Glutathione limits RUNX2 oxidation and degradation to regulate bone formation

JCI Insight · 7 authors, 7 centres

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TL;DR

This preclinical study used mouse models and cell experiments to show that glutathione protects the bone-forming transcription factor RUNX2 from oxidative degradation. When glutathione is limited, RUNX2 is degraded, leading to impaired osteoblast differentiation and reduced bone formation.

Full summary

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The central finding is that de novo GSH biosynthesis is essential for neutralizing ROS and establishing a proosteogenic REDOX environment. Conversely, reducing ROS with catalase stabilized RUNX2 and rescued osteoblast differentiation even when GSH was limited. In a mouse model of cleidocranial dysplasia (Runx2 haploinsufficiency), in utero antioxidant therapy stabilized RUNX2 and improved bone development. The findings imply that metabolic strategies targeting GSH synthesis or ROS scavenging could be potential therapeutic avenues for conditions of low bone mass.

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other

SPECIALTY

preclinical research

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ORIGINAL PAPER

PMC10543723

Glutathione limits RUNX2 oxidation and degradation to regulate bone formation

JCI Insight

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ABSTRACT

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.

CITATION EXPORT

Guoli Hu, Yilin Yu, Deepika Sharma et al.. Glutathione limits RUNX2 oxidation and degradation to regulate bone formation. JCI Insight. (2023). https://doi.org/10.1172/jci.insight.166888

AUTHORS

7 · 7 CENTRES

Guoli Hu, Yilin Yu, Deepika Sharma, Shondra M. Pruett-Miller, Yinshi Ren, Guo-Fang Zhang, Courtney M. Karner

1Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
2Department of Orthopaedic Surgery, Duke University School of Medicine, Durham, North Carolina, USA.
3Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA.
4Center for Excellence in Hip Disorders, Texas Scottish Rite Hospital for Children, Dallas, Texas, USA.
5Department of Medicine, Division of Endocrinology, Metabolism Nutrition, and
6Sarah W. Stedman Nutrition and Metabolism Center & Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, USA.
7Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA.