Dicer inactivation in osteoprogenitor cells compromises fetal survival and bone formation, while excision in differentiated osteoblasts increases bone mass in the adult mouse.
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.
Gaur
Tripti
T
Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Hussain
Sadiq
S
Mudhasani
Rajini
R
Parulkar
Isha
I
Colby
Jennifer L
JL
Frederick
Dana
D
Kream
Barbara E
BE
van Wijnen
Andre J
AJ
Stein
Janet L
JL
Stein
Gary S
GS
Jones
Stephen N
SN
Lian
Jane B
JB
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
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