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Endothelial Cell‐Derived Lactate Triggers Bone Mesenchymal Stem Cell Histone Lactylation to Attenuate Osteoporosis

by Hu, Miao , Jiang, Heng , Zhao, Jianquan , Lin, Tao , Wu, Jinhui , Cai, Chang , Song, Tengfei , Gao, Rui , Gao, Yang , Zhou, Xin , Cai, Zhuyun , Xie, Chong , Wang, Ce , Zhang, Chenglin , Meng, Yichen , Song, Hongyuan , Zhang, Zheng , Tao, Zhengbo , Zhou, Xuhui , Ma, Jun

in Angiogenesis / Blood vessels / Bone density / Bone marrow / Cell growth / Exercise / Genotype & phenotype / histone lactylation / Kinases / lactate / metabolic reprogramming / Metabolism / Metabolites / Osteoporosis / vascular metabolism

2023

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Endothelial Cell‐Derived Lactate Triggers Bone Mesenchymal Stem Cell Histone Lactylation to Attenuate Osteoporosis

2023

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Endothelial Cell‐Derived Lactate Triggers Bone Mesenchymal Stem Cell Histone Lactylation to Attenuate Osteoporosis

2023

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Journal Article

Endothelial Cell‐Derived Lactate Triggers Bone Mesenchymal Stem Cell Histone Lactylation to Attenuate Osteoporosis

Hu, Miao,

Jiang, Heng,

Zhao, Jianquan,

Lin, Tao,

Wu, Jinhui,

Cai, Chang,

Song, Tengfei,

Gao, Rui,

Gao, Yang,

Zhou, Xin,

Cai, Zhuyun,

Xie, Chong,

Wang, Ce,

Zhang, Chenglin,

Meng, Yichen,

Song, Hongyuan,

Zhang, Zheng,

Tao, Zhengbo,

Zhou, Xuhui,

Ma, Jun

2023

Overview

Blood vessels play a role in osteogenesis and osteoporosis; however, the role of vascular metabolism in these processes remains unclear. The present study finds that ovariectomized mice exhibit reduced blood vessel density in the bone and reduced expression of the endothelial glycolytic regulator pyruvate kinase M2 (PKM2). Endothelial cell (EC)‐specific deletion of Pkm2 impairs osteogenesis and worsens osteoporosis in mice. This is attributed to the impaired ability of bone mesenchymal stem cells (BMSCs) to differentiate into osteoblasts. Mechanistically, EC‐specific deletion of Pkm2 reduces serum lactate levels secreted by ECs, which affect histone lactylation in BMSCs. Using joint CUT&Tag and RNA sequencing analyses, collagen type I alpha 2 chain (COL1A2), cartilage oligomeric matrix protein (COMP), ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), and transcription factor 7 like 2 (TCF7L2) as osteogenic genes regulated by histone H3K18la lactylation are identified. PKM2 overexpression in ECs, lactate addition, and exercise restore the phenotype of endothelial PKM2‐deficient mice. Furthermore, serum metabolomics indicate that patients with osteoporosis have relatively low lactate levels. Additionally, histone lactylation and related osteogenic genes of BMSCs are downregulated in patients with osteoporosis. In conclusion, glycolysis in ECs fuels BMSC differentiation into osteoblasts through histone lactylation, and exercise partially ameliorates osteoporosis by increasing serum lactate levels.

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Publisher

John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley

Subject

/ Genotype & phenotype