title: Dicer inactivation in osteoprogenitor cells compromises fetal survival and bone formation, while excision in differentiated osteoblasts increases bone mass in the adult mouse.
abstract: MicroRNA attenuation of protein translation has emerged as an important regulator of mesenchymal cell differentiation into the osteoblast lineage. A compelling question is the extent to which miR biogenesis is obligatory for bone formation. Here we show conditional deletion of the Dicer enzyme in osteoprogenitors by Col1a1-Cre compromised fetal survival after E14.5. A mechanism was associated with the post-commitment stage of osteoblastogenesis, demonstrated by impaired ECM mineralization and reduced expression of mature osteoblast markers during differentiation of mesenchymal cells of ex vivo deleted Dicer(c/c). In contrast, in vivo excision of Dicer by Osteocalcin-Cre in mature osteoblasts generated a viable mouse with a perinatal phenotype of delayed bone mineralization which was resolved by 1 month. However, a second phenotype of significantly increased bone mass developed by 2 months, which continued up to 8 months in long bones and vertebrae, but not calvariae. Cortical bone width and trabecular thickness in Dicer(Deltaoc/Deltaoc) was twice that of Dicer(c/c) controls. Normal cell and tissue organization was observed. Expression of osteoblast and osteoclast markers demonstrated increased coupled activity of both cell types. We propose that Dicer generated miRs are essential for two periods of bone formation, to promote osteoblast differentiation before birth, and control bone accrual in the adult.
authors.affiliation: Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Tripti
authors.initials: T
authors.lastname: Gaur
authors.forename: Sadiq
authors.initials: S
authors.lastname: Hussain
authors.forename: Rajini
authors.initials: R
authors.lastname: Mudhasani
authors.forename: Isha
authors.initials: I
authors.lastname: Parulkar
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Colby
authors.forename: Dana
authors.initials: D
authors.lastname: Frederick
authors.forename: Barbara E
authors.initials: BE
authors.lastname: Kream
authors.forename: Andre J
authors.initials: AJ
authors.lastname: van Wijnen
authors.forename: Janet L
authors.initials: JL
authors.lastname: Stein
authors.forename: Gary S
authors.initials: GS
authors.lastname: Stein
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Jones
authors.forename: Jane B
authors.initials: JB
authors.lastname: Lian
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D016922:Cellular Senescence; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D053487:DEAD-box RNA Helicases / Q000235:genetics* / Q000378:metabolism; D004622:Embryo, Mammalian / Q000378:metabolism; D004722:Endoribonucleases / Q000235:genetics* / Q000378:metabolism; D005804:Genes, Lethal; D051379:Mice; D008815:Mice, Inbred Strains; D010006:Osteoblasts / Q000378:metabolism*; D010012:Osteogenesis / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D043244:Ribonuclease III; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D012333:RNA, Messenger; D004722:Endoribonucleases; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases