Endothelial cell-derived lactate triggers mesenchymal stem cell histone lactylation to attenuate osteoporosis

Wu, J.; Hu, M.; Jiang, H.; ma, j.; Xie, C.; Zhang, Z.; Zhou, X.; Zhao, J.; Tao, Z.; Meng, Y.; Cai, Z.; Song, T.; Zhang, C.; Gao, R.; Song, H.; Gao, Y.; Lin, T.; Wang, C.

doi:10.1101/2023.03.06.531262

bioRxiv · 10.1101/2023.03.06.531262

Endothelial cell-derived lactate triggers mesenchymal stem cell histone lactylation to attenuate osteoporosis

Wu, J.·Hu, M.·Jiang, H.·ma, j.·Xie, C.·Zhang, Z.·Zhou, X.·Zhao, J.·Tao, Z.·Meng, Y.·Cai, Z.·Song, T.·Zhang, C.·Gao, R.·Song, H.·Gao, Y.·Lin, T.·Wang, C.

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Abstract

Blood vessels play a role in osteogenesis and osteoporosis; however, the role of vascular metabolism is unclear. The present study found that ovariectomized mice exhibit reductions in bone blood vessel density and expression of endothelial glycolytic regulator pyruvate kinase M2 (PKM2). Additional data showed that endothelial cell (EC)-specific deletion of Pkm2 impair osteogenesis and worsen osteoporosis in mice. This was attributed to the impaired differentiation ability toward osteoblast of bone mesenchymal stem cells (BMSCs). Mechanistically, EC-specific deletion of Pkm2 reduce serum lactate levels secreted by ECs, which affect histone lactylation of BMSCs. We identified collagen type I alpha 2 chain, cartilage oligomeric matrix protein, ectonucleotide pyrophosphatase/phosphodiesterase 1, and transcription factor 7 like 2 as histone H3K18 lactylation-regulated osteogenic genes using joint CUT&Tag and RNA-sequencing analyses. The overexpression of PKM2 in ECs, addition of lactate, and exercise were observed to restore the phenotype of endothelial Pkm2-deficient mice. Furthermore, metabolomics of the serum indicated that osteoporosis patients showed a relatively low lactate level. The histone lactylation and related osteogenic genes of BMSCs in osteoporosis patients also decreased. In conclusion, the glycolysis of ECs fuels the differentiation of BMSCs into osteoblasts through histone lactylation, and exercise partially ameliorates osteoporosis through increased serum lactate.

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Wu, J., Hu, M., Jiang, H., ma, j., Xie, C., Zhang, Z., Zhou, X., Zhao, J., Tao, Z., Meng, Y., Cai, Z., Song, T., Zhang, C., Gao, R., Song, H., Gao, Y., Lin, T., Wang, C.. 2023-03-06. Endothelial cell-derived lactate triggers mesenchymal stem cell histone lactylation to attenuate osteoporosis. https://doi.org/10.1101/2023.03.06.531262

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