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SIRT2 regulates extracellular vesicle-mediated liver-bone communication
Longshuai Lin1,2,3, Zengya Guo4, Enjun He2
1Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Nature Metabolism
|May 15, 2023
Summary
Researchers found that the protein SIRT2 in liver cells influences bone health. Reducing SIRT2 in the liver protects against bone loss by altering small extracellular vesicles (sEVs) and their cargo, LRG1, impacting osteoclast formation.
Area of Science:
- Metabolism
- Endocrinology
- Cell Biology
Background:
- The relationship between liver and bone metabolism is not well understood.
- Hepatocyte SIRT2 expression increases with age in mice and humans.
- Osteoporosis is a significant health concern linked to aging.
Purpose of the Study:
- To investigate the role of hepatocyte SIRT2 in liver-bone crosstalk.
- To identify mechanisms by which the liver influences bone metabolism.
- To explore potential therapeutic targets for osteoporosis.
Main Methods:
- Utilized mouse models with liver-specific SIRT2 deficiency.
- Analyzed small extracellular vesicles (sEVs) from hepatocytes.
- Investigated the effect of LRG1 on osteoclast differentiation in vitro and in vivo.
- Correlated plasma sEV LRG1 levels with bone mineral density in humans.
Main Results:
- Liver-specific SIRT2 deficiency inhibited osteoclastogenesis and bone loss in osteoporosis models.
- LRG1 was identified as a cargo in hepatocyte-derived sEVs, with levels upregulated in SIRT2-deficient hepatocytes.
- Upregulated sEV LRG1 inhibited osteoclast differentiation by reducing NF-κB p65 nuclear translocation.
- Treatment with LRG1-enriched sEVs attenuated bone loss in mice and inhibited osteoclast differentiation in human cells.
Conclusions:
- Hepatocyte SIRT2 regulates liver-bone crosstalk via sEV-mediated LRG1 transfer.
- LRG1 delivered by sEVs inhibits osteoclast differentiation, offering a potential therapeutic avenue for osteoporosis.
- Targeting hepatocyte-osteoclast communication presents a promising strategy for treating primary osteoporosis.
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