METTL3 accelerates staphylococcal protein A (SpA)-induced osteomyelitis progression by regulating m6A methylation-modified miR-320a.

IF 2.8 3区 医学 Q1 ORTHOPEDICS
Ding Gao, Jian Shi, Siyu Lu, Junyi Li, Kehan Lv, Yongqing Xu, Muguo Song
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引用次数: 0

Abstract

Osteomyelitis (OM) is an inflammatory disease of bone infection and destruction characterized by dysregulation of bone homeostasis. Staphylococcus aureus (SA) has been reported to be the most common pathogen causing infectious OM. Recent studies have demonstrated that N6-methyladenosine (m6A) regulators are associated with the development of OM. However, the molecular mechanism of m6A modifications in OM remains unclear. Here, we investigated the function of methyltransferase-like 3 (METTL3)-mediated m6A modification in OM development. In this study, human bone mesenchymal stem cells (hBMSCs) were treated with staphylococcal protein A (SpA), a vital virulence factor of SA, to construct cell models of OM. Firstly, we found that METTL3 was upregulated in OM patients and SpA-induced hBMSCs, and SpA treatment suppressed osteogenic differentiation and induced oxidative stress and inflammatory injury in hBMSCs. Functional experiments showed that METTL3 knockdown alleviated the inhibition of osteogenic differentiation and the promotion of oxidative stress and inflammation in SpA-treated hBMSCs. Furthermore, METTL3-mediated m6A modification upregulated miR-320a expression by promoting pri-miR-320a maturation, and the mitigating effects of METTL3 knockdown on SpA-mediated osteogenic differentiation, oxidative stress and inflammatory responses can be reversed by miR-320 mimic. In addition, we demonstrated that phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) was a downstream target of miR-320a, upregulation of PIK3CA alleviated miR-320a-induced inhibition of osteogenic differentiation, and upregulation of oxidative stress and inflammatory responses during SpA infection. Finally, we found that silencing METTL3 alleviated OM development by regulating the miR-320a/PIK3CA axis. Taken together, our data demonstrated that the METTL3/m6A/miR-320a/PIK3CA axis regulated SpA-mediated osteogenic differentiation, oxidative stress, and inflammatory responses in OM, which may provide a new therapeutic strategy for OM patients.

METTL3通过调节m6A甲基化修饰的miR-320a,加速葡萄球菌蛋白A(SpA)诱导的骨髓炎进展。
骨髓炎(OM)是一种以骨平衡失调为特征的骨感染和骨破坏的炎症性疾病。据报道,金黄色葡萄球菌(SA)是引起感染性骨髓炎最常见的病原体。最近的研究表明,N6-甲基腺苷(m6A)调节因子与 OM 的发生有关。然而,m6A修饰在OM中的分子机制仍不清楚。在此,我们研究了甲基转移酶样 3(METTL3)介导的 m6A 修饰在 OM 发育中的功能。在这项研究中,我们用葡萄球菌蛋白A(SpA)(SA的一种重要毒力因子)处理人骨间充质干细胞(hBMSCs),构建了OM的细胞模型。首先,我们发现METTL3在OM患者和SpA诱导的hBMSCs中上调,SpA处理抑制了hBMSCs的成骨分化,诱导了氧化应激和炎症损伤。功能实验表明,敲除 METTL3 可减轻 SpA 处理的 hBMSCs 对成骨分化的抑制以及对氧化应激和炎症的促进作用。此外,METTL3介导的m6A修饰通过促进pri-miR-320a的成熟而上调miR-320a的表达,METTL3敲除对SpA介导的成骨分化、氧化应激和炎症反应的缓解作用可被miR-320模拟物逆转。此外,我们还证明磷脂酰肌醇-4,5-二磷酸 3-激酶催化亚基α(PIK3CA)是 miR-320a 的下游靶标,上调 PIK3CA 可减轻 miR-320a 诱导的 SpA 感染过程中对成骨分化的抑制以及氧化应激和炎症反应的上调。最后,我们发现沉默 METTL3 可通过调节 miR-320a/PIK3CA 轴缓解 OM 的发展。总之,我们的数据表明,METTL3/m6A/miR-320a/PIK3CA 轴调控 SpA 介导的 OM 成骨分化、氧化应激和炎症反应,这可能会为 OM 患者提供一种新的治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
4.10
自引率
7.70%
发文量
494
审稿时长
>12 weeks
期刊介绍: Journal of Orthopaedic Surgery and Research is an open access journal that encompasses all aspects of clinical and basic research studies related to musculoskeletal issues. Orthopaedic research is conducted at clinical and basic science levels. With the advancement of new technologies and the increasing expectation and demand from doctors and patients, we are witnessing an enormous growth in clinical orthopaedic research, particularly in the fields of traumatology, spinal surgery, joint replacement, sports medicine, musculoskeletal tumour management, hand microsurgery, foot and ankle surgery, paediatric orthopaedic, and orthopaedic rehabilitation. The involvement of basic science ranges from molecular, cellular, structural and functional perspectives to tissue engineering, gait analysis, automation and robotic surgery. Implant and biomaterial designs are new disciplines that complement clinical applications. JOSR encourages the publication of multidisciplinary research with collaboration amongst clinicians and scientists from different disciplines, which will be the trend in the coming decades.
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