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Mesenchyme-specific overexpression of nucleolar protein 66 in mice inhibits skeletal growth and bone formation

Qin Chen1, Liping Zhang2, Benoit de Crombrugghe2

  • 1*Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA; and Nephrology Division, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA qchen1@mdanderson.org.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|March 10, 2015
PubMed

Insights

Nucleolar protein 66 (NO66) overexpression in mesenchymal cells inhibits skeletal growth and bone formation by down-regulating the IGF1R/Akt signaling pathway. This study investigates NO66

Area of Science:

  • Molecular Biology
  • Developmental Biology
  • Epigenetics

Background:

  • Nucleolar protein 66 (NO66) is a histone demethylase that inhibits osteoblast differentiation in vitro.
  • The in vivo role of NO66 in mammalian skeletogenesis remains unclear.

Purpose of the Study:

  • To investigate the in vivo effects of NO66 overexpression on skeletal development in mice.
  • To elucidate the molecular mechanisms underlying NO66's regulation of bone formation.

Main Methods:

  • Generation of transgenic (TG) mice overexpressing a flag-tagged NO66 transgene under the Prx1 promoter.
  • Analysis of skeletal growth, bone formation, chondrocyte/osteoblast proliferation, and differentiation in NO66-TG mice.
  • Assessment of gene and protein expression, including Igf1, Igf1r, Runx2, Osx, phosphorylated Akt, and H3K36me3.
  • In vitro assays using C2C12 cells to confirm molecular correlations.

Main Results:

  • NO66 overexpression in Prx1-expressing mesenchymal cells significantly inhibited skeletal growth and bone formation.
  • A >50% decrease in chondrocyte/osteoblast proliferation and differentiation was observed in NO66-TG mice.
  • Expression of Igf1, Igf1r, Runx2, and Osx was significantly down-regulated in the bones of NO66-TG mice.
  • Reduced levels of phosphorylated Akt and H3K36me3 suggest an inverse correlation between NO66 activity and IGF1R/Akt signaling.

Conclusions:

  • Mesenchymal overexpression of NO66 inhibits skeletal growth and bone formation in vivo.
  • The observed inhibition is associated with reduced chondrocyte/osteoblast proliferation and differentiation.
  • Down-regulation of the IGF1R/Akt signaling pathway likely contributes to the inhibitory effects of NO66 on skeletal development.
Keywords:
IGF1R/Akt signaling pathwayhistone demethylaseosterixtransgenic mice

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