SGK-1在顳下頜關(guān)節(jié)骨關(guān)節(jié)炎軟骨破壞和炎性疼痛中作用的初步研究

SGK-1在顳下頜關(guān)節(jié)骨關(guān)節(jié)炎軟骨破壞和炎性疼痛中作用的初步研究SGK-1在顳下頜關(guān)節(jié)骨關(guān)節(jié)炎軟骨破壞和炎性疼痛中作用的初步研究

摘要：顳下頜關(guān)節(jié)骨關(guān)節(jié)炎是一種常見的關(guān)節(jié)疾病，嚴(yán)重影響患者的生活質(zhì)量。病理過程中，炎性細(xì)胞浸潤和軟骨破壞是致病機(jī)制的關(guān)鍵步驟。SGK-1是一種主要表達(dá)于關(guān)節(jié)軟骨和滑膜細(xì)胞中的細(xì)胞信號(hào)蛋白，其功能在關(guān)節(jié)疾病中尚未完全闡明。本文通過建立顳下頜關(guān)節(jié)鏡下松弛操作引起的骨關(guān)節(jié)炎模型，探究SGK-1在顳下頜關(guān)節(jié)骨關(guān)節(jié)炎中的作用。結(jié)果表明，SGK-1與炎性因子的誘導(dǎo)和細(xì)胞凋亡相關(guān)性增強(qiáng)。在實(shí)驗(yàn)組中，應(yīng)用SGK-1小分子抑制劑可明顯減輕軟骨破壞和炎性疼痛，改善關(guān)節(jié)功能。因此，我們推測(cè)SGK-1可能是一種可用作顳下頜關(guān)節(jié)骨關(guān)節(jié)炎治療的潛在治療靶點(diǎn)。

關(guān)鍵詞：SGK-1；顳下頜關(guān)節(jié)骨關(guān)節(jié)炎；軟骨破壞；炎性疼痛；治療靶點(diǎn)。

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