Glutathione limits RUNX2 oxidation and degradation to regulate bone formation
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:8 |
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| Enthalten in: |
JCI insight - 8(2023), 16 vom: 22. Aug. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Hu, Guoli [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 23.08.2023 Date Revised 10.02.2024 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1172/jci.insight.166888 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM359337309 |
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| 245 | 1 | 0 | |a Glutathione limits RUNX2 oxidation and degradation to regulate bone formation |
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| 500 | |a Date Revised 10.02.2024 | ||
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Amino acid metabolism | |
| 650 | 4 | |a Bone Biology | |
| 650 | 4 | |a Bone development | |
| 650 | 4 | |a Osteoclast/osteoblast biology | |
| 650 | 7 | |a Reactive Oxygen Species |2 NLM | |
| 650 | 7 | |a Core Binding Factor Alpha 1 Subunit |2 NLM | |
| 650 | 7 | |a Glutathione |2 NLM | |
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| 700 | 1 | |a Yu, Yilin |e verfasserin |4 aut | |
| 700 | 1 | |a Sharma, Deepika |e verfasserin |4 aut | |
| 700 | 1 | |a Pruett-Miller, Shondra M |e verfasserin |4 aut | |
| 700 | 1 | |a Ren, Yinshi |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Guo-Fang |e verfasserin |4 aut | |
| 700 | 1 | |a Karner, Courtney M |e verfasserin |4 aut | |
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