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Mesenchymal Deletion of Histone Demethylase NO66 in Mice Promotes Bone Formation
Author(s) -
Chen Qin,
Sinha Krishna,
Deng Jian Min,
Yasuda Hideyo,
Krahe Ralf,
Behringer Richard R,
de Crombrugghe Benoit
Publication year - 2015
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1002/jbmr.2494
Subject(s) - demethylase , mesenchymal stem cell , histone , cancer research , microbiology and biotechnology , chemistry , biology , genetics , dna
ABSTRACT 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. © 2015 American Society for Bone and Mineral Research.