LDHA promotes osteoblast differentiation through histone lactylation

Nian, Feige; Qian, Yezhou; Xu, Fan; Yang, Mo; Wang, Hongzhi; Zhang, Zhufeng

doi:10.1016/j.bbrc.2022.05.028

Cited by 37 publications

(33 citation statements)

References 19 publications

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“…Recent studies have revealed that histone lactylation occurs widely in human and mouse cells, and controls microglial function, cardiac repair, tumor progression, and inflammation[13b, 16, 31]. During osteoblast differentiation, histone lactylation of the mouse osteoblast precursor cell line increased, suggesting that histone lactylation may participate in osteogenesis[14]. Our data showed that decreased pan-Kla and H3K18la lactylation were observed in BMSCs isolated from PSkm2 ΔEC and OVX mice.…”

Section: Discussionsupporting

confidence: 50%

“…Lactate-derived lactylation of histone lysine residues serves as epigenetic modification to stimulate gene transcription[13]. Histone lactylation of mouse osteoblast precursor cell line increased during osteoblast differentiation, indicating that lactylation played a role in osteogenesis[14]. Pyruvate kinase catalyzes the final rate-limiting step of glycolysis, thus generating ATP and pyruvate, which is then catalyzed by lactate dehydrogenase A (LDHA) to lactate[15].…”

Section: Introductionmentioning

confidence: 99%

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

Jiang

et al. 2023

Preprint

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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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Section: Discussionsupporting

confidence: 50%

Section: Introductionmentioning

confidence: 99%

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

Jiang

et al. 2023

Preprint

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“…Knockdown of LDHA impairs mineralized nodule formation and ALP activity. 18 In our research, we observed an evident lactate production. Besides, the RNA sequencing results proved the upregulation of LDHA in the cementoblast mineralization.…”

Section: Introductionsupporting

confidence: 60%

Glycometabolic reprogramming in cementoblasts: A vital target for enhancing cell mineralization

Wang,

Peng,

Huang

et al. 2023

The FASEB Journal

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Cementum, a constituent part of periodontal tissues, has important adaptive and reparative functions. It serves to attach the tooth to alveolar bone and acts as a barrier delimit epithelial growth and bacteria evasion. A dynamic and highly responsive cementum is essential for maintaining occlusal relationships and the integrity of the root surface. It is a thin layer of mineralized tissue mainly produced by cementoblasts. Cementoblasts are osteoblast‐like cells essential for the restoration of periodontal tissues. In recent years, glucose metabolism has been found to be critical in bone remodeling and osteoblast differentiation. However, the glucose metabolism of cementoblasts remains incompletely understood. First, immunohistochemistry staining and in vivo tracing with 18F‐fluorodeoxyglucose (18F‐FDG) revealed significantly higher glucose metabolism in cementum formation. To test the bioenergetic pathways of cementoblast differentiation, we compared the bioenergetic profiles of mineralized and unmineralized cementoblasts. As a result, we observed a significant increase in the consumption of glucose and production of lactate, coupled with the higher expression of glycolysis‐related genes. However, the expression of oxidative phosphorylation‐related genes was downregulated. The verified results were consistent with the RNA sequencing results. Likewise, targeted energy metabolomics shows that the levels of glycolytic metabolites were significantly higher in the mineralized cementoblasts. Seahorse assays identified an increase in glycolytic flux and reduced oxygen consumption during cementoblast mineralization. Apart from that, we also found that lactate dehydrogenase A (LDHA), a key glycolysis enzyme, positively regulates the mineralization of cementoblasts. In summary, cementoblasts mainly utilized glycolysis rather than oxidative phosphorylation during the mineralization process.

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“…The LDH assay was performed to measure the intracellular LDH in hAECs at the days 0 and 14. LDH was recognized as a marker of progression in osteogenic differentiation [ 26 ] . The incubated hAM tissues were washed thoroughly with cold PBS and suspended in cold LDH assay buffer (Abcam).…”

Section: Methodsmentioning

confidence: 99%

Osteogenic Differentiation Effect of BMP-9 with Phenamil and Simvastatin on Intact Human Amniotic Epithelial Stem Cells

Ahmadi

Ebadi

Tayebi

et al. 2022

IBJ

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Background: Bone tissue engineering has shown to be a promising strategy for repairing bone defects without causing harmful side effects to the patient. Three main building blocks of tissue engineering, including seeding cells, scaffold, and signaling molecules, are required for adequate bone regeneration. The hAM is the innermost of the placental membranes. In addition to providing a source of stem cells and growth factors, hAM has several features that make it an appropriate scaffold containing stem cells for use in tissue engineering purposes. The present investigation aimed to assess the effect of BMP-9 combined with phenamil and simvastatin on osteogenic induction of hAM with its hAECs. Methods: Using six different OMs, we cultured hAM for 14 days. The basic OMs were chosen as the first group and other media were made by adding BMP-9, phenamil, simvastatin, BMP-9 alongside phenamil, and BMP-9 alongside simvastatin to the basic OMs. Finally, viability assay, tissue mineralization, calcium and phosphate content determination, and measurement of LDH, and ALP activity were performed.Results: Among all study groups, groups containing simvastatin showed a significantly lower level of viability. Although all media could induce osteogenic features, the hAECs cultured in media containing BMP-9 and phenamil demonstrated a wider area of mineralization and a significantly higher level of calcium and phosphate content, LDH, and ALP activity. Conclusion: Our findings indicated that the use of phenamil together with BMP-9 could synergistically show in situ osteogenic induction in hAECs, which could be a new insight into translational medicine.

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LDHA promotes osteoblast differentiation through histone lactylation

Cited by 37 publications

References 19 publications

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

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

Glycometabolic reprogramming in cementoblasts: A vital target for enhancing cell mineralization

Osteogenic Differentiation Effect of BMP-9 with Phenamil and Simvastatin on Intact Human Amniotic Epithelial Stem Cells

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