Does signalling pathways inhibition hold therapeutic promise for osteoarthritis?

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JointBoneSpine81(2014)281–283

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Editorial

Does

signaling

pathway

inhibition

hold

therapeutic

promise

for

osteoarthritis?

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t

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Osteoarthritis was long viewed as a degenerative joint dis-easecharacterizedbygradualcartilageattrition.Mechanicalfactors werevery often incriminated and patient managementlimited to pain control. Subsequently, osteoarthritis was defined as a family of diseases involving all the articular and periarticular tissues,includingthemusclesandtendons[1].Therolefor syn-ovitisandsubchondral-bonesclerosishasbeenfirmlyestablished. Research focusedonthejointtissues and documentedchanges in the metabolic activity and phenotype of chondrocytes, syn-oviocytes, and subchondral-bone osteoblasts. Several signaling pathways have been incriminated in these changes. Examples include the nuclear factor kappa-light-chain-enhancer of acti-vated Bcells (NF-␬B) pathway, whose activation by numerous cytokines(e.g.,IL-1)andgrowthfactorsupregulatesthe expres-sionofmanygenesinvolvedinconnectivetissueinflammationand breakdown;andtheNF-␬B/HIF-2␣pathway,whichplaysarolein endochondralossification.Activationof the␬B/HIF-2␣pathway by mechanical factorsor proinflammatory cytokines stimulates productionbythechondrocytesofosteogenicfactors,matrix met-alloproteinase(MMP)-13,andcollagentypeX[2].Anotherrelevant pathwayisJAKs/STATs,whichensures rapidsignaltransduction between membrane receptors and target genes. Janus kinases (JAKs) are involvedin activatingphosphorylation via the tran-scriptionfactorssignaltransducersandactivatorsoftranscription (STATs),whichmigratetothenucleus,where theybindtoDNA sequenceswithintargetgenepromoters.TheJAKs/STATspathway isactivatedbynumerouscytokinessuchasIL-6.JAKs/STATs acti-vationinducestheexpressionofgenesencodingproinflammatory cytokinesandMMPsdirectlyinvolvedincartilagebreakdownand synovialmembraneinflammation[3].Activationofthe Insulin/IGF-1/Pl3k/Akt/forkhead-box class O (FoxO) pathway is related to chondrocyteaging.FoxOfactorsplayacentralroleincell resis-tancetooxidativestress[4]andtheirinhibitionresultsindecreased antioxidantproduction.TheWntpathwayisalsoafocusofactive research.Itsroleiscomplex.Wntpathwayactivationandinhibition

induceosteoarthritisinexperimentalanimals[5].Thesepathways constitutepotentialtreatmenttargets.

Morerecently,osteoarthritishasbeendescribedasametabolic disease,basedonevidenceofacorrelationbetweenclinicalhand osteoarthritisseverityandobesity[6].Obesitydoesnotincreasethe mechanicalloadsonthehands,andasystemiceffectofobesityon handosteoarthritishasthereforebeensuggested[7].Adiposetissue releasesproinflammatorycytokines(e.g.,tumornecrosisfactor-␣, IL-6)andadipokines(e.g.,leptin,adiponectin,andvisfatin),which exert deleterious effectsonjoint tissues (Fig. 1)[8]. Studies of patientswithobesityhaveshownassociationslinking osteoarthri-tistothemetabolicsyndromeanditscomponents(hypertension, dyslipidemia,andtype2diabetes).Furthermore,associationshave been reported between kneeosteoarthritis and metabolic syn-drome components such as type 2 diabetes and hypertension, independentlyfromthepresenceofobesityorotherknownrisk factorsforosteoarthritis[9].Finally,theaccumulationofmetabolic riskfactorssuchasoverweight,hypertension,dyslipidemia,and hyperglycemiaincreasestheriskofkneeosteoarthritis develop-mentandprogression[10].Thelinkbetweenmetabolicsyndrome andosteoarthritismaybechroniclow-gradesystemic inflamma-tioncharacterizedbyelevatedcirculatinglevelsofreactiveoxygen species,oxidizedlow-densitylipoproteins(LDLs),lipidmediators, oradipokines.

These recent datahave changed themanner in which both patients and healthcare professionals view osteoarthritis. Clini-cians andresearchers arenow seekingtoclassify patientswith osteoarthritis based on the disease phenotype. Potential cate-goriesincludemetabolicosteoarthritis,earlygenetic osteoarthri-tis, age-related osteoarthritis, and posttraumatic osteoarthritis. Phenotype-basedclassificationwillresultinmanagement strate-giestailoredtothediseasecharacteristics,therebyincreasingthe responseratestoeachtreatment.

Thetherapeuticobjectiveinpatientswithosteoarthritisisto controlthesymptomsviaacombinationofpharmacologicaland nonpharmacologicaltreatments[11].Themain nonpharmacolog-icaltreatmentsareweightlossandphysicalexercisedesignedto maintainmusclefunctionandtodecreasebodyfat.Nonsteroidal anti-inflammatorydrugsandparacetamolarethemostwidelyused drugsbutcarryahighriskofseveresideeffectsthatlimitstheiruse inpatientswithosteoarthritisandcomorbidities.

In contrastto patientswithrheumatoid arthritis (RA), those withosteoarthritishavenotyetbenefitedfromtreatment break-throughs capable of significantly slowing disease progression.

doi:10.1016/j.jbspin.2014.03.002

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282 Editorial/JointBoneSpine81(2014)281–283

Fig.1.Pathophysiologyofosteoarthritis(OA)associatedwithobesity.MCP-1:monocytechemotacticprotein-1;SAA:serumamyloidA;IL-1␤:interleukin-1beta; TNF-␣:tumornecrosisfactoralpha;IL-6:interleukin-6.Sincearelationshipwasdemonstratedbetweenhandosteoathritisandobesity,obesity-relatedOAisconsideredasa metabolicdiseasesinvolvingsystemicbetweenthetwoconditionsthroughthereleaseofproinflammatorycytokinesbutalsoadipokineslikesleptin,adiponectotvisfatin whichcandirectlyactivatechondrocyteslikemechanicalstressorproinflammatorycytokines.Obesityalsopromotesanumberofco-morbidities,includingthemetabolic syndrome,whichmayincreasetheriskofOA.Finally,OA,particularlyage-relatedOA,isassociatedtochroniclow-gradeinflammationthroughthemediatorreleasedby jointtissuesbutalsobyotherageingtissue.

BiotherapiestargetingIL-1 or TNF have shownlittle efficacyin patientswithhand or kneeosteoarthritis [12]. In addition,the severesideeffectsofthesetargetedtreatmentslimitthe accept-abilityoftheirlong-termuse,astheyaredisproportionatewiththe severityofosteoarthritis.Nevertheless,patientswith osteoarthri-tismaybenefitfromtherapeuticadvancesachievedinRA,notably fromthedevelopmentofsmallmoleculesthatspecificallyinhibit theJAKs.AnexampleisCP-690,550(tofacitinib).JAK/STAT path-wayinhibitionisnowatreatmenttargetnotonlyinRA,butalso inosteoarthritis.TofacitinibinhibitstheactivityofJAKs1,2,and3, exhibitinggreateraffinityforJAK3thanforJAKs1and2. Tofac-itinibhasbeen evaluatedin six phase IIstudies and six phase IIIstudiesincludingabout5000patientswithRA[3].Theresults showedsignificantdecreasesinsymptoms anddisease activity, evenin patientshavingfailedprior biotherapies[13]. The inci-denceofsideeffects(infectionsandgastricperforation)wassimilar tothatseenwithbiotherapies[14].Toourknowledge,tofacitinib hasnotyetbeenevaluatedinpatientswithosteoarthritis. Nev-ertheless,theresultsoftrialsinRAsuggestthattofacitinibmay eventuallybecomethefirstspecificsignalingpathwayinhibitor forevaluationinpatientswithosteoarthritis.Finally,therecently identifiedRunx1inhibitorTD-198946preventsthedevelopment ofcartilagedamagein micewithosteoarthritis inducedby sur-gical meniscectomy and section of the median knee ligament [15].

Signaling pathways hold promise as treatment targets in osteoarthritis,astheirinhibitionoractivationregulatesthe expres-sion of a set of target genes directly involved in joint tissue metabolic dysfunctions. Nevertheless, the first clinical trials in RAhaveshownthatspecificregulationoftheJAK/STATpathway inducesnumerous side effects.Thus, safety concerns maylimit theuseofspecificinhibitorsoractivatorsofsignalingpathways inosteoarthritis.Therisk/benefitratiomustremainatthecenter oftreatmentdecisions,asosteoarthritisisaslowlyprogressiveand

moderatelyseverediseasethatisassociatedwithmultiple comor-bidities.

Disclosureofinterest

YHisthefounderandashareholderofArtialisSAandSynolyne Pharma,twospin-offoftheUniversityofLiège.Hehasreceived consultingfeesfromTilmanSAandtheLaboratoiresExpanscience. HehasalsoreceivedspeakerfeesfromIBSAandBioIberica.

References

[1]LoeserRF,GoldringSR,ScanzelloCR,GoldringMB.Osteoarthritis:adiseaseof

thejointasanorgan.ArthritisRheum2012;64:1697–707.

[2]SaitoT,KawaguchiH.HIF-2alphaasapossibletherapeutictargetof

osteoarthri-tis.OsteoarthritisCartilage2010;18:1552–6.

[3]FeistE,BurmesterGR.SmallmoleculestargetingJAKs–anewapproachinthe

treatmentofrheumatoidarthritis.Rheumatology(Oxford)2013;52:1352–7.

[4]AkasakiY,HasegawaA,SaitoM,etal.DysregulatedFOXOtranscription

fac-torsinarticularcartilageinagingandosteoarthritis.OsteoarthritisCartilage

2014;22:162–70.

[5]LoriesRJ,CorrM,LaneNE.ToWntornottoWnt:theboneandjointhealth

dilemma.NatRevRheumatol2013;9:328–39.

[6]YusufE,NelissenRG,Ioan-FacsinayA,etal.Associationbetweenweightor

bodymassindexandhandosteoarthritis:asystematicreview.AnnRheumDis

2010;69:761–5.

[7]CondeJ,ScoteceM,LopezV,etal.Adipokines:novelplayersinrheumatic

diseases.DiscovMed2013;15:73–83.

[8]SellamJ,BerenbaumF.Isosteoarthritisametabolicdisease?JointBoneSpine

2013;80:568–73.

[9]PuenpatomRA,VictorTW.Increasedprevalenceofmetabolicsyndromein

individualswithosteoarthritis:ananalysisofNHANESIIIdata.PostgradMed

2009;121:9–20.

[10]YoshimuraN,MurakiS,OkaH,etal.Accumulationofmetabolicriskfactorssuch

asoverweight,hypertension,dyslipidaemia,andimpairedglucosetolerance

raisestheriskofoccurrenceandprogressionofkneeosteoarthritis:a3-year

follow-upoftheROADstudy.OsteoarthritisCartilage2012;20:1217–26.

[11]ZhangW,NukiG,MoskowitzRW,etal.OARSIrecommendationsforthe

man-agementofhipandkneeosteoarthritis:partIII:changesinevidencefollowing

systematiccumulativeupdateofresearchpublishedthroughJanuary2009.

Author's personal copy

Editorial/JointBoneSpine81(2014)281–283 283

[12]ChevalierX,EymardF,RichetteP.Biologicagentsinosteoarthritis:hopesand

disappointments.NatRevRheumatol2013;9:400–10.

[13]CoombsJH,BloomBJ, BreedveldFC,etal. Improvedpain,physical

func-tioning and health status in patients with rheumatoid arthritis treated

with CP-690,550, an orally active Janus kinase (JAK) inhibitor: results

fromarandomised,double-blind,placebo-controlledtrial.AnnRheumDis

2010;69:413–6.

[14]KremerJM,CohenS,WilkinsonBE,etal.AphaseIIbdose-rangingstudyofthe

oralJAKinhibitortofacitinib(CP-690,550)versusplaceboincombinationwith

backgroundmethotrexateinpatientswithactiverheumatoidarthritisandan

inadequateresponsetomethotrexatealone.ArthritisRheum2012;64:970–81.

[15]YanoF,HojoH,OhbaS,etal.Anoveldisease-modifyingosteoarthritisdrug

candidatetargetingRunx1.AnnRheumDis2013;72:748–53.

YvesHenrotin∗ UnitédeRecherchesurl’OsetleCartilage,Arthropôle

Liège,Institutdepathologie,niveau+5,CHU Sart-Tilman,4000Liège,Belgium

∗_{Tel.:+3243662516.}

E-mailaddress:yhenrotin@ulg.ac.be Accepted27February2013 Availableonline4April2014