METTL7A-mediated m6A modification of corin reverses bisphosphonates-impaired osteogenic differentiation of orofacial BMSCs

IF 10.8 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE International Journal of Oral Science Pub Date : 2024-05-23 DOI:10.1038/s41368-024-00303-1
Yizhou Jin, Xiao Han, Yuejun Wang, Zhipeng Fan
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Abstract

Bisphosphonate-related osteonecrosis of jaw (BRONJ) is characterized by impaired osteogenic differentiation of orofacial bone marrow stromal cells (BMSCs). Corin has recently been demonstrated to act as a key regulator in bone development and orthopedic disorders. However, the role of corin in BRONJ-related BMSCs dysfunction remains unclarified. A m6A epitranscriptomic microarray study from our group shows that the CORIN gene is significantly upregulated and m6A hypermethylated during orofacial BMSCs osteogenic differentiation. Corin knockdown inhibits BMSCs osteogenic differentiation, whereas corin overexpression or soluble corin (sCorin) exerts a promotion effect. Furthermore, corin expression is negatively regulated by bisphosphonates (BPs). Corin overexpression or sCorin reverses BPs-impaired BMSCs differentiation ability. Mechanistically, we find altered expression of phos-ERK in corin knockdown/overexpression BMSCs and BMSCs under sCorin stimulation. PD98059 (a selective ERK inhibitor) blocks the corin-mediated promotion effect. With regard to the high methylation level of corin during osteogenic differentiation, we apply a non-selective m6A methylase inhibitor, Cycloleucine, which also blocks the corin-mediated promotion effect. Furthermore, we demonstrate that METTL7A modulates corin m6A modification and reverses BPs-impaired BMSCs function, indicating that METTL7A regulates corin expression and thus contributes to orofacial BMSCs differentiation ability. To conclude, our study reveals that corin reverses BPs-induced BMSCs dysfunction, and METTL7A-mediated corin m6A modification underlies corin promotion of osteogenic differentiation via the ERK pathway. We hope this brings new insights into future clinical treatments for BRONJ.

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METTL7A 介导的 corin m6A 修饰可逆转双膦酸盐对口面部 BMSC 骨细胞成骨分化的影响
双膦酸盐相关性颌骨坏死(BRONJ)的特征是口面部骨髓基质细胞(BMSCs)的成骨分化受损。Corin 最近被证明是骨发育和骨科疾病的关键调节因子。然而,corin在与BRONJ相关的骨髓基质细胞功能障碍中的作用仍未明确。我们小组的一项 m6A 表转录组芯片研究表明,在口面部 BMSCs 成骨分化过程中,CORIN 基因显著上调,且 m6A 高甲基化。corin基因敲除抑制BMSCs成骨分化,而corin基因过表达或可溶性corin(sCorin)则具有促进作用。此外,corin 的表达受双磷酸盐(BPs)的负调控。Corin过表达或sCorin能逆转双膦酸盐对BMSCs分化能力的损害。从机理上讲,我们发现在 corin 敲除/过表达 BMSCs 和受 sCorin 刺激的 BMSCs 中,phos-ERK 的表达发生了改变。PD98059(一种选择性 ERK 抑制剂)阻断了 corin 介导的促进作用。考虑到成骨分化过程中 corin 的甲基化水平较高,我们使用了非选择性 m6A 甲基化酶抑制剂 Cycloleucine,它也能阻断 corin 介导的促进效应。此外,我们还证明了 METTL7A 可调节 corin m6A 修饰并逆转 BPs 受损的 BMSCs 功能,这表明 METTL7A 可调控 corin 的表达,从而促进口面部 BMSCs 的分化能力。总之,我们的研究揭示了 corin 逆转 BPs 诱导的 BMSCs 功能障碍,而 METTL7A 介导的 corin m6A 修饰是 corin 通过 ERK 通路促进成骨分化的基础。我们希望这能为 BRONJ 未来的临床治疗带来新的启示。
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来源期刊
International Journal of Oral Science
International Journal of Oral Science DENTISTRY, ORAL SURGERY & MEDICINE-
CiteScore
31.80
自引率
1.30%
发文量
53
审稿时长
>12 weeks
期刊介绍: The International Journal of Oral Science covers various aspects of oral science and interdisciplinary fields, encompassing basic, applied, and clinical research. Topics include, but are not limited to: Oral microbiology Oral and maxillofacial oncology Cariology Oral inflammation and infection Dental stem cells and regenerative medicine Craniofacial surgery Dental material Oral biomechanics Oral, dental, and maxillofacial genetic and developmental diseases Craniofacial bone research Craniofacial-related biomaterials Temporomandibular joint disorder and osteoarthritis The journal publishes peer-reviewed Articles presenting new research results and Review Articles offering concise summaries of specific areas in oral science.
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