Biomechanical Thresholds Regulate Inflammation through the NF-κB Pathway Experiments and Modeling 英文参考文献.docVIP

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Biomechanical Thresholds Regulate Inflammation through the NF-κB Pathway Experiments and Modeling 英文参考文献.doc

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Biomechanical Thresholds Regulate Inflammation through the NF-κB Pathway Experiments and Modeling 英文参考文献

BiomechanicalThresholdsRegulateInflammation throughtheNF-kBPathway:ExperimentsandModeling JinNam1,BaltazarD.Aguda2,3,BjoernRath4,SudhaAgarwal1* 1BiomechanicsandTissueEngineeringLaboratory,CollegeofDentistry,TheOhioStateUniversity,Columbus,Ohio,UnitedStatesofAmerica,2MathematicalBiosciences Institute,TheOhioStateUniversity,Columbus,Ohio,UnitedStatesofAmerica,3CenterforCriticalCare,TheOhioStateUniversityMedicalCenter,Columbus,Ohio,United StatesofAmerica,4OrthopaedicSurgery,UniversityofRegensburg,Regensburg,Germany Abstract Background: During normal physical activities cartilage experiences dynamic compressive forces that are essential to maintaincartilageintegrity.However,atnon-physiologiclevelsthesesignalscaninduceinflammationandinitiatecartilage destruction.Here,byexaminingthepro-inflammatorysignalingnetworks,wedevelopedamathematicalmodeltoshowthe magnitude-dependentregulationofchondrocyticresponsesbycompressiveforces. Methodology/Principal Findings: Chondrocytic cells grown in 3-D scaffolds were subjected to various magnitudes of dynamiccompressivestrain(DCS),andtheregulationofpro-inflammatorygeneexpressionviaactivationofnuclearfactor- kappaB(NF-kB)signalingcascadeexamined.Experimentalevidencesprovidetheexistenceofathresholdinthemagnitude of DCS that regulates the mRNA expression of nitric oxide synthase (NOS2), an inducible pro-inflammatory enzyme. Interestingly,belowthisthreshold,DCSinhibitstheinterleukin-1b(IL-1b)-inducedpro-inflammatorygeneexpression,with the degree of suppression depending on the magnitude of DCS. This suppression of NOS2 by DCS correlates with the attenuationoftheNF-kBsignalingpathwayasmeasuredbyIL-1b-inducedphosphorylationoftheinhibitorofkappaB(IkB)- a,degradationofIkB-aandIkB-b,andsubsequentnucleartranslocationofNF-kBp65.Amathematicalmodeldevelopedto understandthecomplexdynamicsofthesystempredictstwothresholdsinthemagnitudesofDCS,onefortheinhibitionof IL-1b-inducedexpressionofNOS2byDCSatlowmagnitudes,andsecondfortheDCS-inducedexpressionof