Dicer inactivation in osteoprogenitor cells compromises fetal survival and bone formation, while excision in differentiated osteoblasts increases bone mass in the adult mouse

摘要

MicroRNAattenuationofproteintranslationhasemergedasanimportantregulatorofmesenchymalcelldifferentiationintotheosteoblastlineage.AcompellingquestionistheextenttowhichmiRbiogenesisisobligatoryforboneformation.HereweshowconditionaldeletionoftheemDicer/emenzymeinosteoprogenitorsbyemCol1a1/em-CrecompromisedfetalsurvivalafterE14.5.Amechanismwasassociatedwiththepost-commitmentstageofosteoblastogenesis,demonstratedbyimpairedECMmineralizationandreducedexpressionofmatureosteoblastmarkersduringdifferentiationofmesenchymalcellsofexvivodeletedDicersupc/c/sup.Incontrast,invivoexcisionofemDicer/embyemOsteocalcin/em-Creinmatureosteoblastsgeneratedaviablemousewithaperinatalphenotypeofdelayedbonemineralizationwhichwasresolvedby1#xA0;month.However,asecondphenotypeofsignificantlyincreasedbonemassdevelopedby2#xA0;months,whichcontinuedupto8#xA0;monthsinlongbonesandvertebrae,butnotcalvariae.CorticalbonewidthandtrabecularthicknessinDicersupΔoc/Δoc/supwastwicethatofDicersupc/c/supcontrols.Normalcellandtissueorganizationwasobserved.Expressionofosteoblastandosteoclastmarkersdemonstratedincreasedcoupledactivityofbothcelltypes.WeproposethatDicergeneratedmiRsareessentialfortwoperiodsofboneformation,topromoteosteoblastdifferentiationbeforebirth,andcontrolboneaccrualintheadult./p/div