Nothing but skin and bone
Transcript of Nothing but skin and bone
Washington University School of MedicineDigital Commons@Becker
Open Access Publications
2006
Nothing but skin and boneF. Patrick RossWashington University School of Medicine in St. Louis
Angela M. ChristianoColumbia University College of Physicians and Surgeons
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Recommended CitationRoss, F. Patrick and Christiano, Angela M., ,"Nothing but skin and bone." The Journal of Clinical Investigation.,. 1140-1149. (2006).https://digitalcommons.wustl.edu/open_access_pubs/1558
Review series introduction
1140 TheJournalofClinicalInvestigationâ â â http://www.jci.orgâ â â Volumeâ116â â â Numberâ5â â â Mayâ2006
Nothing but skin and boneF. Patrick Ross1 and Angela M. Christiano2
1Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA. 2Departments of Dermatology and Genetics and Development, Columbia University College of Physicians and Surgeons, New York, New York, USA.
Skinandboneâwhatcomestomindathearingthisphrase?Whilecertainlyametaphorfordisease,italsodefinestwoverydifferenttissues,oneaflexibleandcontiguousoutercovering,theotheramorphologicallydiversehardtissuedistributedatover200sitesinthebody.AstheaccompanyingseriesofReviewshighlights,thesetissuesareindeeddiverse,buttherearealsosurprisingsimilarities.Skinistheinterfacebetweentheinternalorgansandtheenvironment,andassuchplaysacrucialroleinthebodyâsdefensemechanism.Theskinanditsmanyappendagesareresponsibleforfunctionsasdiverseasepidermalbarrieranddefense,immunesurveillance,UVprotection,thermoregulation,sweating,lubrication,pigmentation,thesensationsofpainandtouch,and,importantly,theprotectionofvariousstemcellnichesintheskin.Boneservesanumberofpurposes:itprovidesprotectionforvitalorgans,aleverforlocomotion,areservoirforcalcium,andthesiteofadulthematopoiesis.Thetissueiscomposedofosteoblasts,osteoclasts,andtheirindividualprecursorsplusacomplexmixtureofmesenchymal,myeloid,andlymphoidcellsinthemarrowspace.Finally,theendothelialmicroenvironmentprovidesnutritionandisaconduitfortheinfluxandemigrationofcellsthatimpactbonebiologyinseveralimportantways.ThisReviewseriesguidesthereaderthroughthesevariousfacetsof2diverse,yetinterdependent,tissues.
Whileâinâtheâadultâvertebrateâorganism,âboneâandâskinâspendâmuchâofâtheirâtimeâasâseparateâentitiesâwithâvastlyâdifferentâagendas,âtheâskinâdermisâandâtheâboneâoriginateâfromâaâcommonâprimordialâmesenchyme,âandâatâsomeâpointsâinâdevelopmentâtheâoverlyingâepidermisâââinâtheâformâofâtheâapicalâectodermalâridgeâââandâtheâoutgrowthâofâtheâlimbâareâintimatelyâinterdependent.âInâtheâearliestâdaysâofâdevelopment,âandâagainâinâtimesâofâneedâsuchâasâlimbâregenerationâinâtetrapodâvertebrates,âtheâ2âtissuesâmustâcomeâtogetherâandâfunctionâveryâmuchâasâone.âTheâstudyâofâdevelopmen-talâpathwaysâandâepithelial-mesenchymalâinteractionsâinâtheâskinâandâboneâhaveârevealedâsomeâstrikingâparallels,âwhichâareâreprisedâinâbothâorgansâinâtheâadult.
The skin youâre in: donât be fooled by a pretty exteriorDespiteâitsâaestheticallyâpleasingâappendagesâsuchâasâtheâhairâandânails,âitsâpliableânature,âitsâflexibility,âandâitsâresponsive-ness,âtheâskinâisâaâmasterâinâtheâartâofâself-defenseâââprovingâthatâaâtissueâneedânotâbeâhardâinâorderâtoâbeâtough.âInâadditionâtoâservingâasâtheâbodyâsâoutermostâprotectiveâcovering,âtheâskinâbarrierâintegratesâtheâbodyâsâphysiologyâwithâtheâterrestrialâenvi-ronment.âTheâepidermalâbarrierâworksâinâ2âways:âasâanâinside-outâbarrier,âtoâminimizeâtransepidermalâwaterâloss,âandâasâanâoutside-inâbarrier,âasâaâsentryâtoâpreventâinvasionâbyâinfectiousâagentsâandânoxiousâsubstancesâ(1â5).
Inâadditionâtoâtheâ2âmajorâstructuralâlayersâofâtheâskin,âtheâepidermisâandâtheâdermis,âtheâskinâisâalsoâhomeâtoâaânumberâofâotherâcellâtypesâandâstructuresâthatâeachâplayâaâuniqueâroleâinâitsâfunctionâ(6).âThereâareâresidentâdendriticâcells,âknownâasâLangerhansâcells,âwhichâareâtheâantigen-presentingâcellsâofâtheâskinâinterspersedâamongâtheâkeratinocytesâthatâprovideâtheâfirstâ
lineâofâdefenseâagainstâinvasion.âMastâcellsâresideâinâtheâdermis,âandâtheirâdegranulationâreleasesâvasoactiveâaminesâandâotherâproinflammatoryâmediatorsâthatâinduceâimmediateâhypersensi-tivityâresponsesâsuchâasâurticariaâ(7).
Theâskinâisâalsoâpopulatedâbyâeccrineâ(sweat)âglands,âwhichâallowâforâtemperatureâregulationâviaâsympatheticânervousâsystemâcontrolâofâanâintricateânetworkâofâlymphaticâandâbloodâcapillariesâthatâresideâinâtheâdermis,âasâwellâasâtheâapocrineâ(scent)âglands,âwhichâareâbelievedâtoâemitâsecretionsâandâpheromonesâforâsexualâcommunicationâ(8).âTheâsebaceousâglandâisâattachedâtoâtheâhairâfollicleâandâsecretesâsebumâtoâtheâskinâsurfaceâthatâkeepsâitâsup-pleâandâwaterproofâ(9).âTheâhairâfollicle,âinâadditionâtoâgenerat-ingâtheâhairâshaft,âalsoâprovidesâaâprotectiveânicheâtoâseveralâstemâcellâpopulationsâinâtheâskin,âincludingâtheâkeratinocyteâstemâcell,âtheâmelanocyteâstemâcell,âaâpopulationâofâepidermalâneuralâcrestâstemâcells,âandâtheâdermalâstemâcellâcompartment,âknownâasâtheâdermalâpapillaâ(10â13).âThereâareâseveralâcontractileâcellâpopu-lations,âsuchâasâtheâmyoepithelialâcellsâliningâtheâsweatâgland,âthatâcontractâtoâextrudeâliquidâontoâtheâskinâsurfaceâduringâther-moregulation,âasâwellâasâtheâarrectorâpiliâmuscle,âwhichâattachesâtoâtheâhairâfollicleâandâisâresponsibleâforâcreatingâgooseâbumpsâwhenâtheâbodyâsâcoreâtemperatureâfallsâ(14).
Adultâskinâisâalsoâhomeâtoâatâleastâ2âdifferentâneuralâcrestâcellâpopulations:âtheâmelanocyte,âwhichâprovidesâpigmentationâandâUVâprotectionâtoâhumanâepidermisâandâcolorâtoâtheâhairâshaftâ(15),âandâtheâMerkelâcell,âaâneuroendocrineâcellâresponsibleâforâtrans-missionâofâtouchâsensationâthroughâtheâcutaneousânerves,âamongâotherâfunctionsâ(Figureâ1)â(16).Thereâareâalsoâsignificantâanatomi-calâvariationsâinâskinâstructureâonâdifferentâpartsâofâtheâbody,âsuchâasâtheâthick,âprotectiveâepidermisâonâtheâpalmsâandâsolesâcomparedâwithâtheâthinâskinâonâtheâeyelid,âandâspecializedâregionsâwithoutâhairâfollicles,âsuchâasâtheâglabrousâ(lip)âepithelium,âorâwithâaâhighâdensityâofâhairâfollicles,âsuchâasâtheâscalp.
Thusâtheâskinâyouâreâinâisâaâhighlyâspecializedâandâmeticulous-lyâregulatedâorganâsystemâpopulatedâbyânumerousâdifferentâcellâtypesâthatâeachâcontributeâuniquelyâtoâitsâmultitudeâofâfunctionsâ(6).âLikewise,âtheâspectrumâofâskinâdisordersâthatâariseâwhenâtheseâfunctionsâgoâawryâisâvirtuallyâlimitless.âTheâskin-relatedâReviewsâ
Nonstandardabbreviationsused:âBMP,âboneâmorphogenicâprotein;âBP,bullousâpemphigoid;âDkk,âDickkopf;âHPV,âhumanâpapillomavirus;âLRP,âLDLâreceptorârelatedâprotein;âMIP-1α,âmacrophageâinhibitoryâproteinâ1α;âOPG,âosteoprotegerin;ââPTH,âparathyroidâhormone;âPTHrP,âPTH-relatedâprotein;âPV,âpemphigusâvulgaris;âRANKL,receptorâactivatorâofâNF-ÎșBâligand;âTCF/LEF,âTâcellâfactor/lymphoidââenhancerâbindingâfactor.
Conflictofinterest:âTheâauthorsâhaveâdeclaredâthatânoâconflictâofâinterestâexists.
Citationforthisarticle:âJ. Clin. Invest.â116:1140â1149â(2006).âdoi:10.1172/JCI28605.
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review series introduction
TheJournalofClinicalInvestigationâ â â http://www.jci.orgâ â â Volumeâ116â â â Numberâ5â â â Mayâ2006â 1141
inâ thisâ seriesâ focusâ onâ 4â mainâ topics:â theâ epidermalâ barrier,ââautoimmuneâskinâdisease,âepithelialâviralâinfection,âandâtheârela-tionshipâbetweenâtheâskinâandâtheâcentralânervousâsystem.
When the flesh is weakTheâseriesâbeginsâwithâaâReviewâofâepidermalâbarrierâformationâbyâJuliaâSegreâ(17).âInâadditionâtoâservingâasâtheâbodyâsâoutermostâprotectiveâcovering,âtheâskinâisâaâbarrierâbetweenâtheâbodyâandâtheâterrestrialâenvironment.âBarrierâfunctionâisâcriticalâinânewbornâani-mals,âasâshownâbyâtransgenicâanimalâmodelsâwithâbarrierâdefectsâthatâdieâshortlyâafterâbirthâfromâtransepidermalâwaterâloss.
Earlyâstudiesâofâtheâskinâbarrierâfocusedâmainlyâonâitsâremark-ableâphysiochemicalâpropertiesâandâonâdeterminingâtheâuniqueâproteinâcompositionâofâlipidsâandâtheâcornifiedâcellâenvelopeââ
(1,â2,â4,â5).âGeneticâapproachesâandâeffortsâinâgenomicâcloningâhaveârevealedâanâunusuallyâcomplexâclusterâofâgenesâinâhumanâchromosomeâ1q21,âtermedâtheâepidermalâdifferentiationâcom-plex,âwhichâcontainsâmoreâthanâ30âgenesâinvolvedâinâterminalâdifferentiationâofâtheâskinâ(18).
Recentâstudiesâofâtheâmolecularâmechanismsâgoverningâbarrierâformation,âparticularlyâtranscriptionalâevents,âhaveâbegunâtoâshedâlightâonâtheâmolecularâunderpinningsâofâthisâhighlyâregulatedâprocess.âInâherâReviewâ(17),âSegreâdrawsâsomeâintriguingâparallelsâbetweenâtheâformationâofâtheâepidermalâbarrierâandâtheâreprisalâofâtheseâprocessesâinâtheâsettingâofâcommonâskinâdisordersâsuchâasâpsoriasisâorâatopicâdermatitis,âwhichâdisplayâaâperturbationâinâbarrierâfunctionâthatâmayâexacerbateâtheseâconditions.âTakingâcluesâfromâtheâtranscriptionalâandâmolecularâeventsâinvolvedâinâ
Figure 1Schematic illustration of several key elements of the skin. As indicated, the skin is divided into 2 main compartments, epidermal (tan) and dermal (pink), separated by a basement membrane (blue). The epidermis serves as the protective barrier, due to the differentiation of proliferative epithe-lial cells in the basal layer to the terminally differentiated cells in the stratum corneum. The sites and development of HPV infection are indicated at far left: the primary infection occurs in the basal layer, and mature virion sheds in the stratum corneum. Merkel cells are located within the basal layer of the epidermis (purple) and are associated with sensory nerve endings (brown). Two types of cell junctions critical for the integrity of the skin are highlighted here. Desmosomes (upper right inset) form cell-cell junctions, in which cadherins (pink and green), such as desmogleins 1 and 3, are the extracellular bridges and the autoantigens in different forms of pemphigus. Hemidesmosomes (lower right inset) tether the cells to the basement membrane and are composed of a number of proteins, 2 of which â BP230 and BP180 (also known as type XVII collagen) â are auto-antigens in BP. Disruption of these interactions results in loss of adhesion of the cells to one another or to the underlying basement membrane.
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review series introduction
1142 TheJournalofClinicalInvestigationâ â â http://www.jci.orgâ â â Volumeâ116â â â Numberâ5â â â Mayâ2006
formingâtheâbarrierâinâutero,âthisâReviewâproposesâthatâtheâman-agementâofâinflammatoryâskinâdiseaseâmayâbenefitâfromâthera-piesâthatâenhanceârestorationâofâtheâepidermalâbarrier.
A âmultiple hitâ model for the pathogenesis of pemphigus: Tregs to the rescueTheânextâarticleâinâtheâseriesâisâaâReviewâbyâMichaelâHertlâandâcol-leaguesâ(19),âwhoâofferâaânewâperspectiveâonâtheâpathogenesisâofâaâfamilyâofârare,âautoimmuneâblisteringâskinâdiseasesâknownâasâpemphigusâandâpemphigoid.âTheânameâpemphigusâisâderivedâfromâtheâGreekâwordâpemphix,âmeaningââbubbleââorââblister,ââoriginallyâcoinedâbyâMcBrideâinâ1777âandâWichmannâinâ1791.âTheâmoreâsevereâformsâofâpemphigusâareâpotentiallyâlifeâthreateningâandâinvolveâtheâskinâasâwellâasâtheâoralâmucosaâ(20).
Theâautoantigensâinâpemphigusâareâepidermalâdesmosomalâcadherinsâthatâmediateâtheâintercellularâadhesionâofâkeratino-cytes,âspecificallyâdesmogleinâ1âinâpemphigusâfoliaceousâandâdesmogleinâ3âinâpemphigusâvulgarisâ(PV).âLikewise,âtheâautoan-tibodiesâinâbullousâpemphigoidsâ(BPs)âareâ2âhemidesmosomalâproteinsâthatâareâinvolvedâinâcellâbasementâmembraneâattach-mentâofâbasalâkeratinocytes,âspecificallyâtheâ180-kDaâBPâanti-genâ(BP180,âalsoâknownâasâtypeâXVIIâcollagen)âandâtheâ230-kDaâBPâantigenâ(BP230).
Theâ pathognomonicâ blistersâ ofâ pemphigusâ ariseâ fromâ theâbindingâ ofâ circulatingâ autoantigenicâ IgGâ moleculesâ toâ theseâkeratinocyteâproteinsâandâtheâsubsequentâdisruptionâofâintercel-lularâadhesionâeitherâthroughâaâdirectâeffectâonâdesmosomalâorâhemidesmosomalâarchitecture,âbyâtriggeringâcellâsignalingâpro-cessesâthatâresultâinâlossâofâcellâadhesionâ(acantholysis),âorâboth.âThusâtheâcriticalâroleâofâtheâBâcellâinâgeneratingâtheâsecretedâauto-antibodiesâfoundâinâpemphigusâpatientsâhasâlongâbeenâknown.âHertlâandâcolleaguesâfocusâinsteadâonâtheâemergingâimportanceâofâtheâTâcellâinâpemphigusâ(19).âTheseâauthorsâdescribeâaââmul-tipleâhitââmodelâofâlossâofâimmuneâtoleranceâinâpemphigus.âTheâauthorsâreviewâseveralâlinesâofâevidenceâthatâcollectivelyâshowâthatâneitherâcirculatingâIgGânorâautoreactiveâTâcellsâaloneâareâsuf-ficientâtoâelicitâPVâandâsuggestâthatâaâthirdâpopulationâofâcells,âTregs,âmayâbeâcriticalâinâitsâpathogenesis.
TheâroleâofâTregsâinâsuppressingâimmuneâresponses,âcontrol-lingâautoimmunity,âandâmaintainingâtoleranceâhasânotâbeenâwidelyâ studiedâ inâ theâ settingâ ofâ pemphigus;â however,â someârecentâworkâsuggestsâaâpotentialâimbalanceâofâtheseâcellsâinâPVâpatients.âOneâstudyâfoundâthatâTregsâwereâfoundâinâtheâauto-reactiveâTâcellsâofâaâlargeânumberâofâhealthyâindividualsâbutâinâonlyâ20%âofâPVâpatients,âraisingâtheâpossibilityâthatâtheâTregsâwereârequiredâtoâkeepâtheâautoreactiveâTâcellsâfromâevokingâdisease.âAâmultipleâhitâmodelâinâpemphigusâwouldâthereforeârequireâanâautoreactiveâBâcell,âanâautoreactiveâTâcell,âandâfinallyâaâlossâofâTregâsuppressorâactivityâinâorderâtoâsetâtheâstageâforâPV.âTheârequirementâofâthisârareâconstellationâofâeventsâmightâexplainâtheârelativelyâlowâpopulationâincidenceâofâPV,âatâonlyâ1â2âcasesâperâ100,000âindividuals.âHertlâandâcolleaguesâsuggestâthatâfocusingâonâTregsâmayârepresentâaânewâtherapeuticâoppor-tunityâinâtheârestorationâofâimmuneâtoleranceâinâtheâpemphigusâfamilyâofâautoimmuneâbullousâdiseases.
The end of a scourge: HPV no moreTheânextâReview,âbyâDouglasâLowyâandâJohnâSchillerâ(21),âsum-marizesârecentâdevelopmentsâinâunderstandingâhumanâpapil-lomavirusâ(HPV)âandâtheâdevelopmentâofâsuccessfulâHPVâvac-
cines.âHPVsâareâaâlargeâfamilyâofâdouble-strandedâDNAâvirusesâthatâareâvirtuallyâubiquitousâandâinfectâepithelialâtissuesâinclud-ingâtheâskin,âcervix,âandâotherâmucosae.âOverâ75âvariantsâhaveâbeenâidentifiedâfromâhumanâtissues,âaboutâone-thirdâofâwhichâareâsexuallyâtransmittedâandâgiveâriseâtoâaâspectrumâofâlesionsâwithinâtheâgenitalâtract.âSomeâHPVs,âsuchâasâHPV6âorâHPV11,âcauseâonlyâbenignâepithelialâlesionsâsuchâasâgenitalâwarts,âwhileâothers,âsuchâasâHPV16âandâHPV18,âresultâinâlesionsâthatâcanâprogressâtoâinvasiveâcancersâofâtheâcervixâ(22).âHPVsâthatâinfectâtheâcutaneousâepitheliumâhaveâalsoârecentlyâbeenâlinkedâasâaâcofactorâalongâwithâUVâexposureâinâtheâdevelopmentâofânon-melanomaâcancerâofâtheâskinâ(23).
PrimaryâinfectionâofâHPVâinâskinâorâcervicalâepitheliaâusuallyâoccursâwithinâtheâlong-livedâbasalâstemâcells,âwhereinâtheâvirusâreplicatesâandâimmediateâearlyâproteinsâareâexpressed.âAsâtheâepi-thelialâcellsâbeginâtoâdifferentiate,âtheâviralâproteinsâE6âandâE7âareâexpressed.âTheâL1âandâL2âproteinsâareânotâexpressedâuntilâtheâvirusâreachesâtheâupperâspinousâlayers,âwhereâassemblyâoccurs,âandâfinallyâtheâproductionâofâmatureâvirionsâtakesâplaceâinâtheâstratumâcorneum,âfromâwhenceâintactâvirionsâareâshedâ(24).
Initialâ HPVâ exposureâ occursâ duringâ sexualâ activity,â whereâtheâ infectionâofâtheâcervicalâepitheliumâleadsâtoâaâsquamousâintraepithelialâlesionâcausedâbyâeitherâaâlow-riskâHPVâ(e.g.,âHPV6âandâHPV11)âorâaâhigh-riskâHPVâ(e.g.,âHPV16,â-18,â-31,â-33,â-45).ââIncreasedâsexualâactivityâandâtheâtotalânumberâofâpartnersâresultsâinâaâhigherâlifetimeâriskâofâHPVâexposure.âSimilarly,âinâoralâmuco-sa,âhigh-gradeâHPVâlesionsâcanâbeâpromotedâbyâsmokingâandâotherâfactorsâandâresultâinâinvasiveâsquamousâcellâcarcinomasâoverâlongâperiodsâofâtime.âAlthoughâsuchâoccurrencesâareârare,âlow-gradeâsquamousâintraepithelialâlesionsâmayâevolveâintoâinva-siveâsquamousâcarcinomasâoverâtime.
Cervicalâcancerâcomprisesâ10%âofâallâcancersâinâwomenâandâisâtheâsecondâleadingâcauseâofâdeathâfromâcancerâamongâwomenâworldwide.âHPVâDNAâisâ foundâinâoverâ90%âofâcervicalâcancerâlesions.âRoughlyâ80%âofâallâcervicalâcancersâoccurâinâless-developedâcountries,âlargelyâdueâtoâinsufficientâresourcesâforâcervicalâcancerâscreeningâ(e.g.,âPapâsmear).âThisâstrikingâassociationâsuggestsâtheâpossibilityâofâdevelopingâeitherâprophylaxisâorânewâtherapiesâforâcervicalâcancerâbasedâonâtheâmanipulationâofâhumanâimmuneâresponsesâagainstâHPVs.
Recently,âMerckâandâGlaxoSmithKlineâannouncedâstunningâsuccessesâinâtheâdevelopmentâofâvaccinesâagainstâHPVs.âTheseâvac-cinesâwereâdevelopedâagainstâtheâL1âcapsidâprotein,âwhichâinducesâhighâlevelsâofâantibodies.âBothâvaccinesâtargetâHPV16âandâHPV18,âwhichâmakeâupâmoreâthanâ70%âofâcancers,âandâtheâMerckâvaccineâalsoâtargetsâHPV6âandâHPV11,âwhichâaccountâforâaboutâ90%âofâgenitalâwarts.âTheseâvaccinesâhaveâshownânearlyâ100%âefficacyâinâtheâpreventionâofâHPVâinfectionâinâwomen.âInâtheirâReview,âLowyâandâSchillerâ(21)âaddressâmanyâimportantâconsiderationsâinâtheâdesignâandâtestingâofâtheseâvaccines,âincludingâpublicâhealthâandâethicalâissues.âTheseâvaccinesâhaveâgreatâpotentialâtoâpreventâsev-eralâhundredsâofâthousandsâofâcancersâeachâyear,âmostâofâwhichâoccurâinâyoung,âsexuallyâactiveâwomen.
TheâdevelopmentâofâHPVâvaccinesârepresentsâaâpowerfulâillustra-tionâofâtranslationalâresearchâwherebyâadvancesâinâepithelialâvirol-ogyâcanâmoveâintoâtheâcommercialâsectorâforâtheâdevelopmentâofâeventualâlarge-scaleâvaccinationâprograms.âPerhapsâsuccessesâsuchâasâtheâoneâdescribedâbyâLowyâandâSchillerâforâHPVâwillâcarryâoverâintoâsimilarâprogramsâforâherpesvirusâinfections,âaâmostâimpor-tantâcauseâofâmorbidityâinâhumanâpopulations.
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TheJournalofClinicalInvestigationâ â â http://www.jci.orgâ â â Volumeâ116â â â Numberâ5â â â Mayâ2006â 1143
Scratch that itchToâbroadenâourâthinkingâaboutâtheâintimateâconnectionâbetweenâtheâskinâandâtheânervousâsystem,âtheâfinalâskin-relatedâReviewâinâthisâseries,âbyâRalfâPausâandâcolleaguesâ(25),âraisesâsomeâintrigu-ingânewâpossibilitiesâ inâmanagingâaâsymptomâuniqueâtoâder-matology:âpruritus,âorâitching.âDespiteâmanyâyearsâofâresearch,âtheâexactâcauseâofâitchingâisâunknownâandârepresentsâaâcomplexâphysiologicalâphenomenon.âAnâitchâcanâbeâdefinedâasâanâunpleas-antâsensationâthatâprovokesâanâoftenâuncontrollableâdesireâtoâscratch,âwhichâironicallyâcanâbeâinexplicablyâpleasurable.âScratch-ingâisâbelievedâtoârelieveâtheâ itchâbyâ inducingâmildâpainâthatâcausesâaâtemporaryâdistractionâfromâtheâitch.âFrequently,âoneâworsensâtheâother,âsinceâdamageâtoâtheâouterâlayersâofâtheâskinâbyâscratchingâcanâreleaseâadditionalâproinflammatoryâagentsâthatâfurtherâexacerbateâitching.âThisâphenomenonâisâknownâasâtheâitch-scratchâcycle,âwhichâliesâatâtheâcenterâofâcurrentâneurophysi-ologicalâresearchâinâtheâskinâ(26).
Pruritusâcanâbeâaâsymptomâofâinnumerableâskinâdiseases;âhow-ever,âitâcanâalsoâoccurâwhenâthereâisânoâvisibleâevidenceâofâaâskinâlesionâandâinsteadâresultsâfromâaâdisruptionâinâprocessingâofâtheâitchâsensationâinâtheâbrainâorâtheâcircuitryâconnectingâitâwithâtheâskin.âThereâareâmanyâsystemicâdiseasesâthatâcanâcauseâitch,âinclud-ingâkidneyâfailure,âhepatitisâCâinfection,âmultipleâmyeloma,âandâliverâdisease,âamongâothers,âsuggestingâthatâstimuliâfromâoutsideâtheâskin-brainâcircuitâcanâenterâtheâpathwayâandâcauseâitching.
Pruritusâhasâbeenâaâchallengeâfromâtheâresearchâperspectiveâdueâtoâtheâsubjectiveânatureâofâitchingâitself,âtheâabsenceâofâaâpreciseâphysiologicalâdefinitionâorâquantitativeâmeasures,âandâtheâlackâofâsuitableâinâvitroâorâinâvivoâmodelsâtoâmimicâtheâsymptoms.âDespiteâtheseâchallenges,ârecentâadvancesâinâunderstandingâtheâneurophys-iologicalâbasisâofâitchâhaveârevealedâsomeâsurprisingânewâinsights.âTheâskinâisâhomeâtoâaâcomplexânetworkâofânervesâthatâtransmitâdif-ferentâsensations,âincludingâitch,âpain,âtouch,âcold,âandâheat.âInâtheâsimplestâofâterms,âitchingâisâaâresponseâtoâaâchemicalâstimulusâthatâtransmitsâtheseâsignalsâbackâtoâtheâbrainâ(27).âTeasingâoutâwhichânerveâfibersâareâresponsibleâforâitchâhasâbeenâaâformidableâtask,âandâforâmanyâyearsâitâwasâbelievedâthatâitchâsimplyâhijackedânerveâcircuitsâfromâtheâpainâpathwaysâandâwasâmerelyâaâmodifiedâformâofâpain.âHowever,âtheâdiscoveryâofâitch-specificâneuronsârevealedâthatâthereâare,âinâfact,âdistinctâsensoryâsystemsâforâitchâandâpainâ(nociception).âInâtheirâReviewâ(25),âPausâandâcolleaguesâdiscussâsomeâpotentiallyânovelâtherapeuticâopportunitiesâthatâhaveâarisenâfromâaâbetterâunderstandingâofâitchâfromâtheâpointâofâviewâofâtheâskinâasâwellâasâtheâbrain.
What lies beneathTheâskin-relatedâReviewsâwithinâthisâseriesâfocusâmainlyâonâ4âvariationsâonâtheâthemeâofâtheâepithelialâcutaneousâdisease,âsinceâtheâepidermalâbarrier,âtheâdestructionâofâkeratinocytesâinâpemphigus,âviralâinfectionâofâepithelialâcellsâbyâHPV,âandâtheâoriginsâofâitchingâallârelateâinâsomeâwayâtoâtheâepidermisâorâitsâresidentâcells.âThereâisâfarâmoreâtoâtheâskinâthanâtheâepider-mis,âandâtoâconsiderâitâinâisolationâwouldâbeâjustâscratchingâtheâsurface.âTheâdermis,âhomeâofâmesenchymalâcellsâinâtheâskin,âwasânotâtouchedâuponâextensivelyâinâtheseâReviews,ânorâwasâtheâvastâsubjectâofâdevelopmentalâpathwaysâsuchâasâWntâsignalingâ(reviewedâinârefs.â28,â29).âInterestingly,âinâearlyâdevelopment,âundifferentiatedâmesenchymalâcellsâcanâgiveâriseâtoâtheâfibro-blastsâofâskinâdermis,âtoâadipocytes,âtoâcartilage,âtoâmuscle,âorâtoâbone,âsuggestingâthatâthereâareâcommonâthemesâatâplayâinâ
differentiationâofâtheseâtissuesâ(30).âSinceâmesenchymalâcellsâandâsignalingâpathwaysâareâtheâprimaryâfocusâofâtheâsecondâhalfâofâthisâReviewâseries,âweâshallânowâcutâstraightâtoâtheâboneâandâexamineâwhatâliesâbeneath.
BonePhysiologicalâboneâturnoverâcanâbeâdividedâintoâ2âtemporalâphases:âmodeling,âwhichâoccursâduringâdevelopmentâ(aâtopicânotâaddressedâinâthisâseries;âforârecentâreviewsâseeârefs.â31,â32),âandâremodeling,âaâlifelongâprocessâinvolvingâtissueârenewal.âRemodelingâstartsâwithâremovalâbyâosteoclastsâofâmatrix,âaâmixtureâofâinsolubleâproteinsâinâwhichâtypeâIâcollagenâisâpredominantâ(>90%)âandâaâpoorlyâcrys-talline,âchemicallyâmodifiedâhydroxyapatite.âFollowingâresorption,âosteoblastsâareârecruitedâtoâtheâsite,âwhereâtheyâsecreteâandâmineral-izeânewâmatrix.âUntilâaboutâageâ30â35âbonereplacementâexceedsâorâequalsâremoval,âthusâincreasingâorâmaintainingâboneâmass;âthereaf-ter,âboneâmassâdecreases,âreflectingâtheâpredominanceâofâosteoclastâactivity.âTheâmajorâthrustâofâtheâbone-relatedâReviewâarticlesâcon-tainedâwithinâthisâseriesâisâtoâoutlineâselectedânewâandâimportantâaspectsâofâosteoblastâandâosteoclastâbiologyâ(forâanâexcellentâreviewâofâtheâpathophysiologyâofâosteoporosisâseeâref.â33).
Osteoblast biologyOsteoblastsâareâspecializedâfibroblastsâthatâsecreteâandâcalcifyâaâspecificâmatrix.âTheirâlineageâspecificationâfromâmesenchymalâstemsâ cellsâ isâ regulatedâ byâ aâ plethoraâ ofâ signals.â Aâ rangeâ ofâcytokinesâmodulateâosteoblastâdifferentiation,âincludingâboneâmatrixâderivedâTGF-ÎČ,âboneâmorphogenicâproteinâ2â(BMP-2),âBMP-4,âandâBMP-7,âandâtheirâinhibitorsânoggin,âchordin,âgremlin,âandâsclerostin,âtheâlastâidentifiedâbyâpositionalâcloningâofâfamiliesâwithâincreasedâboneâmass.âSimilarly,ânumerousâhormonesâimpactâosteoblastâfunctionâpositivelyâincludingâIGF-1,âparathyroidâhor-moneâ(PTH),âPTH-relatedâproteinâ(PTHrP),â1,25(OH)2D3,âleptin,âglucocorticoids,âtheâNotchâpathway,âandâmembersâofâtheâleukemiaâinhibitoryâfactor/IL-6âfamily.
Transcriptionâfactorsâ thatâregulateâtheâosteoblastâ includeâaârangeâofâhomeodomainâproteins:âtheâactivatorâproteinâ(AP)âfam-ilyâmembersâJun,âFos,âandâFra,âSmads,âCCAAT/enhancerâbindingâproteinâÎČâ(C/EBPÎČ)âandâC/EBPÎŽ,âlymphoid-enhancingâfactorâ(aâWntâ effector),â activatingâ transcriptionâ factorâ 4,â Runt-relatedâtranscriptionâfactorâ2â(Runx2),âandâosterix,âtheâlastâ3âofâwhichâareâconsideredâmasterâgenesâforâosteoblastâdifferentiation.âInâcontrastâtoâtheâosteoclastâ(seeâbelow),âtheâosteoblastâsâbest-characterizedâintracellularâsignalingâpathwayâisâtheâp42/44âMAPKâsystem.
Osteoblastsâ ligateâ existingâ matrixâ viaâÎČ1â integrins,â formingâaâmonolayerâthatâisâlinkedâbyâcadherins.âOnceâactive,âtheâcellsâsecreteâaâmatrixâcontainingâtypeâIâcollagenâandâsmallerâbutâsig-nificantâamountsâofâosteocalcin,âmatrixâglaâprotein,âosteopontin,âboneâsialoprotein,âmanyâminorâcomponents,âand,âimportantly,âgrowthâ factorsâ suchâ asâ BMPsâ andâ TGF-ÎČ.â Keyâ ectoproteins,âincludingâprogressiveâankylosisâgeneâ(ANK)âandâtissueânonspe-cificâalkalineâphosphataseâ(TNAP),âexportâpyrophosphateâgener-atedâintracellularlyâandâcleaveâthisâsmall-moleculeâinhibitorâofâcalcification,ârespectivelyâ(34).âInâcontrastâtoâtheirâproapoptoticâroleâinâosteoclasts,âbisphosphonatesâincreaseâosteoblastâlifespanâandâperhapsâfunctionâ(35).
TheâtextâbelowâfocusesâonâWntâsignalingâinâosteoblastsâandâtheâroleâofâtheseâcellsâasâsupportersâofâtheâHSCânicheâandâtargetsâforâosteoclastogenicâhormones.âDetailedâreviewsâofâosteoblastâbiologyâareâavailableâ(36â40).
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Wnt signalingInâthisâseries,âtheâReviewâarticleâbyâOrmondâMacDougaldâandâcol-leaguesâ(41)âfocusesâonâtheâroleâofâWntâsignalingâinâosteoblastâfor-mationâandâfunction.âWnts,âaâfamilyâofâsecretedâglycoproteinsâwithâmultipleâinhibitors,âareâligandsâforâtheâfamilyâofâ7-membraneâspanningâfrizzledâreceptorsâandâplayâaâprominentâroleâinâbothâtheâearlyâandâlaterâstagesâofâosteoblastâdifferentiation.âWntâantago-nistsâincludeâDickkopfsâ(Dkks)âandâsecretedâfrizzled-relatedâpro-teinsâ(sFRPs).âWhileâtheirâsignalingâpathwaysâwereâcharacterizedâoriginallyâinâtermsâofâdevelopment,âWntsâregulateânumerousâcellu-larâfunctionsâandâhaveâbeenâlinkedârecentlyâtoâcancerâandâstemâcellâbiology.âItâisâalsoâclearâthatâindividualâWntsâutilizeâcanonicalâandânoncanonicalâpathwaysâ(42);âtheâendogenousâWntâligandsâinâboneâremainâunidentified,âalthoughâWnt10bâwasârecentlyâimplicatedâbyâMacDougaldâetâal.â(43).âTheâcanonicalâpathwayâisâwellâestablishedâandâinvolvesâWnt-dependentâinhibitionâofâproteasome-mediatedâdegradationâofâÎČ-catenin,âwhichâformsâcomplexesâwithâmembersâofâtheâTâcellâfactor/lymphoidâenhancerâbindingâfactorâ(TCF/LEF)âfamilyâthatâregulateâtranscriptionâwhenâitâaccumulatesâ inâtheânucleus.âTheânoncanonicalâpathway,âalsoâfrizzledâdependent,âacti-vatesâdifferentâintracellularâsignalsâincludingâtheâcalcium-calmod-ulin-PKCâaxisâandâtheâRhoâfamilyâofâsmallâGTPases.
MacDougaldâandâcolleaguesâreviewâtheâcurrentâinformationâonâWntsâandâboneâbiology.âTheâstoryâbeganâwithâtheâidentifi-cationâofâloss-âandâgain-of-functionâmutationsâinâLDLârecep-torârelatedâproteinâ5â(LRP5),âaâfrizzledâcoreceptor,âthatâcorrelateâwithâchangesâinâhumanâboneâmass.âMoreârecentâstudiesâshowedâthatâÎČ-catenin,âwhichâisâdownstreamâofâtheâWntâLRP5/6âfriz-zledâ axis,â isâ indispensableâ forâ osteoblastâ differentiationâ inâtheâmouseâ(44).âSeveralâpapersâcitedâbyâMacDougaldâetâal.âareâworthyâofâcommentâhere.âWhereasâmiceâlackingâfrizzled-relat-edâproteinâ1âhaveâincreasedâboneâmassâarisingâfromâmarkedlyâdecreasedâosteoblastâapoptosis,âandâLrp5â/ââmiceâexhibitâaâpre-dominantâdeficitâinâosteoblastânumberâandâfunction,âCol1-Cre;âÎČ-cateninc/câanimalsâshowâmainlyâaâsecondaryâdefectâinâosteo-clasts.âTheseâresultsâmayâreflectâdifferentâmodesâofâWntâsignal-ing:âcanonicalâversusânoncanonicalâpathways,âWnt-dependentâversusâ-independentâsignaling,âorâuniqueârolesâforâdifferentâWntâfamilyâmembers.âIdentificationâofâdownstreamâtargetsâofâWntâsignalingâisâanâunderexploredâsubject:âosteoprotegerinâ(OPG)âwasâidentifiedâasâaâdirectâtargetâinâosteoblasts,âandâtheâanabolicâgenesâsubjectâtoâWntâregulationâareânotâknownâbutâmayâincludeâBMPs.âDespiteâtheâimpliedâimportanceâofâcanonicalâWntâsig-nalingâinâosteoblastâbiology,âtheâroleâofâtheâTCF/LEFâfamilyâofâ
Figure 2Cell-cell interactions in bone marrow. HSCs, the precursors of osteoclasts, reside in a stem cell niche provided by osteoblasts, which, together with stromal cells, derive from mesenchymal stem cells. Bone degradation (arrows) results in release of matrix-associated growth factors, which stimulate mesenchymal cells and thus bone formation. This âcouplingâ is an essential consequence of osteoclast activity (98). Addition-ally, matrix-derived factors stimulate cancer cell proliferation in the so-called âvicious cycle.â Finally, cancer cells release cytokines that target mesenchymal cells and thus activate bone resorption.
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transcriptionâfactorsâisâunclear.âSinceâÎČ-cateninâparticipatesâinâtranscriptionalâcomplexesâwithâmoleculesâotherâthanâTCF/LEFs,âsomeâtargetâgenesâmayânotâbeâregulatedâviaâTCF/LEFâbindingâsites.âFinally,âMacDougaldâetâal.âmayâunderstateâtheâproblemâofâtargetingâglycogenâsynthaseâkinaseâ3â(GSK3),âaâdownstreamâeffectorâofâWnt/ÎČ-cateninâsignalingâandâaâmoleculeâforâwhichâaânumberâofâpotentâ inhibitorsâhaveâbeenâdevelopedâ(45).âAsâpointedâout,âlong-termâtreatmentâwithâGSK3âinhibitorsâmayâpredisposeâcellsâtoâanâoncogenicâmutation.âOnâtheâotherâhand,âlithiumâions,âaânonspecificâinhibitorâofâGSK3,âhaveâbeenâusedâforâdecadesâwithoutâapparentâproblemsâinâthisâregardâ(45).
The hematopoietic stem cell nicheInâtheâReviewâbyâTongâYinâandâLinhengâLiâ(46),âtheâauthorsâsum-marizeâanotherânewâandâexcitingâarenaâinâboneâbiology,âtheâHSCâniche.âTheâmodel,âproposedâsimultaneouslyâbyâLiâandâcowork-ersâandâCalviâetâal.â(47,â48)âsuggestsâthatâmesenchymalâcells,âinâtheâformâofâbone-liningâosteoblasts,âareâcentralâtoâtheâmainte-nanceâofâHSCsâandâtheirâproliferationâand/orâdifferentiation.âTheâsystemâisâcomplexâsinceâ(a)âmanyâ ligandsâandâreceptorsâthatâmodulateâinteractionâbetweenâmyeloidâandâmesenchymalâcellsâandâhenceâexpressionâofâparacrineâfactorsâareâpresentâonâbothâcellâtypesâandâ(b)âmanyâofâtheâligandsâand/orâreceptorsâareâthemselvesâregulatedâbyâcytokines.âTheâauthorsâalsoâsummarizeâdataâsuggestingâthatâboneâmarrowâendotheliumâactsâasâaânicheâforâaâfunctionallyâdistinctâcellâpopulation.âInârelatedâfindings,âtheâworkâofâBrandiâandâCollin-OsdobyâindicatesâthatâvascularâendothelialâcellsârespondâtoâinflammatoryâcytokinesâbyâsecretingâreceptorâactivatorâofâNF-ÎșBâligandâ(RANKL)âandâchemokinesâthatâareâchemoattractiveâforâosteoclastâprecursorsâandâaugmentâtheâosteoclastogenicâcapacityâofâRANKLâ(49).
Boneâmarrowâisâalsoâtheâenvironmentâinâwhichâspecificâmetas-tasesâmanifestâtheirâosteolyticâand/orâosteogenicâphenotypes.âCancerâcellsâfacilitateâtheirâinfiltrationâintoâtheâmarrowâcavityâbyâstimulatingâosteoclastâformationâandâfunction.âAnâinitialâstimu-lusâisâPTHrPâgenerationâbyâlungâandâbreastâcancerâcellsâ(50â52),âthusâenhancingâmesenchymalâproductionâofâRANKLâandâM-CSFâwhileâdecreasingâthatâofâOPGâ(seeâOsteoclast biology).âTheâresultingâ
increaseâinâmatrixâdissolutionâreleasesâbone-residingâcytokinesâandâ growthâ factorsâ that,â byâ feedbackâ mechanisms,â increaseâgrowthâand/orâsurvivalâofâcancerâcells.âThisâloopâhasâbeenâtermedââtheâviciousâcycleââ(Figureâ2)â(51).âMultipleâmyelomaâusesâaâdif-ferentâbutâ relatedâ strategy,ânamelyâ secretionâofâmacrophageâinhibitoryâproteinâ1αâ(MIP-1α)âandâmonocyteâchemoattractantâprotein-1â(MCP-1),âbothâofâwhichâareâchemotacticâandâprolif-erativeâforâosteoclastâprecursorsâ(53,â54).âMetastasisâofâprostateâcancerâtoâboneâhasâbothâlyticâandâblasticâcomponents,âwithâtheânetâresultâbeingâdepositionâofâexcessâwovenâboneâ(55).âAârecentâstudyâsuggestsâthatâBMP-6,âproducedâbyâcancerâcells,âstimulatesâtheirâinvasiveâandâproliferativeâcapacityâ(56).âSimilarly,âinhibi-tionâofâVEGFâalsoâbluntsâprostateâmetastasisâ(57),âsuggestingâthatâmultipleâcytokinesâplayâaâroleâinâproliferationâandâinvasionâofâthisâcancer.âFutureâstudiesâwillâundoubtedlyârevealâadditionalâmoleculesâmediatingâboneâlossâinâmetastaticâdisease.
Osteoclast biologyTheâosteoclastâisâgeneratedâbyâdifferentiationâandâfusionâofâprecur-sorsâofâtheâmonocyte/macrophageâlineage,âgivingâriseâtoâaâpolykary-onâwithâuniqueâcellularâandâmolecularâproperties.âTwoâcytokinesâmediateâ basalâ osteoclastogenesis,â RANKLâ (58)â andâ M-CSF,ââalsoâcalledâCSF-1â(59).âBothâproteins,âproducedâbyâmarrowâstromalâcellsâandâtheirâderivativeâosteoblasts,âareâmembraneâbound,âandâthusâdifferentiationâofâosteoclastsârequiresâdirectâinteractionâofâtheseânonhematopoietic,âbone-residingâcellsâwithâosteoclastâpre-cursorsâ(60).âTheâdiscoveryâofâRANKLâwasâprecededâbyâidentifica-tionâofâitsâphysiologicalâinhibitorâOPG,âtoâwhichâitâbindsâwithâhighâaffinityâ(61).âM-CSFâregulatesâmanyâaspectsâofâmyeloidâprecursorsâandâmatureâosteoclasts,âincludingâproliferationâand/orâsurvival,âdifferentiation,âandâtheâcytoskeletalârearrangementsârequiredâforâefficientâboneâresorptionâ(59).
Aâcombinationâofâbiochemistryâandâgeneticsâhelpsâtoâexplainâhowâosteoclastsâresorbâboneâ(58,â62).âTheâcapacityâofâosteoclastsâtoâisolateâtheâenclosedâareaâbetweenâthemselvesâandâtheâunderlyingâboneâisâatâtheâheartâofâtheirâfunction.âTheâacidicâpHâ(~4.5)âdecal-cifiesâtheâtissue,âexposingâtheâorganicâmatrixâtoâdegradationâbyâlysosomal-derivedâproteases,âparticularlyâcathepsinâKâ(Figureâ3).ââ
Figure 3Mechanism of osteoclastic bone resorption. The osteoclast adheres to bone via binding of RGD-containing proteins (green triangle) to the integrin αvÎČ3, initiating signals that lead to insertion into the plasma membrane of lysosomal vesicles that contain cathepsin K (Ctsk). Consequently, the cells generate a ruffled border above the resorption lacuna, into which is secreted hydrochloric acid and acidic proteases such as cathepsin K. The acid is generated by the combined actions of a vacuolar H+ ATPase (red arrow), its coupled Clâ channel (pink box), and a basolateral chlorideâbicar-bonate exchanger. Carbonic anhydrase converts CO2 and H2O into H+ and HCO3
â. Solubilized mineral components are released when the cell migrates; organic degradation products are partially released similarly and partially trans-cytosed to the basolateral surface for release.
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Theâfactâthatâdysfunctionâofâtheâprotonâpump,âClââchannel,âorâcathepsinâKâresultsâinâhumanâdiseasesâofâexcessâboneâmass,ânamelyâosteopetrosisâorâpyknodysostosisâ(58,â62),âattestsâtoâtheirâcriticalâroleâinâosteoclastâfunction.
Thisâ modelâ ofâ boneâ degradationâ requiresâ closeâ appositionâbetweenâtheâosteoclastâandâbone,âaâroleâprovidedâbyâintegrinsâinâtheâformâofâαÎČâheterodimersâ(63).âConsistentâwithâtheâfactâthatâαvÎČ3âisâtheâprincipalâintegrinâinâosteoclasts,âÎČ3
â/ââmiceâareâhypo-calcemicâandâgenerateâfewerâandâshallowerâresorptiveâlacunaeâonâdentinâslicesâthanâdoâtheirâwild-typeâcounterpartsâ(62).âBasedâonâtheseâandâmanyâinâvitroâobservations,âsmall-moleculeâinhibitorsâofâosteoclastâfunctionâthatâtargetâαvÎČ3âareâinâdevelopmentâ(64).
Integrinâactivationâmediatesâbothâcellularâadhesionâandâtrans-membraneâsignalingâ(65).âImportantâdownstreamâtransducersâincludeâtheâproto-oncogeneâc-src,âimportantâforâmembraneâruf-flingâandâosteoclastâmigrationâ(66),âandâRacâandâRho,âmembersâofâaâsmallâsubfamilyâofâtheâsmallâGTPaseâsuperfamilyâthatâareâcentralâtoâremodelingâofâtheâactinâcytoskeletonâinâmanyâcellâtypesâ(67)âandâplayâaâsimilarâroleâinâosteoclasticâboneâresorptionâ(68).âItâisânowâclearâthatâbisphosphonatesâblockâboneâresorptionâbyâinhibitingâmembraneâtargetingâofâaânumberâofâsmallâGTPasesâ(69).
Regulators of osteoclast functionSmall molecules.âTheâsteroidâhormoneâ1,25(OH)2D3playsâaâmajorâroleâinâregulatingâcalciumâandâphosphateâhomeostasis.âDeficiencyâofâtheâhormoneâincreasesâboneâlossâbyâalteringâtheâRANKL/OPGâ
ratioâsecondaryâtoâhypocalcemiaâandâresultingâinâhyperparathy-roidismâ(61).âInâcontrast,âhighâlevelsâofâtheâsteroidâdirectlyâstimu-lateâmesenchymalâcellâexpressionâofâRANKLâandâsuppressesâthatâofâOPGâ(61)âasâwellâasâsuppressâtheâproosteoclastogenicâhormoneâPTHâ(70).âAârecentâintriguingâstudyâidentifiesâaâvitaminâDâana-logâthatâpreventsâboneâlossâinâoophorectomizedâmiceâbyâinhibit-ingâRANKL-inducedâexpressionâofâc-Fos,âaâtranscriptionâfactorârequiredâforâosteoclastogenesisâ(71).
Bothâendogenousâglucocorticoidsâandâtheirâsyntheticâanalogs,âwhichâcontinueâtoâbeâaâmainstayâofâimmunosuppressiveâtherapy,âhaveâmajorâimpactsâonâboneâbiologyâ(38)âbecauseâofâsevereâosteo-porosisâarisingâfromâdecreasedâboneâformationâandâresorptionâ(low-turnoverâosteoporosis).âTheâmajorityâofâtheâevidenceâfocusesâonâtheâosteoblastâasâtheâprimeâtarget,âwithâglucocorticoidsâincreas-ingâapoptosisâofâtheseâbone-formingâcellsâ(72).âHowever,âhumanâstudiesâdocumentâaârapidâ initialâdecreaseâ inâboneâresorption,âsuggestingâthatâtheâosteoclastâand/orâitsâprecursorsâmayâalsoâbeâimpactedâbyâtheâsteroidâviaâanâill-definedâmechanism.âOneâpos-sibilityâisâthatâtheâapoptoticâimpactâonâosteoblastsâdecreasesâlocalâlevelsâofâRANKLâandâM-CSF.âAlternatively,âglucocorticoidsâhaveâbeenâshownâtoâdecreaseâosteoclastâapoptosisâ(73).
Aâwideârangeâofâclinicalâinformationâdemonstratesâthatâexcess prostaglandins stimulateâboneâlossâbyâtargetingâstromalâandâosteoblasticâcells,âthusâstimulatingâexpressionâofâRANKLâandâsuppressingâthatâofâOPGâ(33).âThisâincreaseâinâtheâRANKL/OPGâratioâ isâ sufficientâ inâ itselfâ toâexplainâtheâclinicalâ findingsâofâ
Figure 4Role of cytokines, hormones, steroids, and prostaglandins in osteoclast formation. Under the influence of other cytokines (not shown), an HSC commits to the myeloid lineage, expresses the M-CSF receptor colony-stimulating factor receptor 1 (c-Fms) and then, driven by M-CSF/c-Fms signaling and the RANKL receptor RANK, differentiates into an osteoclast. Mesenchymal cells in the marrow respond to a range of hormonal and cytokine stimuli, secreting a mixture of pro- and antiosteoclastogenic proteins, the latter primarily being OPG. Glucocorticoids (GCs) suppress bone resorption indirectly (by inducing death of osteoblasts) but possibly also target osteoclasts and/or their precursors. Estrogen (E2) inhibits secretion of RANKL and TNF-α by T cells via a complex mechanism (not shown); the sex steroid also inhibits osteoclast function.
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increasedâosteoclasticâactivity.âHowever,âhighlightingâagainâtheâdilemmaâofâinterpretingâinâvitroâstudies,âprostaglandinsâregulateâosteoclastogenesisâperâseâinâmurineâcellâculturesâbutâhaveâana-bolicâconsequencesâinâvivoâ(74).
Proteins.âInâadditionâtoâM-CSFâandâRANKL,âseveralâproteinsâplayâimportantârolesâinâosteoclastâbiologyâ(Figureâ4).âOPG,âanâendogenousâRANKLâinhibitor,âisâsecretedâbyâmesenchymalâcellsâbothâbasallyâandâinâresponseâtoâotherâregulatoryâsignals,âinclud-ingâcytokinesâandâbone-targetingâsteroidsâ(61).âGeneticâdeletionâofâOPGâinâmiceâandâhumansâleadsâtoâprofoundâosteopetrosisâ(58,â75),âwhileâglobalâoverexpressionâofâtheâmoleculeâinâmiceâresultsâ inâ severeâ osteoporosisâ (58).â Importantly,â postmeno-pausalâwomenâexhibitâhigherâlevelsâofâRANKLâonâtheirâboneâmarrowâstroma,âandâtreatmentâwithâestrogenâreversesâthisâout-comeâ(76).âFinally,âaârecentâstudyâdemonstratesâthatâaâhuman-ized,âmonospecificâantibodyâtoâRANKLâincreasesâboneâlossâinâosteoporosisâpatientsâ(77).âTogether,âtheseâobservationsâindicateâthatâcirculatingâOPGâmodulatesâtheâbone-resorptiveâactivityâofâRANKLâandâsuggestâthatâtheâRANKL/OPGâratioâinâserumâwillâbecomeâaâclinicallyâimportantâindex.
ProinflammatoryâcytokinesâsuppressâOPGâexpressionâwhileâenhancingâthatâofâRANKLâ(61).âThusâmanyâpatientsâwithâosteo-lyticâdiseaseâhaveâalteredâserumâlevelsâofâRANKLâand/orâOPGâasâaâresultâofâhighâlevelsâofâTNF-α,âIL-1,âPTH,âorâPTHrP.âSerumâPTHâlevelsâareâincreasedâinâhyperparathyroidismâofâwhateverâetiology,âwhereasâPTHrPâisâsecretedâbyâbone-targetingâlungâandâbreastâcar-cinomasâ(50,â51).âAttestingâtoâtheâimportanceâofâTNF-α,âantibod-iesâagainstâtheâcytokineâorâaâsolubleâTNFâreceptorâIgGâfusionâproteinâpotentlyâsuppressâboneâlossâinâdisordersâofâinflammatoryâosteolysisâsuchâasârheumatoidâarthritisâ(78).âInâhumans,âanâIgGâfusionâproteinâcontainingâtheâactiveâcomponentâofâtheâIL-1ârecep-torâantagonistâenhancesâtheâabilityâofâantiâTNF-αâantibodiesâtoâdecreaseâboneâlossâinârheumatoidâarthritisâ(79).
OsteoimmunologyItâhasâbecomeâclearâoverâtheâpastâfewâyearsâthatâtheâimmuneâsystemâplaysâanâimportantâroleâinâboneâbiology;âperhapsânowhereâisâthisâmoreâevidentâthanâinâtheâworkâofâtheâPacificiâgroup.âInâthisâseries,âtheâReviewâbyâM.âNealeâWeitzmannâandâRobertoâPacificiâexploresâhowâestrogenâdeprivationâleadsâtoâboneâlossâ(80).âInâshort,âtheyâreportâthatâestrogen,âtheâmainâsexâsteroidâregulatingâboneâmassâinâbothâmenâandâwomenâ(81),âsuppressesâtheâcapacityâofâantigen-presentingâcellsâtoâstimulateâTâcellâactivation,âanâeventâthatânormallyâresultsâinâsecre-tionâofâaârangeâofâproresorptiveâcytokinesâincludingâTNF-α,âIL-6,âandâRANKL.âNotably,âinâthisâcircumstanceâRANKLâisâcleavedâfromâtheâcellâsurface.âTNF-αâandâIL-6âactâonâstromalâcellsâandâosteoclastâprecursorsâtoâenhanceâboneâresorptionâbyâregulatingâexpressionâofâpro-â(i.e.,âRANKLâandâM-CSF)âandâantiosteoclastogenicâ(i.e.,âOPG)âcytokinesâinâtheâcaseâofâmesenchymalâcellsâandâbyâsynergizingâwithâRANKLâitselfâinâtheâcaseâofâmyeloidâosteoclastâprecursors.
Whileâtheseâstudiesâunderscoreâtheâinterfaceâbetweenâboneâandâtheâimmuneâsystem,âtheyârepresentâonlyâaâfractionâofâtheâworkâinâtheââhotâânewâareaâofâosteoimmunology.âTheâelegantâworkâofâTakayanagiâandâcolleaguesâsuggestsâthatâIFN-Îłâisâanâimportantâsuppressorâofâosteoclastâformationâandâfunctionâ(82).âNeverthe-less,âtheseâfindingsâareâinâconflictâwithâinâvivoâobservationsâinâhumans,âincludingâtheâreportâthatâIFN-Îłâtreatmentâofâchildrenâwithâosteopetrosisâamelioratesâtheâdiseaseâ(83)âandâtheâfactâthatâaânumberâofâinâvivoâstudiesâindicateâthatâIFN-Îłâstimulatesâboneâresorptionâ (ref.â 84â andâ referencesâ therein).â Thisâ conundrumâ
highlightsâagainâtheâneedâtoâdiscriminateâbetweenâinâvitroâcul-tureâexperimentsâusingâsingleâcytokinesâandâresultsâinâvivo.âManyâadditionalâ reportsâhaveâ implicatedâotherâcytokinesâ inâregula-tionâofâtheâosteoclast,âincludingânumerousâILs,âGM-CSF,âIFN-Îł,âstromalâcellâderivedâfactorâ1,âMIP-1α,âandâMCPâ(85â88),âbutâatâthisâtimeâtheâresultsâareâeitherâcontradictory,âasâforâGM-CSFââinâ theâ murineâ versusâ humanâ systems,â orâ lackâ directâ proofâ inâhumans.âFutureâstudiesâareâlikelyâtoâclarifyâtheâcurrentlyâconfusingâdataâset.âFinally,âseveralâgroupsâhaveâprovidedâevidenceâthatâmol-eculesâtraditionallyâconsideredâasâsolelyâimmuneâreceptors,âsuchâasâDNAXâactivatingâproteinâofâ12âkDaâ(DAP12),âFcRÎłâandâtriggeringâreceptorsâexpressedâinâmyeloidâcells,âandâtheirâligandsâonâcellsâofâtheâstromalâandâmyeloid/lymphoidâlineages,âareâdownstreamâofâRANKLâandâM-CSFâsignalingâ(89,â90).âMutationsâinâDAP12âleadâtoâaârareâboneâdisease,âNasu-Hakolaâdisease,âinâwhichâpatientsâexhibitâboneâcystsâandâconcomitantâdemyelinationâ(91).
More than skin deep, and down to the boneFinally,âweâreturnâtoâtheâquestionâposedâinâtheâintroduction.âWhatâareâtheâcommonâlinksâbetweenâskinâandâbone?âOneârecur-ringâthemeâisâthatâWntsâareâimportantâandâexhibitâdiversityâinâfunctionâinâbothâtissues.âInâtheâskin,âWnts,âBMPs,âandâotherâsig-nalingâpathwaysâareârequiredâforâearlyâpatterningâandâforâmor-phogenesisâofâtheâskinâappendagesâincludingâhair,âteeth,ânails,âandâmammaryâglandsâ(28,â29).âLikewise,âinâbone,âWnts,âBMPs,âandâFGFsâareârequired,âamongâotherâfactors,âforâcriticalâaspectsâofâboneâdevelopment.âInâearlyâdevelopment,âtheâoverlyingâectodermâplaysâanâinstructiveâroleâandâsecretesâmorphogensâtoâtheâunderly-ingâboneâinâtheâformâofâtheâapicalâectodermalâridgeâduringâlimbâoutgrowthâ(92,â93).âInâtheâadult,âWntâsignalingâisâreprisedâagainâduringâtissueâhomeostasisâandâisâaâkeyâregulatorâofâtheâhairâcycleâasâwellâasâosteoblastâandâosteoclastâregulation.âBothâskinâandâboneâareâhomeâtoâspecializedâstemâcellânichesâthatâprovideâaâsafeâhavenâforâtheirârelevantâprogenitorâcellâpopulations.âThereâareâcommonâtranscriptionalâregulatorsâofâboneâandâskin,âsuchâasâtheâvitaminâDâreceptor,âwhoseâcascadeâofâdownstreamâeffectorsâareâclearlyâcrucialâinâbothâtissues,âsinceâmutationsâinâthisâgeneâcauseâprofoundâeffectsâinâtheâformâofâirreversibleâalopeciaâasâwellâasâricketsâ(94).âItâhasâalreadyâbeenâshownâthatâhairâfollicleâdermalâpapillaâcellsâcanâdifferentiateâintoâadipocyteâandâosteogenicâcellsâinâcultureâ(95),âandâfurther,âthatâtheyâcanârepopulateâtheâentireâhematopoieticâsystemâ(96).âTheâdermalâpapillaâisâeasilyâidentifiedâwithinâtheâskinâbyâitsâstrongâexpressionâofâalkalineâphosphatase,âgenerallyâconsideredâaâmarkerâofâboneâformationâ(97).âGivenâtheâanatomicalâproximityâofâtheâtwoâtissues,âitâisânotâbeyondâtheârealmâofâpossibilityâthatâaâcommonâadultâmesenchymalâprogeni-torâcellâpopulationâsupportsâbothâtheâskinâdermisâandâunder-lyingâbone.âDespiteâtheirâphenotypicâextremesâofâsoftnessâandâhardness,âfutureâstudiesâinâskinâandâboneâbiologyâmayârevealâthatâtheyâhaveâfarâmoreâinâcommonâthanâmeetsâtheâeye.
Addressâcorrespondenceâto:âF.âPatrickâRoss,âDepartmentâofâPathol-ogyâandâImmunology,âWashingtonâUniversityâSchoolâofâMedicine,âCampusâBoxâ8118,â660âSouthâEuclidâAvenue,âSt.âLouis,âMissouriâ63110,âUSA.âPhone:â(314)â454-8079;âFax:â(314)â454-5505;âE-mail:â[email protected].âOrâto:âAngelaâM.âChristiano,âDepartmentsâofâDermatologyâandâGeneticsâandâDevelopment,âColumbiaâUni-versity,â630âWestâ168thâStreet,âVC-1526,âNewâYork,âNewâYorkâ10032,âUSA.âPhone:â(212)â305-9565;âFax:â(212)â305-7391;âE-mail:â[email protected].
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review series introduction
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review series introduction
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