Perichondrium phenotype and border function are regulated by Ext1 and heparan sulfate in developing long bones: A mechanism likely deranged in Hereditary Multiple Exostoses

摘要

Duringlimbskeletogenesisthecartilaginouslongboneanlagenandtheirgrowthplatesbecomedelimitedbyperichondriumwithwhichtheyinteractfunctionally.Yet,littleisknownabouthow,despitebeingsointimatelyassociatedwithcartilage,perichondriumacquiresandmaintainsitsdistinctphenotypeandexertsitsborderfunction.BecauseperichondriumbecomesderangedandinterruptedbycartilaginousoutgrowthsinHereditaryMultipleExostoses(HME),apediatricdisordercausedbyemEXT/emmutationsandconsequentheparansulfate(HS)deficiency,weaskedwhetheremEXT/emgenesandHSnormallyhaverolesinestablishingitsphenotypeandfunction.Indeed,conditionalemExt1/emablationinperichondriumandlateralchondrocytesflankingtheepiphysealregionofmouseembryolongboneanlagenndash;aregionencompassingthegrooveofRanvierndash;causedectopiccartilageformation.AsimilarresponsewasobservedwhenHSfunctionwasdisruptedinlongboneanlagenexplantsbygenetic,pharmacologicalorenzymaticmeans,aresponseprecededbyectopicBMPsignalingwithinperichondrium.Thesetreatmentsalsotriggeredexcesschondrogenesisandcartilagenoduleformationandoverexpressionofchondrogenicandmatrixgenesinlimbbudmesenchymalcellsinmicromassculture.Interestingly,thetreatmentsdisruptedtheperipheraldefinitionandborderofthecartilagenodulesinsuchawaythatmanynodulesovergrewandfusedwitheachotherintolargeamorphouscartilaginousmasses.InterferencewithHSfunctionreducedthephysicalassociationandinteractionsofBMP2withHSandincreasedthecellresponsivenesstoendogenousandexogenousBMPproteins.Insum,emExt/emgenesandHSareneededtoestablishandmaintainperichondrium'sphenotypeandborderfunction,restrainpro-chondrogenicsignalingproteinsincludingBMPs,andrestrictchondrogenesis.AlterationsinthesemechanismsmaycontributetoexostosisformationinHME,particularlyattheexpenseofregionsrichinprogenitorcellsincludingthegrooveofRanvier./p/div