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

• DOI: 10.1002/advs.202301300
• Publication Date: 2023-09-27T06:07:54Z
• Authors: Jinhui Wu; Miao Hu; Heng Jiang; Jun Ma; Chong Xie; Zheng Zhang; Xin Zhou; Jianquan Zhao; Zhengbo Tao; Yichen Meng; Zhuyun Cai; Tengfei Song; Chenglin Zhang; Rui Gao; Chang Cai; Hongyuan Song; Yang Gao; Tao Lin; Ce Wang; Xuhui Zhou
• Keywords: PKM2

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