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Glutathione limits RUNX2 oxidation and degradation to regulate bone formation.

Publication ,  Journal Article
Hu, G; Yu, Y; Sharma, D; Pruett-Miller, SM; Ren, Y; Zhang, G-F; Karner, CM
Published in: JCI Insight
August 22, 2023

Reactive oxygen species (ROS) are natural products of mitochondrial oxidative metabolism and oxidative protein folding. ROS levels must be well controlled, since elevated ROS has been shown to have deleterious effects on osteoblasts. Moreover, excessive ROS is thought to underlie many of the skeletal phenotypes associated with aging and sex steroid deficiency in mice and humans. The mechanisms by which osteoblasts regulate ROS and how ROS inhibits osteoblasts are not well understood. Here, we demonstrate that de novo glutathione (GSH) biosynthesis is essential in neutralizing ROS and establish a proosteogenic reduction and oxidation reaction (REDOX) environment. Using a multifaceted approach, we demonstrate that reducing GSH biosynthesis led to acute degradation of RUNX2, impaired osteoblast differentiation, and reduced bone formation. Conversely, reducing ROS using catalase enhanced RUNX2 stability and promoted osteoblast differentiation and bone formation when GSH biosynthesis was limited. Highlighting the therapeutic implications of these findings, in utero antioxidant therapy stabilized RUNX2 and improved bone development in the Runx2+/- haplo-insufficient mouse model of human cleidocranial dysplasia. Thus, our data establish RUNX2 as a molecular sensor of the osteoblast REDOX environment and mechanistically clarify how ROS negatively impacts osteoblast differentiation and bone formation.

Duke Scholars

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Published In

JCI Insight

DOI

EISSN

2379-3708

Publication Date

August 22, 2023

Volume

8

Issue

16

Location

United States

Related Subject Headings

  • Reactive Oxygen Species
  • Oxidation-Reduction
  • Osteogenesis
  • Mice
  • Humans
  • Glutathione
  • Core Binding Factor Alpha 1 Subunit
  • Animals
  • 42 Health sciences
  • 32 Biomedical and clinical sciences
 

Citation

APA
Chicago
ICMJE
MLA
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Hu, G., Yu, Y., Sharma, D., Pruett-Miller, S. M., Ren, Y., Zhang, G.-F., & Karner, C. M. (2023). Glutathione limits RUNX2 oxidation and degradation to regulate bone formation. JCI Insight, 8(16). https://doi.org/10.1172/jci.insight.166888
Hu, Guoli, Yilin Yu, Deepika Sharma, Shondra M. Pruett-Miller, Yinshi Ren, Guo-Fang Zhang, and Courtney M. Karner. “Glutathione limits RUNX2 oxidation and degradation to regulate bone formation.JCI Insight 8, no. 16 (August 22, 2023). https://doi.org/10.1172/jci.insight.166888.
Hu G, Yu Y, Sharma D, Pruett-Miller SM, Ren Y, Zhang G-F, et al. Glutathione limits RUNX2 oxidation and degradation to regulate bone formation. JCI Insight. 2023 Aug 22;8(16).
Hu, Guoli, et al. “Glutathione limits RUNX2 oxidation and degradation to regulate bone formation.JCI Insight, vol. 8, no. 16, Aug. 2023. Pubmed, doi:10.1172/jci.insight.166888.
Hu G, Yu Y, Sharma D, Pruett-Miller SM, Ren Y, Zhang G-F, Karner CM. Glutathione limits RUNX2 oxidation and degradation to regulate bone formation. JCI Insight. 2023 Aug 22;8(16).

Published In

JCI Insight

DOI

EISSN

2379-3708

Publication Date

August 22, 2023

Volume

8

Issue

16

Location

United States

Related Subject Headings

  • Reactive Oxygen Species
  • Oxidation-Reduction
  • Osteogenesis
  • Mice
  • Humans
  • Glutathione
  • Core Binding Factor Alpha 1 Subunit
  • Animals
  • 42 Health sciences
  • 32 Biomedical and clinical sciences