FTO SUMOylation regulates the differentiation of bone marrow mesenchymal stromal cells in inflammatory bowel disease-induced bone loss.

IF 7.5 1区生物学 Q1 CELL BIOLOGY

Cell reports Pub Date : 2025-07-04 DOI:10.1016/j.celrep.2025.115953

Haoming Wang, Jiandong Guo, Lijun Li, Hongwei Xie, Jiateng Zhang, Wanda Zhang, Ying Liu, Qingliang Ma, Shiyu Wang, Putao Yuan, Zhiwei Jie, Shunwu Fan, Ziang Xie

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Abstract

The gut-bone axis is critical for body homeostasis, but bone loss often complicates inflammatory bowel disease (IBD) with unclear mechanisms. Here, we found that IBD mice showed reduced bone formation, with bone marrow mesenchymal stromal cells (BMSCs) favoring adipogenesis over osteogenesis. Altered N⁶-methyladenosine (m⁶A) modifications of BMSCs were confirmed in IBD mice, and further investigation revealed that the SUMOylation of FTO was involved. Nude mice with FTO-K216/357/365R mutation exhibited increased bone sizes and volumes versus control mice. Tocilizumab, an interleukin (IL)-6R monoclonal antibody, combined with AAV-FTO-3KR, mitigated bone loss and enhanced bone formation in IBD mice. Our findings reveal that SUMOylation of FTO is involved in the differentiation of BMSCs in mice with IBDs. The outcome could be blocked by redirecting differentiation toward osteoblast treatment with AAV-FTO-3KR and the clinical-stage inhibitor, tocilizumab.

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FTO SUMOylation调节炎症性肠病诱导的骨质流失中骨髓间充质细胞的分化。

肠-骨轴对体内稳态至关重要，但骨丢失常使炎症性肠病（IBD）并发症，机制尚不清楚。在这里，我们发现IBD小鼠的骨形成减少，骨髓间充质间质细胞（BMSCs）倾向于脂肪生成而不是骨生成。在IBD小鼠中证实了骨髓间充质干细胞n6 -甲基腺苷（m6A）修饰的改变，进一步的研究表明FTO的sumo化参与其中。FTO-K216/357/365R突变裸鼠的骨大小和体积比对照小鼠增加。Tocilizumab是一种白细胞介素(IL)-6R单克隆抗体，与AAV-FTO-3KR联合使用，可减轻IBD小鼠的骨质流失并增强骨形成。我们的研究结果表明，FTO的summoylation参与了ibd小鼠骨髓间充质干细胞的分化。通过使用AAV-FTO-3KR和临床期抑制剂tocilizumab将分化转向成骨细胞治疗，可以阻断这一结果。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.