorknownasAnthraxtoxinreceptor1(ANTXR1)/Tumorendothelialmarker8(TEM8)inhemangiomaendothelialcells.MicethatarehomozygousforTem8nullalleleshavechangesindermalbloodvesselsthataresimilartothoseseeninhemangiomatumors.Inaddition,themiceexhibitgrowthretardation,bonelossandcraniofacialdefectssimilartothoseseeninpatientswiththerecessiveGAPOsyndrome.Patientswiththissyndromearehomozygousforloss-of-functionmutationsinTEM8andexhibitgrowthretardation,alopecia,pseudo-anodontiaandopticatrophy,aswellasothercraniofacialdefects,bonelossandhemangioma.TEM8isthereforeacriticalregulatorofvascularendothelialandosteoblasticfunctionsinadditiontocontrollingtheactivitiesofgrowthplatesandsynchondrosesattheskullbase.
References:1. Jinnin,M.,etal.,SuppressedNFAT-dependentVEGFR1expressionandconstitutiveVEGFR2signalingininfantile
hemangioma .Nat.Med.,2008.14(11):p.1236-1246.
Craniofacial dysmorphogenesis andinfantile hemangioma – the antrax toxin receptor connection
Bjorn R. Olsen, M.D., Ph.D.
ProfessorDepartmentofOralandDevelopmentalBiology,HarvardSchoolofDentalMedicine
26
Bjorn R. Olsen
CURRICULUM VITAE
Education
1967 Ph.D.UniversityofOslo,Norway1967 M.D.UniversityofOsloMedicalSchool,Norway
Position
1990-1993 Chairman,PrograminCellandDevelopmental Biology,HarvardMedicalSchool,Boston,MA1993- HerseyProfessorofCellBiology,Departmentof CellBiology,HarvardMedicalSchool,Boston,MA1996-2002 ProfessorofOralBiology,HarvardSchoolof DentalMedicine,Boston,MA1996-2002 Chairman,Harvard-ForsythDepartmentofOral Biology,HarvardSchoolofDentalMedicine, Boston,MA2002- ProfessorofOralandDevelopmentalBiology, HarvardSchoolofDentalMedicine,Boston,MA2002-2005 Chairman,DepartmentofOralandDevelopmental Biology,HarvardSchoolofDentalMedicine, Boston,MA2005- DeanforResearch,HarvardSchoolofDental Medicine,Boston,MA
Award and Honors
2000 HonoraryDoctorofScienceDegree,Universityof MedicineandDentistryofNewJersey2000 HonoraryDoctorofScienceDegree,UniversityofOslo, Norway2001 DistinguishedFacultyAward,HarvardSchoolofDental Medicine2006 H.C.JacobæusPrizeandlecturer,H.C.Jacobæus’ ForelæsningerFoundation,Sweden2006 Member,ScanBaltAcademy2006 SeniorResearchPrize,AmericanSocietyofMatrix Biology2007 Co-chairman,GordonResearchConference“Cartilage Biology&Pathology”2009 Chairman,GordonResearchConference“Cartilage Biology&Pathology”2009 Co-chairman,GordonResearchConference“Bonesand Teeth”2010 IADRDistinguishedScientistAwardforCraniofacial BiologyResearch2010 ISMBDistinguishedInvestigatorAward2010 AmericanAssociationfortheAdvancementofScience Fellow2011 HenryGrayAward,AmericanAssociationof Anatomists2011 Chairman,GordonResearchConference“Bonesand Teeth”2011 Fellow,AmericanAssociationofAnatomists2011 HonoraryDoctorDegree,OkayamaUniversity,Japan
Publications
Sun,X-D,Jeng,L,Bolliet,C,Olsen,BR,Spector,M.Non-1.viralendostatinplasmidtransfectionofmesenchymalstemcellsviacollagenscaffolds.Biomaterials ,200930:1222-1231.Hou,B,Kolpakova-Hart,E,Fukai,N,Wu,K,Olsen,BR.2.Thepolycystickidneydisease1(Pkd1)geneisrequiredfortheresponsesofosteochondroprogenitorcellstomidpalatalsutureexpansioninmice.Bone ,2009,44:1121-1133.PMC2680722Faye,C,Chautard,E,Olsen,BR,Ricard-Blum,S.Thefirst3.draftoftheendostatininteractionnetwork.J.Biol.Chem.2009,284:22041-22047.PMC2755928Galli,C,Fu,Q,Wang,WF,Olsen,BR,Manolagas,SC,Jilka,R,4.andO’Brien,CA.CommitmenttotheosteoblastlineageisnotrequiredforRANKLgeneexpression.JBiolChem2009,284:12654-12662.PMC2675994Olsen,BR.Geneticsofhumanskeletaldisease.In:5. TheSkeletalSystem,ed.OlivierPourquié.ColdSpringHarborLaboratoryPress.2009,pp.317-340.Boye,E,Jinnin,M,Olsen,BR.Infantilehemangioma–6.challenges,newinsightsandtherapeuticpromise.JCraniofSurg ,2009,20:1-7.PMID:19190505.Boye,E,Olsen,BR.Signalingmechanismsininfantile7.hemangioma.CurrOpinHematol .2009,16:202–208.PMC2895461Xu,L,PolurI,LimC,ServaisJM,DobeckJ,LiY,Olsen8.BR.Early-onsetosteoarthritisofmousetemporomandibularjointinducedbypartialdiscectomy.OsteoarthrCartilage2009,17:917-922.PMC2941347Gebauer,JM,Keene,DR,Olsen,BR,Sorokin,LM,Paulsson,9.M,Wagener,R.MouseAMACO,akidneyandskinbasementmembraneassociatedmoleculethatmediatesRGD-dependentcellattachment.MatrixBiol 2009,28:456-462.(NoBROgrant)OlsenBR.Whenprimaryciliafail.10. MatrixBiol 2009;28:443-4.Review.PMID:19939339.Mukherjee,PM,Wang,CJ,Chen,I-P,Jafarov,T,Olsen,11.BR,Yueki,Y,Reichenberger,EJ.CherubismgeneSh3bp2isimportantforoptimalboneformation,osteoblastdifferentiationandfunction.AmJOrthodDentofacialOrthop.2010,138:140.e1-140.e11.PMC3268358Besschetnova,TY,Kolpakova-Hart,E,Guan,Y,Zhou,J,12.Olsen,BR,Shah,JV.Identificationofsignalingpathwaysregulatingprimaryciliumlengthandflow-mediatedadaptation.Curr.Biol.,2010,20:182-187.PMC2990526.Harnagea,C,Vallie`res,M,Pfeffer,CP,Wu,D,Olsen,BR,13.Pignolet,A,Legare,F,Gruverman,A.Two-dimensionalnanoscalestructuralandfunctionalimaginginindividualcollagentype-Ifibrils.BiophysJ ,2010,98:3070-3077.PMC2884257Nicolae,C,Olsen,BR.Unexpectedmatrixdiseasesand14.noveltherapeuticstrategies.CellTissueRes.2010,339:155–165.ReviewJinnin,M,Ishihara,T,Boye,E,Olsen,BR.Recentprogress15.
27
Bjorn R. Olsen
instudiesofinfantilehemangioma.JDerm.2010,37:283-298.Review.Faye,C,Inforzato,A,Bignon,M,Hartmann,DJ,16.Muller,L,Ballut,LOlsen,BR,Day,AJ,Ricard-Blum,S.Transglutaminase-2:anewendostatinpartnerintheextracellularmatrixofendothelialcells.Biochem.J .2010,427:467-475.PMCID:PMC2876729.Jeng,L,Olsen,BR,Spector,M.Engineeringendostatin-17.producingcartilaginousconstructsforcartilagerepairusingnon-viraltransfectionofchondrocyte-andmesenchymalstemcell(msc)-seededcollagenscaffolds.TissEngPartA,2010,16:3011-3021.PMC3189205Clarkin,C,Olsen,BR.Onbone-formingcellsandblood18.vesselsinbonedevelopment.Preview.CellMetabol ,2010,12:314-316.Preview.PMC3031181Medici,D,Shore,EM,Lounev,VY,Kaplan,FS,Kalluri,R,19.Olsen,BR.Conversionofvascularendothelialcellsintomultipotentstem-likecells.NatMed2010,16:1400-1406.PMC3209716Mauney,J,Olsen,BR,VollochV.Matrixremodelingas20.stemcellrecruitmentevent:anovelinvitromodelforhomingofhumanbonemarrowstromalcellstothesiteofinjuryshowscrucialroleofextracellularcollagenmatrix.MatrixBiol .2010,29:657-663.Medici,D,Olsen,BR.Transformingbloodvesselsintobone.21.CellCycle2011,10:362-363.Freefulltexthttp://www.landesbioscience.com/journals/cc/article/14519/PfefferCP,OlsenBR,GanikhanovF,LegareF.Imaging22.skeletalmuscleusingharmonicgenerationandcoherentanti-StokesRamanscatteringmicroscopy.BiomedOptExpress2011;27:1366-76.PMC3087593BerendsenA,OlsenBR.Tankyraselosesitsgripon23.SH3BP2incherubism.Cell 2011;147:1222-3.PMID:22153068.Jeng,L,Olsen,BR,Spector,M.Engineeringendostatin-24.expressingcartilaginousconstructsusinginjectablebiopolymerhydrogels.ActaBiomat ,2012,8:2203-2212.PMID:22370447(noNIHgrant).Ionescu,I,Kozhemyakina,E,Nicolae,C,Kaestner,KH,25.Olsen,BR,Lassar,AB.FoxAfamilymembersarecrucialregulatorsofthehypertrophicchondrocytedifferentiationprogram.DevCell 2012;22:927-39.PMC3356573Papadaki,ME,Lietman,SA,Levine,MA,Olsen,BR,Kaban26.LB,Reichenberger,EJ.Cherubism:BestclinicalPractice..OrphanetJRareDis .2012,7Suppl1:S6.PMC3359956Reichenberger,EJ,Levine,MA,Olsen,BR,Papadaki,ME,27.Lietman,SA.TheroleofSH3BP2inthepathophysiologyofcherubism.OrphanetJRareDis .2012,7Suppl1:S5.PMC3359958Jumlongras,D,Lachke,SA,O'Connell,DJ,Aboukhalil,28.A,Li,X,Choe,SE,Ho,JW,Turbe-Doan,A,Robertson,EA,Olsen,BR,Bulyk,ML,Amendt,BA,andMaas,RL.AnEvolutionarilyConservedEnhancerRegulatesBmp4ExpressioninDevelopingIncisorandLimbBud.PLoS
ONE2012;7:e38568.PMC3373496Medici,D,Olsen,BR.Theroleofendothelial-mesenchymal29.transitioninheterotopicossification.JBMR2012;27:1619-22.PMID:22806925.Review.KatebiN,Kolpakova-HartE,LinCY,OlsenBR.Themouse30.palateanditscellularresponsestomidpalatalsutureexpansionforces.OrthoCraniofacRes2012;15:148-158.NIHMS512089Medici,D.andOlsen,B.R.(2012).Transformationof31.VascularEndothelialCellsintoMultipotentStem-LikeCells:RoleoftheActivin-LikeKinase-2Receptor.StemCellsandCancerStemCells:TherapeuticApplicationsinDiseaseandInjury.Springer.Volume8,Chapter19Medici,D,Olsen,BR.Rapamycininhibitsproliferationof32.hemangiomaendothelialcellsbyreducingHIF-1-dependentexpressionofVEGF.PLoSONE,2012;7(8):e42913.PMC3416768Liu,Y,Berendsen,A,Jia,S,Lotinun,S,Baron,R,Ferrara,33.N,Olsen,BR.IntracellularVEGFregulatesthebalancebetweenosteoblastandadipocytedifferentiation.JCI ,2012;122:3101-3112.PMC3428080Adams,A,McBratney-Owen,B,Newby,B,Bowen,M,34.Olsen,BR,Warman,ML.PresphenoidalsynchondrosisfusioninDBA/2Jmice.MammalGenome,2013,24:54-62.PMC3560942Olsen,BR.Matrixmoleculesandtheirligands.In:35.PrinciplesofTissueEngineering.R.G.(Lanza,R,Langer,R,andVacanti,J.ed).4nded.,inpress,AcademicPress,pp.Duncan,MD,Yang,C,Tanjore,H,Boyle,PM,Keskin,D,36.Sugimoto,H,Zeisberg,M,Olsen,BR,Kalluri,R.TypeXVIIIcollagenisessentialforsurvivalduringacuteliverinjury.DisModelMech ,2013Apr4.Epubaheadofprint.Freefulltext.Toh,WS,Foldager,CB,Olsen,BR,Spector,M.Basement37.membranemoleculeexpressionattendanttochondrogenesisbynucleuspulposuscellsandmesenchymalstemcells.JOrthopRes ,2013,Epubaheadofprint.(noNIHgrant)Volloch,V,Olsen,BR.Whycellularstresssuppresses38.adipogenesisinskeletaltissue,butisineffectiveinadiposetissue:Controlofmesenchymalcelldifferentiationviaintegrinbindingsitesinextracellularmatrices.MatBiol,2013Jun18.doi:pii:S0945-053X(13)00091-7.10.1016/j.matbio.2013.06.001.[Epubaheadofprint].NIHMSID#504634Berendsen,AD,Olsen,BR.Osteoblast-adipocytelineage39.plasticityintissuedevelopment,maintenanceandpathology.Review.CellMolLifeSci.inpress.NIHMS514666Olsen,BR,Ehrlich,YH,Yalak.Extracellularprotein40.phosphorylationrevisited.Submittedforpublication.Opinion.Liu,Y,Olsen,BR.DistinctVEGFfunctionsduringbone41.developmentandhomeostasis.Submittedforpublication.Berendsen,AD,Olsen,BR.HowVascularEndothelial42.GrowthFactorA(VEGF)RegulatesDifferentiationofMesenchymalStemCells.JHC,Submittedforpublication.Review.NIHBonegrantsupport.
29
Accordingtoourpreviousstudies,thenumberofmesenchymalstemcells(MSCs)insynovialfluidincreaseinkneeswithanteriorcruciateligamentinjury(Rheumatology2008),meniscusinjury(ClinOrthopRelatRes2014),andosteoarthritis(JOrthopRes2011).ThemorphologyandgeneprofilesinsynovialfluidMSCsweremoresimilartothoseinsynovialMSCsthaninbonemarrowMSCs.Principalcomponentanalysisofgeneprofilesforvariousmesenchymaltissues-derivedMSCsandchondrocytesdemonstratedthatMSCsfromintraarticulartissuesandchondrocyteswereclosertoeachotherthanMSCsfromextraarticulartissues(JOrthopRes2008).SynoviummaybeareservoirforMSCstocontributetotheintraarticulartissuerepair.Afterintraarticulartissues,suchascartilage,meniscus,andligament,areinjured,MSCsmaybemobilizedfromsynoviumtosynovialfluid,adheretotheinjuredsite,andcontributetotherepair.However,thenumberofMSCsislimited,therefore,theinjuredtissuescannotbehealedinthenaturalcourse.TransplantationofenoughnumberofsynovialMSCstotheinjuredtissuesmaypromoteintraarticulartissuehealing.
MSCsareattractivecellsourceforcartilageandmeniscusregeneration.OurinvitroandinvivochondrogenicassaydemonstratedthatsynovialandbonemarrowMSCshadahigherchondrogenicabilitythanadiposeandmuscleMSCs(ArthritisRheum2005,CellTissueRes2007,CellTissueRes2008).HumansynovialMSCsexpandedmoreinhumanserumthanbonemarrowMSCs(ArthritisRheum2008).Inrat,rabbit,andpigstudies,transplantationofsynovialMSCspromotedcartilageandmeniscusregeneration(StemCells2007,StemCells2009,Cytotherapy2012,OsteoarthritisCartilage2012,JBoneJointSurgAm2012,BiochemBiophysResCommun2013).
Currentcelltherapyforcartilageandmeniscusregenerationrequiresinvasiveprocedures.WehavedevelopedanovelimplantationprocedurewithsynovialMSCs.CartilageormeniscusdefectisfilledwithsynovialMSCsuspensionfor10minutes.Accordingtoourinvitroandinvivostudies,morethan60%cellsadheredtothedefect,andpromotedcartilageandmeniscusregeneration(ArthritisResTher2008,JOrthopRes2013).
Wearecurrentlydoingclinicaltrialforcartilageregeneration.AllpatientshavetheircartilagedefectsfilledwithsynovialMSCsarthroscopically.FavorableresultsareobtainedbyMRIimaginginmanycases,bysecondlookarthroscopies,andbybiopsies.Ourmethodhassuchadvantagesthatnoperiostealcoverageorscaffoldwererequiredandthattransplantationispossiblearthroscopically.Wearealsotryingtoregenerateosteoarthritisofthekneewithosteotomyormeniscuscentralization(ArthroscTech2012)byusingsynovialMSCs.WearegoingtostartanotherclinicaltrialformeniscustreatmentwithsynovialMSCs.
Cartilage and meniscus regeneration withsynovial stem cells
Ichiro Sekiya, M.D., Ph.D.
ProfessorCenterforStemCellandRegenerativeMedicine,TokyoMedicalandDentalUniversity
30
Ichiro Sekiya
CURRICULUM VITAE
Education
1984-1990 MD,SchoolofMedicine,TokyoMedicalandDental University1996-2000 PhD,SchoolofMedicine,TokyoMedicaland DentalUniversity
Position
1990-1996 OrthopedicSurgeryat10hospitalsinJapan2000-2000 CenterforGeneTherapy,MCPHahnemann University,Philadelphia,USA2000-2002 CenterforGeneTherapy,TulaneUniversity,New Orleans,USA2002-2008 TokyoMedicalandDentalUniversity2008-2011 AssociateProfessor,CartilageRegeneration TokyoMedicalandDentalUniversity2011-2013 Professor,CartilageRegeneration TokyoMedicalandDentalUniversity2013- Director/Professor CenterforStemCellandRegenerativeMedicine TokyoMedicalandDentalUniversity2013- Professor AppliedRegenerativeMedicine TokyoMedicalandDentalUniversity
Publications
Transplantationofneuronalcellsinducedfromhuman1.mesenchymalstemcellsimprovesneurologicalfunctionsafterstrokewithoutcellfusion.XuH,MikiK,IshibashiS,InoueJ,SunL,EndoS,SekiyaI,MunetaT,InazawaJ,DezawaM,MizusawaH.JNeurosciRes.2010;88(16):3598-609.RepairofolecranonfracturesusingfiberWirewithout2.metallicimplants:reportoftwocases.NimuraA,NakagawaT,WakabayashiY,SekiyaI,OkawaA,MunetaT.JOrthopSurgRes.2010Oct12;5:73.EffectofCTslicethicknessonaccuracyofimplant3.positioninginnavigatedtotalhiparthroplasty.HirasawaN,MatsubaraM,IshiiK,HagioS,OkudaN,SekiyaI,MunetaT.ComputAidedSurg.2010Nov2.Intradiscaltransplantationofsynovialmesenchymalstem4.cellspreventsintervertebraldiscdegenerationthroughsuppressionofmatrixmetalloproteinase-relatedgenesinnucleuspulposuscellsinrabbits.MiyamotoT,MunetaT,TabuchiT,MatsumotoK,SaitoH,TsujiK,SekiyaI.ArthritisResTher.2010;12(6):R206.Hipacetabulardysplasiaandjointlaxityoffemaleanterior5.cruciateligament-injuredpatients.YamazakiJ,MunetaT,JuYJ,MoritoT,OkuwakiT,SekiyaI.AmJSportsMed.2011Feb;39(2):410-4.Radiographicdescriptionoffemoraltunnelplacement6.expressedasintercondylarclocktimeindouble-bundleanteriorcruciateligamentreconstruction.YamazakiJ,MunetaT,KogaH,SekiyaI,JuYJ,MoritoT,YagishitaK.KneeSurgSportsTraumatolArthrosc.2011Mar;19(3):418-23.Ketoprofenabsorptionbymuscleandtendonaftertopical7.ororaladministrationinpatientsundergoinganteriorcruciateligamentreconstruction.SekiyaI,MoritoT,HaraK,YamazakiJ,JuYJ,YagishitaK,MochizukiT,TsujiK,MunetaT.AAPSPharmSciTech.2010Mar;11(1):154-8.BMP-7inhibitscartilagedegenerationthroughsuppression8.ofinflammationinratzymosan-inducedarthritis.TakahashiT,MunetaT,TsujiK,SekiyaI.CellTissueRes.2011May;344(2):321-32.High-flexPosteriorCruciate-RetainingvsPosterior9.Cruciate-SubstitutingDesignsinSimultaneousBilateralTotalKneeArthroplastyAProspective,RandomizedStudy.YagishitaK,MunetaT,JuYJ,MoritoT,YamazakiJ,SekiyaI.JArthroplasty.2012Mar;27(3):368-74.Effectsofdifferentinitialbundletensioningstrategieson10.theoutcomeofdouble-bundleACLreconstruction:acohortstudy.MunetaT,KogaH,JuYJ,YagishitaK,SekiyaI.SportsMedArthroscRehabilTherTechnol.2011Jul28;3:15.Surgicalmanagementofgrade3medialkneeinjuries11.combinedwithcruciateligamentinjuries.KogaH,MunetaT,YagishitaK,JuYJ,SekiyaI.KneeSurgSportsTraumatolArthrosc.2012Jan;20(1):88-94.Humanmesenchymalstemcellsinsynovialfluidincrease12.inthekneewithdegeneratedcartilageandosteoarthritis.
31
Ichiro Sekiya
SekiyaI,OjimaM,SuzukiS,YamagaM,HorieM,KogaH,TsujiK,MiyaguchiK,OgishimaS,TanakaH,MunetaT.JOrthopRes.2012Jun;30(6):943-9.TheEffectofGraftFixationAnglesonAnteroposterior13.andRotationalKneeLaxityinDouble-BundleAnteriorCruciateLigamentReconstruction:EvaluationUsingComputerizedNavigation.KogaH,MunetaT,YagishitaK,JuYJ,SekiyaI.AmJSportsMed.2012Mar;40(3):615-23.Epub2011Nov22.Arthroscopic,histologicalandMRIanalysesofcartilage14.repairafteraminimallyinvasivemethodoftransplantationofallogeneicsynovialmesenchymalstromalcellsintocartilagedefectsinpigs.NakamuraT,SekiyaI,MunetaT,HatsushikaD,HorieM,TsujiK,KawarasakiT,WatanabeA,HishikawaS,FujimotoY,TanakaH,KobayashiE.Cytotherapy.2012Mar;14(3):327-38.Implantationofallogenicsynovialstemcellspromotes15.meniscalregenerationinarabbitmeniscaldefectmodel.HorieM,DriscollMD,SampsonHW,SekiyaI,CaroomCT,ProckopDJ,ThomasDB.JBoneJointSurgAm.2012Apr18;94(8):701-12.Hyaluronaninjectiontherapyforathleticpatientswith16.patellartendinopathy.MunetaT,KogaH,JuYJ,MochizukiT,SekiyaI.JOrthopSci.2012Apr17.Remnantvolumeofanteriorcruciateligamentcorrelates17.preoperativepatients'statusandpostoperativeoutcome.MunetaT,KogaH,JuYJ,HorieM,NakamuraT,SekiyaI.KneeSurgSportsTraumatolArthrosc.2012Apr28.Intra-articularinjectionofhumanmesenchymalstem18.cells(MSCs)promoteratmeniscalregenerationbybeingactivatedtoexpressIndianhedgehogthatenhancesexpressionoftypeIIcollagen.HorieM,ChoiH,LeeRH,RegerRL,YlostaloJ,MunetaT,SekiyaI,ProckopDJ.OsteoarthritisCartilage.2012Oct;20(10):1197-207.Isolationandcharacterizationofmultipotential19.mesenchymalcellsfromthemousesynoviumFutamiI,IshijimaM,KanekoH,TsujiK,Ichikawa-TomikawaN,SadatsukiR,MunetaT,Arikawa-HirasawaE,SekiyaI,KanekoK.PLoSOne.2012;7(9):e45517.Incidenceandriskfactorsformedialtibialstresssyndrome20.andtibialstressfractureinhighschoolrunners.YagiS,MunetaT,SekiyaI.KneeSurgSportsTraumatolArthrosc.2012Aug9.Osteopontinlevelinsynovialfluidisassociatedwiththe21.severityofjointpainandcartilagedegradationafteranteriorcruciateligamentruptureYamagaM,TsujiK,MiyatakeK,YamadaJ,AbulaK,JuYJ,SekiyaI,MunetaT.PLoSOne.2012;7(11):e49014Propertiesandusefulnessofaggregatesofsynovial22.mesenchymalstemcellsasasourceforcartilageregeneration.SuzukiS,MunetaT,TsujiK,IchinoseS,MakinoH,UmezawaA,SekiyaI.ArthritisResTher.2012Jun7;14(3):R136.Arthroscopiccentralizationofanextrudedlateral23.
meniscus.KogaH,MunetaT,YagishitaK,WatanabeT,MochizukiT,HorieM,NakamuraT,OkawaA,SekiyaI.ArthroscTech.2012Oct22;1(2):e209-12.IntraoperativeJointGapsAffectPostoperativeRangeof24.MotioninTKAsWithPosterior-stabilizedProstheses.WatanabeT,MunetaT,SekiyaI,BanksSA.ClinOrthopRelatRes.2013Apr;471(4):1326-33.HumanYKL39(chitinase3-likeprotein2),anosteoarthritis-25.associatedgene,enhancesproliferationandtypeIIcollagenexpressioninATDC5cells.MiyatakeK,TsujiK,YamagaM,YamadaJ,MatsukuraY,AbulaK,SekiyaI,MunetaT.BiochemBiophysResCommun.2013Feb1;431(1):52-7.Comparativesequentialmorphologicalanalysesduringin26.vitrochondrogenesisandosteogenesisofmesenchymalstemcellsembeddedincollagengels.IchinoseS,TagamiM,MunetaT,MukohyamaH,SekiyaI.MedMolMorphol.2013Mar;46(1):24-33.Thekinematicanalysisoffemalesubjectsafterdouble-27.bundleanteriorcruciateligamentreconstructionduringsingle-legsquatting.YamazakiJ,MunetaT,JuYJ,KogaH,MoritoT,SekiyaI.JOrthopSci.2013Mar;18(2):284-9.EffectofPosterolateralBundleGraftFixationAngles28.onGraftTensionCurvesandLoadSharinginDouble-BundleAnteriorCruciateLigamentReconstructionUsingaTranstibialDrillingTechnique.KogaH,MunetaT,YagishitaK,JuYJ,MochizukiT,HorieM,NakamuraT,OkawaA,SekiyaI.Arthroscopy.2013Mar;29(3):529-38.Isolationandcharacterizationofhumanmesenchymalstem29.cellsderivedfromshouldertissuesinvolvedinrotatorcufftears.UtsunomiyaH,UchidaS,SekiyaI,SakaiA,MorideraK,NakamuraT.AmJSportsMed.2013Mar;41(3):657-68.Synovialstemcellsinmusculoskeletalregeneration.Atesok30.K,DoralMN,BilgeO,SekiyaI.JAmAcadOrthopSurg.2013Apr;21(4):258-9.5.IntraarticularInjectionofSynovialStemCellsPromotes31.MeniscalRegenerationinaRabbitMassiveMeniscalDefectModel.HatsushikaD,MunetaT,HorieM,KogaH,TsujiK,SekiyaI.JOrthopRes.2013Sep;31(9):1354-9.Transplantationofaggregatesofsynovialmesenchymal32.stemcellsregeneratesmeniscusmoreeffectivelyinaratmassivemeniscaldefect.KatagiriH,MunetaT,TsujiK,HorieM,KogaH,OzekiN,KobayashiE,SekiyaI.BiochemBiophysResCommun.2013Jun14;435(4):603-9.Effectoffemoraltunnelpositionongrafttensioncurves33.andkneestabilityinanatomicdouble-bundleanteriorcruciateligamentreconstruction.KogaH,MunetaT,YagishitaK,WatanabeT,MochizukiT,HorieM,NakamuraT,SekiyaI.KneeSurgSportsTraumatolArthrosc.2013Sep24.TransplantationofAchillestendontreatedwithBMP-734.promotesmeniscusregenerationinaratmassivemeniscusdefectmodel.OzekiN,MunetaT,KogaH,KatagiriH,OtabeK,OkunoM,TsujiK,KobayashiE,MatsumotoK,SaitoH,SaitoT,SekiyaI.ArthritisRheum.2013Jul29.
33
Thepaceoffracturerepairslowswithaging,butthecriticalmediatorsinthisprocessarenowknown.Herewedeterminedtherelativecontributionofmesenchymalprogenitorcellage,hematopoieticcellage,andcirculatingfactorsoninvivoboneregenerationandinvitroosteoblastdifferentiation.Exposuretoyouthfulcirculationbyheterochronicparabiosisreversedtheslowedfracturerepaircharacteristicofaginginmice.Thisrejuvenationresultedinincreasedmineralizationandosteoblasticactivityofoldmesenchymalprogenitorcells.Todetermineifcirculatingcellsplayedaroleinthisrejuvenation,weexaminedtheabilityofoldandyoungbonemarrowcellsinwhichwecoulddeletecellswithosteogenicpotentialtoenhancetheosteogeniccapacityofoldbonemarrowcells.Conditionedmediafromanadherentpopulationofyoungcellsrejuvenatedtheosteogeneiccapacityofoldcells.Similarly,engraftmentofyounghematopoieticcellsintooldanimalsrescuedfracturerepairandosteogenicpotentialinamechanismthatdidnotrequireosteoblastsfromthedonoranimal.β-cateninsignaling,apathwayimportantinboneregenerationandosteoblastdifferentiation,wasshowntobemodulatedduringrejuvenation.Reductionofβ-cateninsignalingduringearlyfracturerepairimprovedboneregenerationinoldmice.Thesedatademonstratethatthecirculatorysystemcarrieswithinita“youthfactor"thatisabletorejuvenatebonerepairandosteoblastdifferentiationthroughmodulationofβ-catenin.Thisdataraisesthepossibilitythatagentsthatmodulateβ-catenincanimprovethequalityofbonerepairintheagingpopulation.
Fracture repair and beta-catenin in agingand disease : implications for an approachto therapy
Benjamin A. Alman, M.D.
ProfessorDepartmentofOrthopaedicSurgery,UniversityofToronto
34
Benjamin A. Alman
CURRICULUM VITAE
Education
HighSchool NortheastHighschool,Philadelphia, PennsylvaniaUSA1978HighSchoolDiplomaCollege UniversityofPennsylvania,Philadelphia, Pennsylvania,USA1982.BSc,Material ScienceandEngineering(SummacumLaude)ProfessionorgraduateSchool JeffersonMedicalCollege,ThomasJefferson University,Philadelphia,Pennsylvania,USA1986 MD
Position
2002-present UniversityofToronto,Toronto,Ontario,Canada, Member,CollaborativeProgramin DevelopmentalBiology2002-present UniversityofToronto,Toronto,Ontario,Canada, Member,CollaborativePrograminMolecular Medicine2002-present TheResearchInstituteoftheHospitalforSick Children,Toronto,Ontario,Canada,Senior Scientist,PrograminDevelopmentalandStem CellBiology2004-present UniversityofToronto,Toronto,Ontario,Canada, ViceChairResearch,Surgery2004-present UniversityofToronto,Toronto,Ontario,Canada, Professor,Surgery2004-present UniversityofToronto,Toronto,Ontario,Canada, Professor,LaboratoryMedicineandPathobiology2005-present TheHospitalforSickChildren,Toronto,Ontario, Canada,Head,DivisionofOrthopaedics2006–present UniversityofToronto,Toronto,Ontario,Canada, A.J.LatnerProfessorandChairofOrthopaedics2011-present UniversityofToronto,Toronto,Ontario,Canada, InterimDirector,TorontoMusculoskeletal Centre(Extra-DepartmentalUnit)
Award and Honors
2013 2013ASEAwardforExcellenceinInnovation, AssociationforSurgicalEducation,LosAngles, California,UnitedStates.(Distinction)Awardedtothe TorontoOrthopaedicBootCamp.Annualawardfor exemplaryperformanceinsurgicaleducationwiththe intenttorecognizenovelideasand/ormethodsfor improvingteachingandlearning.2012 FellowshipintheCanadianAcademyofHealth Sciences,CanadianAcademyofHealthSciences, Ottawa,Ontario,Canada.FellowsoftheAcademy areelectedonthebasisoftheirdemonstrated leadership,creativity,distinctivecompetenciesand commitmenttoadvanceacademichealthsciences.
Publications
ChenY,AlmanBA.Wntpathway,anessentialroleinbone1.regeneration.JournalofCellularBiochemistry.2009:106(3):353-362.GurungA,UddinF,HillRP,FergusonPC,AlmanBA.2.Beta-cateninisamediatoroftheresponseofthefibroblaststoirradiation.AmericanJournalofPathology.2009:174(1):248-255.GiampietroPF,DunwoodieSL,KusumiK,Pourquie3.O,TassyO,OffiahAC,CornierAS,AlmanBA,BlankRD,RaggioCL,GlurichL,TurnpennyPD.Progressintheunderstandingofthegeneticetiologyofvertebralsegmentationdisordersinhumans.AnnalsNYAcademyofScience.2009:1151:38-67.LavoieJF,BiernaskieJA,ChenY,BagliD,AlmanB,4.KaplanDR,MillerFD.Skin-derivedprecursorsdifferentiateintoskeletogeniccelltypesandcontributetobonerepair.StemCellsDevelopment.2009:18(6):893-906.HoL,AlmanB.Protectingthehedgerow:p53and5.hedgehogpathway.CellCycle.2010:9(3):506-511.LipaJE,QiuW,HuangN,AlmanBA,PangCY.6.Pathogenesisofradiation-inducedcapsularcontractureintissueexpanderandimplantbreastreconstruction.PlasticReconstructionSurgery.2010:125(2):437-445.SzauterKM,OrdasA,LaxerRM,PopeE,Wherrett7.D,AlmanB,MinkM,BoydCD,CsiszarK,HinekA.Anovelfibroticdisorderassociatedwithincreaseddermalfibroblastproliferationanddownregulationofgenesofthemicrofibrillarnetwork.BritishJournalofDermatology.2010:163(5):1102-1115.OffiahA,AlmanB,CorneirAS,GiampietroPF,TassyO,8.WadeA,TurnpennyPD,ICVAS(InternationalConsortiumforVertebralAnomaliesandScoliosis).Pilotassessmentofaradiologicclassificationsystemforsegmentationdefectsofthevertebrae.AmericanJournalofMedicalGeneticsPartA.2010:152A(6):1357-1371.BovéeJVMG,HogendoornPC,WunderJS,AlmanBA.9.Cartilagetumorsandbonedevelopment:Molecularpathologyandhintsintotherapeutictargets.NatureReviewsCancer.2010:10(7):481-488.AlmanBA,WedgeJ.RobertBruceSalter,C.C.,MD,10.FRCSC.Dec15,1924-May10,2010.JournalofChildren'sOrthopaedics.2010:4(4):275-276.Amini-NikS,KraemerD,CowanML,GunaratneK,11.NadesanP,AlmanBA,MillerJD.Ultrafastmid-IRlaserscalpel:Proteinsignalsofthefundamentallimitstominimallyinvasivesurgery.PLoSONE.2010:5(9):pii:e13053.WuC,AminiNikS,NadesanP,StanfordWL,AlmanBA.12.Aggressivefibromatosis(desmoidtumor)isderivedfrommesenchymalprogenitorcells.CancerResearch.2010:70(19):7690-7698.RockelJS,AlmanBA.Don'thedgeyourbets:Hedgehog13.signalingasacentralmediatorofenchondralbone
35
Benjamin A. Alman
developmentandcartilagediseases.JournalofOrthopaedicResearch.2011:29(6):810-815.SonnadaraRR,VanVlietA,SafirO,AlmanB,FergusonP,14.KraemerW,ReznickR.OrthopaedicBootcamp:Examiningtheeffectivenessofanintensivesurgicalskillscourse.Surgery.2011:149(6):745-749.HongH,NadesanP,PoonR,AlmanBA.Testosterone15.regulatescellproliferationinaggressivefibromatosis(desmoidtumour).BritishJournalofCancer.2011:104(9):1452-1458.BielefeldKA,Amini-NikS,WhetstoneH,PoonR,Youn16.A,WangJ,AlmanBA.Fibronectinandbeta-cateninactinaregulatoryloopindermalfibroblaststomodulatecutaneoushealing.JournalofBiologicalChemistry.2011:286(31):27687-27697.HsuSC,ZhangX,YuC,LiZJ,WunderJS,HuiCC,Alman17.BA.Kif7promotesHedgehogsignalingingrowthplatechondrocytesbyrestrictingtheinhibitoryfunctionofSufu.Development.2011:138(17):3791-3801.Amini-NikS,GlancyD,BoimerC,WhetstoneH,Keller18.C,AlmanBA.Pax7expressingcellscontributetodermalwoundrepairtegulatingscarsizethroughabeta-cateninmediatedprocess.StemCells.2011:29(9):1371-1379.Robanus-MaandagE,BoschC,Amini-NikS,Knijnenburg19.J,SzuhaiK,CerveraP,PoonR,EcclesD,RadiceP,GiovanniniM,AlmanBA,TejparS,DevileeP,FoddeR.Familialadenomatouspolyposis-associateddesmoidsdisplaysignificantlymoregeneticchangesthansporadicdesmoids.PLoSONE.2011:6(9):e24354.AtesokKI,AlmanBA,SchemitschEH,PeyserA,Mankin20.H.Osteoidosteomaandosteoblastoma.JournaloftheAmericanAcademyofOrthopaedicSurgeons.2011:19(11):678-689.AlmanBA,KelleySP,NamD.Healthyself:Using21.endogenousregenerationtorepairbone.TissueEngineering.PartBRev.2011:17(6):431-436.FattahA,CypelT,DonnerEJ,WangF,AlmanBA,Zuker22.RM.Thefirstsuccessfullowerextremitytransplantation:6-yearfollow-upandimplicationsforcorticalplasticity.AmericanJournalofTransplant.2011:11(12):2762-2767.WangCY,WeiQ,HanI,SatoS,Ghanbari-AzarnierR,23.WhetstoneH,PoonR,HuJ,ZhengF,ZhangP,WangW,WunderJS,AlmanBA.Hedgehogandnotchsignalingregulateself-renewalofundifferentiatedpleomorphicsarcoma.CancerResearch.2012:72(4):1013-1022.ZolkipliZ,SherlockM,BiggarWD,TaylorG,Hutchison24.JS,PeliowskiA,AlmanBA,LingSC,TeinI.Abnormalfattyacidmetabolisminspinalmuscularatrophymaypredisposetoperioperativerisks.EuropeanJournalofPediatricNeurology.2012:16(5):549-553.SparrowDB,ChapmanG,SmithAJ,MattarMZ,Major25.JA,O'ReillyVC,SagaY,ZackaiEH,DormansJP,AlmanBA,McGregorL,KageyamaR,KusumiK,DunwoodieSL.Amechanismforgene-environmentinteractioninthe
etiologyofcongenitalscoliosis.Cell.2012:149(2):295-306.PoonR,HongH,WeiX,PanJ,AlmanBA.Ahigh26.throughputscreenidentifiesNefopamastargetingcellproliferationinβ-catenindrivenneoplasticandreactivefibroproliferativedisorders.PLoSONE.2012:7(5):e37940.McAdamLC,MayoAL,AlmanBA,BiggarWD.The27.Canadianexperiencewithlong-termdeflazacorttreatmentinDuchennemusculardystrophy.ActaMyol.2012:31(1):16-20.SonnadaraRR,GarbedianS,SafirO,NousiainenM,Alman28.B,FergusonP,KraemerW,ReznickR.OrthopaedicBootCampII:Examiningtheretentionratesofanintensivesurgicalskillscourse.Surgery.2012:151(6):803-807.NamD,MauE,WangY,WrightD,SilkstoneD,Whetstone29.H,WhyneC,AlmanB.T-lymphocytesenableosteoblastmaturationviaIL-17Fduringtheearlyphaseoffracturerepair.PLoSONE.2012:7(6):e40044.AliSA,AlmanB.RNAextractionfromhumanarticular30.cartilagebychondrocyteisolation.AnalyticalBiochemistry.2012:429(1):39-41.BlackKP,AlmanBA,LevineWN,NestlerSP,PinneySJ.31.OrthopaedicResidentEducation-It'sawholenewgame:
“IfI'mgoingtobeaspinesurgeon,whydoIneedtolearnhowtoreconstructananteriorcruciateligament?”AOAcriticalissues.JournalofBoneandJointSurgery(Am).2012:94(13).MaezawaY,BinnieM,LiC,ThornerP,HuiC-C,Alman32.B,TaketoMM,QuagginSE.AnewCredrivermouseline,Tcf21/Pod1-Cre,targetsmetanephricmesenchyme.PLoSONE.2012:7(7):e40547.TsoiKM,DaiQ,AlmanBA,ChanWC.Arequantumdots33.toxic?Exploringthediscrepancybetweencellcultureandanimalstudies.AccChemRes.2012:Aug1(Epubaheadofprint).BielefeldKA,Amini-NikS,AlmanBA.Cutaneous34.woundhealing:Recruitingdevelopmentalpathwaysforregeneration.CellularandMolecularLifeSciences.2012:Oct4(Epubaheadofprint).HsuC,ZhangX,ChengS,WunderJS,HuiCC,Alman35.BA.Suppressoroffused(Sufu)mediatestheeffectofParathyroidhormone-likehormone(Pthlh)onchondrocytedifferentiationinthegrowthplate.JournalofBiologicalChemistry.2012:287(43):36222-36228.HoL,AliSA,Al-JazraweM,KandelR,WunderJS,36.AlmanBA.PrimaryciliaattenuateHedgehogsignallinginneoplasticchondrocytes.Oncogene.2012:Dec17(Epubaheadofprint)..CampM,MattinglyDA,GrossAE,NousiainenMT,Alman37.BA,McKneallyMF.Patients'viesonsurgeons'financialconflictsofinterest.JournalofBoneandJointSurgery(Am).2013:95(2):e91-98.AlmanBA,FergusonP,KraemerW,NousiainenMT,38.ReznickRK.Competency-basededucation:anewmodelforteachingorthopaedics.InstrCourseLect.2013;62:565-9.
37
Currenttherapeuticstrategiesofcatabolicbonediseasessuchasosteoporosisandmetastatictumorsinbonetargetosteoclastsinordertoreduceornormalizetheelevatedboneresorptionactivity.BothbisphosphonatesandhumanizedmonoclonalantibodyagainstRANKLaresuchanti-resorptiveagentsachievingthistherapeuticgoalalbeitthroughdifferentpharmacokinetics.
Osteonecrosisofthejaw(ONJ)inmaxillaandmandiblehasemerged,however,asararebutseveresideeffectreportedbetween0.5%to18%amongthosepatientswhoweretreatedwithanti-resoptiveagents.Whileclinicalpresentationsvarysignificantly,ONJsymptomscommonlydemonstratethelackofresolutioninchronicinflammationoforalmucosa.Oralmucosaiscomposedofstratifiedepitheliumandthinconnectivetissue,andconsideredoneofthemostprotectivetissuebarriersfromenvironmentalstresses,chemicaldamageandbacterialinfection.BarriertissuesareknowntocontainTcellsexpressingacanonicalgammadeltaTcellreceptor.ImmunosurveillanceandpromptresponsetoinjurybythebarriertissuearethoughttoinvolvegammadeltaTcells.
OurrecentstudiesusingTcrd-H2BEGFPmicedemonstratedtheprolongedretentionofgammadeltaTcellsingingival/palataltissueaftermaxillarymolarextractionwhenmicewereinjectedwithzoledronate(ZOL).Furthermore,thedevelopmentofONJ-likelesionwassignificantlymodulatedinZOL-treatedTcrd-/-mice.Thus,wepostulatethatthecloseapproximationbetweenjawboneandoralbarrierimmunitymay,inpart,contributetothepathogenesisofONJ.
ItwasnotedthatanimalmodelsofONJ-likelesionrevealedanunusualco-localizationofinflammatorycellswithZOL-affectedosteoclasts.OsteoclastsaredifferentiatedfromthemonocyticlineageofmyeloidimmunecellswiththepresenceofM-CSFandRANKL.Oncedifferentiated,osteoclastshavebeenconsideredtofunctionasbonecells.However,theuniqueandconsistentobservationonthedistinctassociationbetweenZOL-affectedosteoclastsandlymphocytesaswellasneutrophilsmaysuggestayetuncoveredfunctionofosteoclastsasimmunecells.
OurpreliminarycharacterizationofosteoclastsderivedfromhumanCD14+monocytessuggestedthesecretionofasetofcytokines.Typically,osteoclasticcytokinesexhibitedasimilarprofileofmyeloid-derivedsuppressorcells(MDSC).MDSCnotonlysuppresseslymphocytescontributingtotheresolutionofinflammation;butfurthersupportstissuerepairbyinducingvascularformationandsecretinggrowthfactors.Thispresentationwillhighlightanewconceptofosteoclastactivitiesasanimmunecells,inparticular,withMDSC-likecharacteristics.Contributionsofosteoclaststophysiologicalboneremodelingandcouplingwithosteoblasts,aswellaspathologicalcontributionstoONJandmetastatictumorsinbonemarrowwillbediscussed.
Osteoclast as MDSC (myeloid-derived suppressor cell) and its role inONJ and tumor bone metastasis
Ichiro Nishimura, D.D.S., D.M.Sc., D.M.D., F.A.P.
ProfessorWeintraubCenterforReconstructiveBiotechnologyUCLASchoolofDentistry
38
Ichiro Nishimura
CURRICULUM VITAE
Education
1981 D.D.S.TokyoDentalCollege,Tokyo,Japan1986 D.M.Sc.HarvardUniversity,Cambridge, MA(Ph.D.equivalent)1986 CertificatePostgraduateProsthodontics(BoardEligible) HarvardSchoolofDentalMedicine,Boston,MA1993 D.M.D.HarvardSchoolofDentalMedicine,Boston,MA
Position
1990-93 FacultyMember,CommitteeofCell& DevelopmentalBiologyHarvardMedicalSchool, Boston,MA1994-97 AssociateProfessorofProstheticDentistry HarvardSchoolofDentalMedicine,Boston,MA1997-99 AssociateProfessor(withtenure) AdvancedProsthodontics,Biomaterialsand HospitalDentistry UCLASchoolofDentistry,LosAngeles,CA1999-PresentProfessor(withtenure) AdvancedProsthodontics,Biomaterialsand HospitalDentistry UCLASchoolofDentistry,LosAngeles,CA2000-PresentProfessorofOralBiology(JointAppointment) UCLASchoolofDentistry,LosAngeles,CA2012-PresentAffiliateProfessorofBioengineering DepartmentofBioengineering UCLAHenrySamueliSchoolofEngineeringand AppliedScience
Award and Honors
2000 FellowofBiotechnology:PolicyIssuesandRegulatory FrameworksSalzburgSeminar,Salzburg,Austria2000 AppreciationofServiceU.S.DepartmentofHealthand HumanServices,PublicHealthService,NIH,National InstituteofDentalCraniofacialResearch2004 DistinguishedScientistAwardinProsthodonticsand ImplantologyInternationalAssociationforDental Research2004 TheodoreM.HesburghCertificateofExcellencefor FacultyDevelopmenttoEnhanceUndergraduate TeachingandLearningUCLAFreshmanCluster ProgramFacultymemberinBiotechnologyandSociety TIAA-CREF2005 AppreciationofServiceU.S.DepartmentofHealthand HumanServices,PublicHealthService,NIH,National InstituteofDentalCraniofacialResearch
Publications
YukiI、LeeD,MurayamaY,ChiangA,VintersHV,1.NishimuraI,WangJCC,IshiiA,BenjaminWM,VinuelaF:Thrombosisandhealingintheexperimentalaneurysmmodel,partII:Thrombusorganizationinthesettingofbioabsorbablepolymers,JNeurosurg ,107:109-120,2007.NishimuraI:Nanotechnologyanditsapplicationsindental2.implant,ClinResDent ,4:29-35,2007.ThakorD,SpigelmanI,TabataY,NishimuraI.:3.Subcutaneousperipheralinjectionofcationizedgelatin/DNApolyplexesasaplatformfornoninvasivegenetransfertosensoryneurons,MolecularTherapy ,15:2124-2131,2007.EgusaH,IidaK,KobayashiM,LinT,ZhuM,ZukP,Hedrik4.M,NishimuraI:Down-regulationofextracellularmatrix-relatedgeneclusterduringosteogenicdifferentiationofbonemarrowandadiposetissue-derivedstromalcells.TissueEng ,13:2589-2600,2007.OhJ,WangCJ,PooleM,KimE,DavisRC,NishimuraI,5.PaeEK:Thegenomesegmentonmousechromosome12determinesmaxilla,JDentRes ,86:1203-1206,2007.WangCJ,IidaK,EgusaH,HokugoA,JewettA,Nishimura6.I:Trabecularbonedeteriorationincol9a1+/- miceassociatedwithenlargedosteoclastsadheredtocollagenIX-deficientbone,JBoneMinerRes ,23(6):837-849,2008.OhJ-H,NishimuraI.:Copynumbervariationinthehuman7.genomeanditsimplicationforhumandisease.JKoreanAcadMaxillofacPlasticReconstrucSurg ,30:205-212,2008.ThakorDK,LinA,MatsukaY,MeyerE,RuangsriS,8.NishimuraI,SpigelmanI:IncreasedperipheralnerveexcitabilityandlocalNaV1.8mRNAup-regulationinpainfulneuropathy,MolPain ,5(1):14,2009.[Openaccess][Highlyaccessedarticle ]KellyJ,LinA,WangCJ,ParkS,NishimuraI:Theeffect9.ofvitaminDinsufficiencyonimplantosseointegration.JProsthodont ,18(6):473-478,2009.LinA,WangCJ,KellyJ,GubbiP,NishimuraI:Theroleof10.titaniumimplantsurfacemodificationwithhydroxyapatititenanoparticlesinprogressiveearlybone-implantfixationinvivo .IntJOralMaxiofacImplants ,24(5):808-816,2009.NishimuraI,ThakorD,LinA,RuangsriS,Spigelman11.I:Molecularstrategiesfortherapeutictargetingofprimarysensoryneuronsinchronicpainsyndromes,InTranslationalPainResearch:FromMousetoMan ,Ed.KrugerL,LightA.pp139-161,CRCPress,BocaRaton,FL,2009.LinA,HokugoA,ChoiJ,NishimuraI:Smallcoiled-coil12.cytoskeleton-associatedmolecule,FGFR1OP2/wit3.0facilitatesfibroblast-drivenwoundclosure.AmJPathol ,176(1):108-121,2010.HokugoA,ChristensenR,ChungEM,SungEC,Felsenfeld13.AL,SayerJ,GarrettN,AdamsJS,NishimuraI:Increasedprevalenceofbisphosphonate-relatedosteonecrosisofthejawwithvitaminDdeficiencyinrats.JBoneMinRes ,
39
Ichiro Nishimura
25(6):1337-49,2010.Nishimura,I:Implantinterfacetobonetissue:Biomimetic14.surfacefunctionalizationthroughnanotechnology,InInterfaceOralHealthScience2009 ,Ed,FukumotoT,IwamoriM,SuzukiO,pp60-66,SpringerJapan,Tokyo,Japan,2010.YukiI,UchiyamaN,MurayamaY,NienYL,LeeD,15.EbaraM,IshiiA,ChiangA,VintersHV,NishimuraI,WuBM,VinuelaF:Intravasculartissuereactionsinducedbyvarioustypesofbioabsorbablepolymericmaterials:correlationbetweenthedegradationprofilesandcorrespondingtissuereactions.Neuroradiology ,52(11):1017-24,2010.LinA,HokugoA,NishimuraI:Woundclosureandwound16.management:Anewtherapeuticmoleculartarget.CellAdhesion&Migration ,4(3):396-399,2010.MussanoF,LeeK,ZukP,TranL,CacalanoN,Jewett17.A,CarossaS,NishimuraI:Differentialeffectofionizingradiationexposureonmultipotentanddifferentiation-restrictedbonemarrowmesenchymalstemcells.JCellBiochem,111(2):322-32,2010.NishimuraI.:GEM21S:Futureperspectivesofdental18.biologics(commissionedreview:inJapanese).DentalDiamond ,2010.CohenM,NishimuraI,TamplenM,HokugoA,Beumer19.J,SteinbergM,ShuJD,AbemayerE,NabiliV:Animalmodelofradiogenicbonedamagetostudymandibularosteoradionecrosis,AmJOtolaryngol ,32(4):291-300,2011.MengattoCM,MussanoF,HondaY,ColwellC,NishimuraI:20.Circadianrhythmandcartilageextracellularmatrixgenesinosseointegration:Agenome-widescreeningofimplantfailurebyvitaminDdeficiency.PloSOne ,6(1):e15848,2011.SuwanwelaJ,LeeJ,LinA,UcerC,DevlinH,Sinsheimer21.J,GarrettN,NishimuraI:AGeneticAssociationStudyofSingleNucleotidePolymorphismsinFGFR1OP2/wit3.0andLong-termAtrophyofEdentulousMandible.PloSOne ,6(1):e16204,2011.TempletonM,TrappK,NishimuraI,ArminB,SteinbergM,22.BeumerJ,AbemayorE,NabiliV:Standardizedanalysisofmandibularosteoradionecrosisinaratmodel,OtolaryngolHeadNeckSurg ,145(3):404-10,2011.ButzF,OgawaT,NishimuraI:Interfacialshearstrength23.ofendosseousimplants,IntJOralMaxillofacImp ,26(4):746-51,2011.MawardiH,GiroG,KajiyaM,OhtaK,AlmazrooaS,24.AlshwaimiE,WooS-B,NishimuraI,KawaiT:Aroleoforalbacteriainbisphosphonate-inducedosteonecrosisofjaw,JDentRes ,90(11):1339-45,2011.RuangsriS,LinA,MulpuriY,LeeK,SpigelmanI,25.NishimuraI:AxonalNav1.8mRNAaccumulationandsciaticnerveinjury-inducedpainfulneuropathyinrats,JBiolChem,286(46):39836-47,2011.HondaY,DingX,MussanoF,WibergA,HoCM,26.NishimuraI:Applicationoffeedbacksystemcontrol(FSC)
toidentifytheoptimizedosteogenicdrugcocktails,IEEE,10.1109/MHS.2011.6102147,2011.ArminBB,HokugoA,NishimuraI,TamplenM,Beumer27.JIII,SteinbergML,AbemayorE,NabiliV.Brachytherapy-mediatedbonedamageinaratmodelinvestigatingmaxillaryosteoradionecrosis,ArchOtolaryngolHeadNeckSurg ,138(2):167-171,2012.KahenasaN,SungE,NabiliV,KellyJ,GarretN,Nishimura28.I:Resolutionofpainandcompletehealingofmandibularosteoradionecrosisusingpentoxifyllineandtocopherol,acasereport,OralSurgOralMedOralPatholOralRadiolEndodontol ,113(4):e18-e23,2012.ChengW,NishimuraI:HighThroughputScreeningof29.BiologicallyFunctionalSmallMoleculesforModulatingtheExpressionofFGFR1OP2/wit3.0inFibroblasts,JCalDentAssoc ,40(12):929-31,934-7,2012.HokugoA,SunS,ParkS,McKennaC,NishimuraI:30.Equilibrium-dependentbisphosphonateinteractionwithcrystallinebonemineralexplainstheanti-resorptivepharmacokineticsandtheprevalenceofosteonecrosisofthejawinaratmodel,Bone ,53(1):59-68,2013.HaJ,OsherSJ,NishimuraI:Mathematicalfiltering31.minimizedmetallichalationoftitaniumimplantinmicroCTimage,JCalDentAssoc ,41(1):41-5,2013.DevlinH,NishimuraI(Editors):OralandCranialImplants32.–RecentResearchDevelopment,Springer,Heidelberg,Germany,2013.NishimuraI:Geneticbackgroundofimplantfailure,in33. OralandCranialImplants–RecentResearchDevelopments ,DevlinH,NishimuraI,Eds.Springer,Heidelberg,Germany,2013.ParkS,NishimuraI:Biosphosphonatesanddentalimplant34.treatment,inOralandCranialImplants–RecentResearchDevelopments ,DevlinH,NishimuraI,Eds.Springer,Heidelberg,Germany,2013.NishimuraI:Geneticnetworksinosseointegration,35. JDentRes ,inpress,2013.HondaY,DingX,MussanoF,WibergA,HoCM,36.NishimuraI:Guidingosteogenicfateofmouseandhumanmesenchymalstemcellsthroughfeedbacksystemcontrol,ScientificReports ,Accepted,2013.KellyJA,MallyaS,NabiliV,NishimuraI:Currentclinical37.managementofintraoralosteoradionecrosis,JProsthetDent ,Submitted,2013.NishimuraI:Acquisitionandmaintenanceof38.osseointegration,InImplantSurgery ,BeumerJIIIEd.Quintessence,Chicago,IL,Submitted,2013.NishimuraI,GarrettN,BeumerJ:Edentulouspatients,39.Patternsofboneresorptionandclinicaloutcomes:osseointegratedimplants,InImplantSurgery ,BeumerJIIIEd.Quintessence,Chicago,IL,Submitted,2013.
43
Poster Session List
Name Grade
MaChengshan 4
NurmaaDashzeveg 4
BijayaHaobam 4
RumanaKhanom 4
DuartePuertoCarolinaLizeth 4
ZayarLin 4
JunpeiShirakawa 4
YukihikoHashida 4
Md.SofiqulIslam 4
MayumiOgita 4
NadilaWali 4
TadashiHosoya 4
NaokiKimura 4
WaruneePluemsakunthai 4
ChengXu 4
GerardoJoseJovesMendez 4
MasayoshiUezono 4
DawudAbduweli 3
GuJie 3
SuphanantachatSupreda 3
LiHui 3
SurapornsawasdThunyaporn 3
ThanitPrasitsak 3
RajapaksheMudiyanselageAnupamaRasadariRajapakshe 3
ThanatvarakornOrnnicha 3
YusukeMatsuo 3
YokoYoshihashi 3
MaheswariKuppusamy 3
MohannadIssaMichaelNassar 3
KenjiOgura 3
KahaerAbula 3
TakayukiYamada 3
UeharaDanielaTiaki 2
Nuylan,MichelleLoyola 2
AlaaAbdulahadTurkistani 2
ALSAYED,EHABZAKIE 2
45
Name Grade
HuaQiao 2
Khunkar,SaharJameelM 2
KenchiTakenaka 2
KongKalyan 2
BabaBista 2
MakiriKawasaki 2
NatsukaUmezawa 1
JunYamada 4
TakashiTaniyama 4
Munetaka Iwata 4
ArataYuki 4
MadokaOnuma 4
NobutakeOzeki 4
YuMatsukura 3
YusukeNakagawa 3
HidetoshiKaburagi 2
MasanoriSaito 2
SatoshiSumiya 2
KatsuakiYanagisawa 2
MakikoInoue 2
MioUdo 2
ShinpeiKondo 2
RyusukeSaito 2
ToshiyukiOhara 2
MikioShioda 1
KaoriNakamura 1
HiroakiYasuda 1
JinyingPiao
KojiFujita