ESPEYB20 3. Bone, Growth Plate and Mineral Metabolism Advances in Growth, Bone Biology, and Mineral Metabolism (6 abstracts)
3.14. SIRT2 regulates extracellular vesicle-mediated liver-bone communication
Lin L , Guo Z , He E , Long X , Wang D , Zhang Y , Guo W , Wei Q , He W , Wu W , Li J , Wo L , Hong D , Zheng J , He M & Zhao Q
Nat Metab. 2023 May;5(5):821–841. doi: 10.1038/s42255-023-00803-0. PMID: 37188819. https://pubmed.ncbi.nlm.nih.gov/37188819/
In Brief: These authors studied liver-specific SIRT2 knockout mice to examine how loss of hepatocyte SIRT2 (Sirtuin 2) prevents bone loss in aged mice. Hepatocyte SIRT2 deficiency led to upregulation of Leucine rich α2 glycoprotein (LRG1) in hepatocyte-derived small extracellular vesicles (sEVs) which inhibited osteoclastogenesis in bone marrow.
Commentary: Liver-bone communication has been implicated in bone homeostasis. Patients with chronic liver disease show altered bone metabolism and often develop osteoporosis. SIRT2 encodes a deactelyase that is abundantly expressed in the liver and is involved in the regulation of multiple cellular processes such as aging, metabolism and inflammation, but its role in bone is unknown.
In this study, hepatocyte SIRT2 levels were found to be upregulated in aged mice and elderly humans. Liver-specific SIRT2 knockout mice (SIRT2-KOhep) mice at 18 months of age showed increased BV/TV, increased trabecular number and decreased trabecular separation than their control littermates which showed obvious bone loss. Plasma from aged SIRT2-KOhep mice suppressed in-vitro osteoclast differentiation and reduced the number of TRAP+ osteoclasts. Probing further, small extracellular vesicles (sEVs) isolated from SIRT2-KOhep plasma and co-cultured with bone marrow derived monocytes (BMDMs) inhibited osteoclast differentiation. Combining mass spectrometry and RNA sequencing to compare global plasma protein profiles, LRG1 was found to be increased in SIRT2-KOhep plasma sEVs and in the osteoclast progenitors of SIRT2-KOhep mice. Hepatic SIRT2-KOhep upregulated sEV-LRG1 transfer to BMDMs to suppress osteoclastogenesis by preventing NF-κβ p65 activation. Moreover, pharmacological treatment with a SIRT2 inhibitor or sEV-LRG1 was therapeutically beneficial in mouse models of osteoporosis and human primary cell cultures.
These findings illustrate a novel mechanism of hepatocyte-osteoclast communication, involving sEVs-LRG1 and SIRT2, wherein hepatic SIRT2 regulates osteoclastogenesis in the bone marrow. This insight may provide a novel therapeutic approach to treat osteoporosis.
Volume 20
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ESPE Yearbook of Paediatric Endocrinology
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