Mesenchymal Deletion of Histone Demethylase NO66 in Mice Promotes Bone Formation.
Our previous studies indicated that the Jumonji C (JmjC)-domain-containing NO66 is a histone demethylase with specificity for methylated histone H3K4 and H3K36. NO66 binds to the transcription factor Osterix (Osx) and inhibits its transcriptional activity in promoter assays. However, the physiological role of NO66 in formation of mammalian bones is unknown. Here, using a genetically engineered mouse model, we show that during early skeletal development, Prx1-Cre-dependent mesenchymal deletion of NO66 promotes osteogenesis and formation of both endochondral as well as intramembranous skeletal elements, leading to a larger skeleton and a high bone mass phenotype in adult mice. The excess bone formation in mice where NO66 was deleted in cells of mesenchymal origin is associated with an increase in the number of preosteoblasts and osteoblasts. Further analysis revealed that in the embryonic limbs and adult calvaria of mice with deletion of NO66 in cells of mesenchymal origin, expression of several genes including bone morphogenetic protein 2 (Bmp2), insulin-like growth factor 1 (Igf1), and osteoclast inhibitor osteoprotegerin was increased, concurrent with an increase in expression of bone formation markers such as osterix (Osx), type I collagen, and bone sialoprotein (Bsp). Taken together, our results provide the first in vivo evidence that NO66 histone demethylase plays an important role in mammalian osteogenesis during early development as well as in adult bone homeostasis. We postulate that NO66 regulates bone formation, at least in part, via regulating the number of bone-forming cells and expression of multiple genes that are critical for these processes.
Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Qin
Q
Chen
Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Krishna
K
Sinha
Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Jian Min
JM
Deng
Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Hideyo
H
Yasuda
Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Ralf
R
Krahe
Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Richard R
RR
Behringer
Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Benoit
B
de Crombrugghe
D016475:3T3 Cells; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism; D001842:Bone and Bones / Q000378:metabolism*; D002454:Cell Differentiation; D024042:Collagen Type I / Q000378:metabolism; D005260:Female; D005452:Fluoresceins / Q000737:chemistry; D017353:Gene Deletion; D005786:Gene Expression Regulation; D005838:Genotype; D006657:Histones / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D058574:Integrin-Binding Sialoprotein / Q000378:metabolism; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008648:Mesoderm / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000378:metabolism; D010012:Osteogenesis / Q000235:genetics*; D010641:Phenotype; D000076182:Sp7 Transcription Factor; D014157:Transcription Factors / Q000378:metabolism*; D055114:X-Ray Microtomography
C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D024042:Collagen Type I; D005452:Fluoresceins; D006657:Histones; C546872:Ibsp protein, mouse; D058574:Integrin-Binding Sialoprotein; D000076182:Sp7 Transcription Factor; C479466:Sp7 protein, mouse; D014157:Transcription Factors; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I; D056484:Jumonji Domain-Containing Histone Demethylases; C000600449:nucleolar protein 66, mouse; C007740:fluorexon
BONE FORMATION; DEVELOPMENT; KNOCKOUT MICE; NO66; Osx