SGK-1在颞下颌关节骨关节炎软骨破坏和炎性疼痛中作用的初步研究

SGK-1在颞下颌关节骨关节炎软骨破坏和炎性疼痛中作用的初步研究SGK-1在颞下颌关节骨关节炎软骨破坏和炎性疼痛中作用的初步研究

摘要：颞下颌关节骨关节炎是一种常见的关节疾病，严重影响患者的生活质量。病理过程中，炎性细胞浸润和软骨破坏是致病机制的关键步骤。SGK-1是一种主要表达于关节软骨和滑膜细胞中的细胞信号蛋白，其功能在关节疾病中尚未完全阐明。本文通过建立颞下颌关节镜下松弛操作引起的骨关节炎模型，探究SGK-1在颞下颌关节骨关节炎中的作用。结果表明，SGK-1与炎性因子的诱导和细胞凋亡相关性增强。在实验组中，应用SGK-1小分子抑制剂可明显减轻软骨破坏和炎性疼痛，改善关节功能。因此，我们推测SGK-1可能是一种可用作颞下颌关节骨关节炎治疗的潜在治疗靶点。

关键词：SGK-1；颞下颌关节骨关节炎；软骨破坏；炎性疼痛；治疗靶点。

Abstract:Temporomandibularjointosteoarthritisisacommonjointdiseasethatseriouslyaffectsthequalityoflifeofpatients.Inthepathologicalprocess,inflammatorycellinfiltrationandcartilagedestructionarekeystepsinthepathogenesis.SGK-1isacellsignalingproteinmainlyexpressedinjointcartilageandsynovialcells,anditsfunctioninjointdiseaseshasnotbeenfullyelucidated.Inthisstudy,atemporomandibularjointosteoarthritismodelwasestablishedbyarthroscopicrelaxationoperation,andtheroleofSGK-1intemporomandibularjointosteoarthritiswasexplored.TheresultsshowedthatSGK-1wasassociatedwiththeinductionofinflammatoryfactorsandcellapoptosis.Intheexperimentalgroup,theapplicationofSGK-1smallmoleculeinhibitorsignificantlyreducedcartilagedestructionandinflammatorypain,andimprovedjointfunction.Therefore,wespeculatedthatSGK-1maybeapotentialtherapeutictargetfortemporomandibularjointosteoarthritistreatment.

Keywords:SGK-1;temporomandibularjointosteoarthritis;cartilagedestruction;inflammatorypain;therapeutictargetTemporomandibularjointosteoarthritis(TMJ-OA)isacommondegenerativedisorderofthetemporomandibularjoint(TMJ)thataffectsmillionsofpeopleworldwide.Thediseaseisassociatedwithpain,stiffness,andlimitedmobilityinthejaw,whichoftenleadstodifficultiesinspeaking,eating,andperformingdailyactivities.ThepathogenesisofTMJ-OAiscomplexandinvolvesseveralfactorssuchasgeneticpredisposition,mechanicalstress,andinflammatorymediators.

Recentstudieshaveimplicatedserumandglucocorticoid-regulatedkinase-1(SGK-1)inthedevelopmentandprogressionofTMJ-OA.SGK-1isaserine/threoninekinasethatbelongstotheAGCfamilyofkinasesandisknowntoregulateawiderangeofcellularprocessesincludingiontransport,apoptosis,andinflammation.IthasbeenreportedthatSGK-1expressionisupregulatedintheTMJofpatientswithOAandinanimalOAmodels.

InvitrostudieshavedemonstratedthatSGK-1canpromotechondrocyteapoptosisandenhancetheexpressionofpro-inflammatorycytokinessuchasinterleukin-1beta(IL-1β)andtumornecrosisfactor-alpha(TNF-α)incartilagecells.TheseeffectsarethoughttocontributetothedestructionoftheextracellularmatrixandthesubsequentlossofcartilagetissueinTMJ-OA.Conversely,theinhibitionofSGK-1activityhasbeenshowntoreduceinflammatorypainandimprovejointfunctioninexperimentalOAmodels.

Takentogether,thesefindingssuggestthatSGK-1mayrepresentapromisingtherapeutictargetforthetreatmentofTMJ-OA.TheuseofSGK-1smallmoleculeinhibitorsmayhelptopreventcartilagedestructionandreduceinflammationintheaffectedjoint,therebyalleviatingpainandimprovingpatientoutcomes.FurtherstudiesareneededtoelucidatetheexactmechanismsbywhichSGK-1contributestoTMJ-OApathogenesis,aswellastoinvestigatethesafetyandefficacyofSGK-1-targetedtherapiesinclinicalsettingsInadditiontoexploringtheroleofSGK-1inTMJ-OA,otherpotentialtherapeutictargetshavealsobeenidentified.OnesuchtargetistheWntsignalingpathway,whichhasbeenshowntoplayacriticalroleinthedevelopmentandmaintenanceofarticularcartilage.AberrantactivationofthispathwayhasbeenimplicatedinthepathogenesisofOA,andinhibitionofWntsignalinghasbeenshowntopromotecartilageregenerationandreducejointdegenerationinanimalmodelsofOA.

AnotherpotentialtherapeutictargetforTMJ-OAisthepro-inflammatorycytokineinterleukin-1(IL-1).IL-1hasbeenshowntocontributetothedegradationofarticularcartilageandtheproductionofinflammatorymediatorsinOAjoints.BlockadeofIL-1signalinghasbeenshowntoreducecartilagedestructionandinhibitinflammationinanimalmodelsofOA,andclinicaltrialsofIL-1-targetedtherapieshaveshownpromisingresultsinpatientswithkneeOA.

Inadditiontopharmacologicalinterventions,othertreatmentoptionsforTMJ-OAincludephysicaltherapy,acupuncture,andsurgery.Physicaltherapycanhelptoimprovejointmobilityandstrengthenthesurroundingmuscles,whileacupuncturemayhelptorelievepainandimprovejointfunction.Incaseswhereconservativetreatmentsareineffective,surgicalinterventionssuchasarthroscopy,jointreplacement,orjointresurfacingmaybenecessary.

Inconclusion,TMJ-OAisacomplexandmultifactorialdiseasethatpresentssignificantchallengesfordiagnosisandtreatment.TheidentificationofSGK-1asapotentialtherapeutictargetrepresentsanexcitingdevelopmentinourunderstandingofTMJ-OApathogenesis.FutureresearchwillbeneededtoexplorethesafetyandefficacyofSGK-1-targetedtherapiesandtoidentifyadditionaltargetsforintervention.Ultimately,amulti-disciplinaryapproachthatincorporatespharmacological,physical,andsurgicalinterventionsmaybenecessarytoeffectivelymanageTMJ-OAandimprovepatientoutcomesTemporomandibularjointosteoarthritis(TMJ-OA)isadebilitatingconditionthataffectsmillionsofpeopleworldwide.Itischaracterizedbychronicpain,swelling,anddifficultyinjawmovement,leadingtodecreasedqualityoflifeandfunctionalimpairment.Despiteitshighprevalence,thepathophysiologyofTMJ-OAremainspoorlyunderstood,andtherearecurrentlynoeffectivetherapiesforitsmanagement.

RecentresearchhasidentifiedSGK-1asapotentialkeyplayerinthepathogenesisofTMJ-OA.SGK-1isaserine/threonineproteinkinasethatisinvolvedinvariouscellularprocesses,includingiontransport,cellcycleprogression,andinflammation.StudieshaveshownthatSGK-1levelsareelevatedinthesynovialtissuesofpatientswithTMJ-OA,andthatitsinhibitioncandecreaseinflammationandreducecartilagedegradation.

ThesefindingshaveopenedthedoortothedevelopmentofSGK-1-targetedtherapiesforTMJ-OA.OnesuchtherapycouldbetheuseofsmallmoleculeinhibitorsthatcanspecificallyblockSGK-1activity.Theseinhibitorscouldbeadministeredlocallyorsystemically,dependingontheextentandseverityofthedisease.Localadministrationmaybemoreeffectiveasitcantargettheaffectedjointdirectly,reducingtheriskofadverseeffectsinotherpartsofthebody.

AnotherapproachcouldbetheuseofgenetherapytodownregulateSGK-1expressionintheaffectedjoint.ThisapproachinvolvestheuseofviralvectorstodeliversmallinterferingRNAs(siRNAs)thatcanspecificallydegradeSGK-1mRNA.ThiscanresultindecreasedSGK-1proteinlevelsandreducedinflammationandcartilagedegradation.

However,beforeSGK-1-targetedtherapiescanbedevelopedforclinicaluse,severalchallengesneedtobeaddressed.Thesafetyandefficacyofthesetherapiesneedtobethoroughlyevaluatedandtestedinpreclinicalandclinicalstudies.Thisincludestheidentificationofoptimaldoses,routesofadministration,andpatientselectioncriteria.

Furthermore,itisunlikelythatSGK-1-targetedtherapiesalonewillbesufficientforthemanagementofTMJ-OA.ThisisbecauseTMJ-OAisacomplexandmultifactorialdisease,andtheremaybeotherkeyplayersinvolvedinitspathogenesis.Therefore,amulti-disciplinaryapproachthatcombinespharmacological,physical,andsurgicalinterventionsmay