{"title":"一碳代谢支持 s-腺苷蛋氨酸和 m6A 甲基化,从而控制 BMSCs 的成骨和骨形成。","authors":"Wenjie Zhang, Yujia Bai, Lili Hao, Yiqing Zhao, Lujin Zhang, Wenqian Ding, Yipin Qi, Qiong Xu","doi":"10.1093/jbmr/zjae121","DOIUrl":null,"url":null,"abstract":"<p><p>The skeleton is a metabolically active organ undergoing continuous remodeling initiated by bone marrow stem cells (BMSCs). Recent research has demonstrated that BMSCs adapt the metabolic pathways to drive the osteogenic differentiation and bone formation, but the mechanism involved remains largely elusive. Here, using a comprehensive targeted metabolome and transcriptome profiling, we revealed that one-carbon metabolism was promoted following osteogenic induction of BMSCs. Methotrexate (MTX), an inhibitor of one-carbon metabolism that blocks S-adenosylmethionine (SAM) generation, led to decreased N6-methyladenosine (m6A) methylation level and inhibited osteogenic capacity. Increasing intracellular SAM generation through betaine addition rescued the suppressed m6A content and osteogenesis in MTX-treated cells. Using S-adenosylhomocysteine (SAH) to inhibit the m6A level, the osteogenic activity of BMSCs was consequently impeded. We also demonstrated that the pro-osteogenic effect of m6A methylation mediated by one-carbon metabolism could be attributed to HIF-1α and glycolysis pathway. This was supported by the findings that dimethyloxalyl glycine rescued the osteogenic potential in MTX-treated and SAH-treated cells by upregulating HIF-1α and key glycolytic enzymes expression. Importantly, betaine supplementation attenuated MTX-induced m6A methylation decrease and bone loss via promoting the abundance of SAM in rat. Collectively, these results revealed that one-carbon metabolite SAM was a potential promoter in BMSC osteogenesis via the augmentation of m6A methylation, and the cross talk between metabolic reprogramming, epigenetic modification, and transcriptional regulation of BMSCs might provide strategies for bone regeneration.</p>","PeriodicalId":185,"journal":{"name":"Journal of Bone and Mineral Research","volume":" ","pages":"1356-1370"},"PeriodicalIF":5.1000,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"One-carbon metabolism supports S-adenosylmethionine and m6A methylation to control the osteogenesis of bone marrow stem cells and bone formation.\",\"authors\":\"Wenjie Zhang, Yujia Bai, Lili Hao, Yiqing Zhao, Lujin Zhang, Wenqian Ding, Yipin Qi, Qiong Xu\",\"doi\":\"10.1093/jbmr/zjae121\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>The skeleton is a metabolically active organ undergoing continuous remodeling initiated by bone marrow stem cells (BMSCs). Recent research has demonstrated that BMSCs adapt the metabolic pathways to drive the osteogenic differentiation and bone formation, but the mechanism involved remains largely elusive. Here, using a comprehensive targeted metabolome and transcriptome profiling, we revealed that one-carbon metabolism was promoted following osteogenic induction of BMSCs. Methotrexate (MTX), an inhibitor of one-carbon metabolism that blocks S-adenosylmethionine (SAM) generation, led to decreased N6-methyladenosine (m6A) methylation level and inhibited osteogenic capacity. Increasing intracellular SAM generation through betaine addition rescued the suppressed m6A content and osteogenesis in MTX-treated cells. Using S-adenosylhomocysteine (SAH) to inhibit the m6A level, the osteogenic activity of BMSCs was consequently impeded. We also demonstrated that the pro-osteogenic effect of m6A methylation mediated by one-carbon metabolism could be attributed to HIF-1α and glycolysis pathway. This was supported by the findings that dimethyloxalyl glycine rescued the osteogenic potential in MTX-treated and SAH-treated cells by upregulating HIF-1α and key glycolytic enzymes expression. Importantly, betaine supplementation attenuated MTX-induced m6A methylation decrease and bone loss via promoting the abundance of SAM in rat. Collectively, these results revealed that one-carbon metabolite SAM was a potential promoter in BMSC osteogenesis via the augmentation of m6A methylation, and the cross talk between metabolic reprogramming, epigenetic modification, and transcriptional regulation of BMSCs might provide strategies for bone regeneration.</p>\",\"PeriodicalId\":185,\"journal\":{\"name\":\"Journal of Bone and Mineral Research\",\"volume\":\" \",\"pages\":\"1356-1370\"},\"PeriodicalIF\":5.1000,\"publicationDate\":\"2024-09-02\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Bone and Mineral Research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1093/jbmr/zjae121\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ENDOCRINOLOGY & METABOLISM\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Bone and Mineral Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1093/jbmr/zjae121","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
One-carbon metabolism supports S-adenosylmethionine and m6A methylation to control the osteogenesis of bone marrow stem cells and bone formation.
The skeleton is a metabolically active organ undergoing continuous remodeling initiated by bone marrow stem cells (BMSCs). Recent research has demonstrated that BMSCs adapt the metabolic pathways to drive the osteogenic differentiation and bone formation, but the mechanism involved remains largely elusive. Here, using a comprehensive targeted metabolome and transcriptome profiling, we revealed that one-carbon metabolism was promoted following osteogenic induction of BMSCs. Methotrexate (MTX), an inhibitor of one-carbon metabolism that blocks S-adenosylmethionine (SAM) generation, led to decreased N6-methyladenosine (m6A) methylation level and inhibited osteogenic capacity. Increasing intracellular SAM generation through betaine addition rescued the suppressed m6A content and osteogenesis in MTX-treated cells. Using S-adenosylhomocysteine (SAH) to inhibit the m6A level, the osteogenic activity of BMSCs was consequently impeded. We also demonstrated that the pro-osteogenic effect of m6A methylation mediated by one-carbon metabolism could be attributed to HIF-1α and glycolysis pathway. This was supported by the findings that dimethyloxalyl glycine rescued the osteogenic potential in MTX-treated and SAH-treated cells by upregulating HIF-1α and key glycolytic enzymes expression. Importantly, betaine supplementation attenuated MTX-induced m6A methylation decrease and bone loss via promoting the abundance of SAM in rat. Collectively, these results revealed that one-carbon metabolite SAM was a potential promoter in BMSC osteogenesis via the augmentation of m6A methylation, and the cross talk between metabolic reprogramming, epigenetic modification, and transcriptional regulation of BMSCs might provide strategies for bone regeneration.
期刊介绍:
The Journal of Bone and Mineral Research (JBMR) publishes highly impactful original manuscripts, reviews, and special articles on basic, translational and clinical investigations relevant to the musculoskeletal system and mineral metabolism. Specifically, the journal is interested in original research on the biology and physiology of skeletal tissues, interdisciplinary research spanning the musculoskeletal and other systems, including but not limited to immunology, hematology, energy metabolism, cancer biology, and neurology, and systems biology topics using large scale “-omics” approaches. The journal welcomes clinical research on the pathophysiology, treatment and prevention of osteoporosis and fractures, as well as sarcopenia, disorders of bone and mineral metabolism, and rare or genetically determined bone diseases.