Acetyl-CoA-dependent ac4C acetylation promotes the osteogenic differentiation of LPS-stimulated BMSCs

• Published in: International immunopharmacology 2024-05, Vol.133, p.112124, Article 112124
• Main Authors: Bai, Yujia, Zhang, Wenjie, Hao, Lili, Zhao, Yiqing, Tsai, I-Chen, Qi, Yipin, Xu, Qiong
• Format: Article
• Language: English
• Subjects: Ac4C; Acetyl-CoA; Bone marrow mesenchymal stem cells; Inflammation; Osteogenic differentiation
• ISSN: 1567-5769; 1878-1705; 1878-1705
• DOI: 10.1016/j.intimp.2024.112124

•The content of acetyl-CoA was downregulated during the osteogenic induction of BMSCs in the pro-inflammatory environment.•Acetyl-CoA-dependent ac4C modification promoted osteogenic differentiation of BMSCs.•Fatty acid oxidation was the functional consequence of NAT10-mediated ac4C acetylation.•Acetyl-CoA was effective in repair of LPS-induced bone defects in rats. The impaired osteogenic capability of bone marrow mesenchymal stem cells (BMSCs) caused by persistent inflammation is the main pathogenesis of inflammatory bone diseases. Recent studies show that metabolism is disturbed in osteogenically differentiated BMSCs in response to Lipopolysaccharide (LPS) treatment, while the mechanism involved remains incompletely revealed. Herein, we demonstrated that BMSCs adapted their metabolism to regulate acetyl-coenzyme A (acetyl-CoA) availability and RNA acetylation level, ultimately affecting osteogenic differentiation. The mitochondrial dysfunction and impaired osteogenic potential upon inflammatory conditions accompanied by the reduced acetyl-CoA content, which in turn suppressed N4-acetylation (ac4C) level. Supplying acetyl-CoA by sodium citrate (SC) addition rescued ac4C level and promoted the osteogenic capacity of LPS-treated cells through the ATP citrate lyase (ACLY) pathway. N-acetyltransferase 10 (NAT10) inhibitor remodelin reduced ac4C level and consequently impeded osteogenic capacity. Meanwhile, the osteo-promotive effect of acetyl-CoA-dependent ac4C might be attributed to fatty acid oxidation (FAO), as evidenced by activating FAO by L-carnitine supplementation counteracted remodelin-induced inhibition of osteogenesis. Further in vivo experiments confirmed the promotive role of acetyl-CoA in the endogenous bone regeneration in rat inflammatory mandibular defects. Our study uncovered a metabolic-epigenetic axis comprising acetyl-CoA and ac4C modification in the process of inflammatory osteogenesis of BMSCs and suggested a new target for bone tissue repair in the context of inflammatory bone diseases.