Fumarate Restrains Alveolar Bone Restoration via Regulating H3K9 Methylation

• Published in: Journal of dental research 2024-11, Vol.103 (12), p.1302-1312
• Main Authors: Zhang, Y.Y., Xiang, J., He, Y.Y., Liu, X., Ye, H.Y., Xu, L., Bai, H.L., Zhang, H., Zhang, H.M., Liu, W.Z., Zhai, Q.M., Ji, P., Cannon, R.D.
• Format: Article
• Language: English
• Subjects: Alveolar bone; Alveolar Process - drug effects; Alveolar Process - metabolism; Animals; Bone growth; Bone Regeneration - drug effects; Cell differentiation; Cell Differentiation - drug effects; Cells, Cultured; Chromatin; DNA methylation; Epigenesis, Genetic; Epigenetics; Fumarates - pharmacology; Gene silencing; Histones; Histones - metabolism; Humans; Immunoprecipitation; Inflammation; Jumonji Domain-Containing Histone Demethylases - metabolism; Ketoglutaric acid; Metabolic flux; Metabolism; Methylation - drug effects; Nerve Tissue Proteins - metabolism; Next-generation sequencing; Osteogenesis; Osteogenesis - drug effects; Periodontal diseases; Periodontal ligament; Periodontal Ligament - cytology; Periodontal Ligament - drug effects; Periodontal Ligament - metabolism; Regeneration; Stem cells; Stem Cells - drug effects; Stem Cells - metabolism; Transcriptomes; Transposase; Tricarboxylic acid cycle
• ISSN: 0022-0345; 1544-0591; 1544-0591
• DOI: 10.1177/00220345241279555

Nonresolving inflammation causes irreversible damage to periodontal ligament stem cells (PDLSCs) and impedes alveolar bone restoration. The impaired tissue regeneration ability of stem cells is associated with abnormal mitochondrial metabolism. However, the impact of specific metabolic alterations on the differentiation process of PDLSCs remains to be understood. In this study, we found that inflammation altered the metabolic flux of the tricarboxylic acid cycle and induced the accumulation of fumarate through metabolic testing and metabolic flux analysis. Transcriptome sequencing revealed the potential of fumarate in modulating epigenetics. Specifically, histone methylation typically suppresses the expression of genes related to osteogenesis. Fumarate was found to impede the osteogenic differentiation of PDLSCs that exhibited high levels of H3K9me3. Various techniques, including assay for transposase-accessible chromatin with high-throughput sequencing, chromatin immunoprecipitation sequencing, and RNA sequencing, were used to identify the target genes regulated by H3K9me3. Mechanistically, accumulated fumarate inhibited lysine-specific demethylase 4B (KDM4B) activity and increased H3K9 methylation, thus silencing asporin gene transcription. Preventing fumarate from binding to the histone demethylase KDM4B with α-ketoglutarate effectively restored the impaired osteogenic capacity of PDLSCs and improved alveolar bone recovery. Collectively, our research has revealed the significant impact of accumulated fumarate on the regulation of osteogenesis in stem cells, suggesting that inhibiting fumarate production could be a viable therapeutic approach for treating periodontal diseases.