Inflammation Can Be a High-Risk Factor for Mucosal Nonunion of MRONJ by Regulating SIRT1 Signaling When Treated with an Oncologic Dose of Zoledronate

IF 4.7 2区医学 Q1 CHEMISTRY, MEDICINAL Drug Design, Development and Therapy Pub Date : 2024-07-04 DOI:10.2147/dddt.s456811

Siqi Zhu, Yajun Cui, Weidong Zhang, Yu Ji, Lingshuang Li, Shenglei Luo, Jing Cui, Minqi Li

{"title":"Inflammation Can Be a High-Risk Factor for Mucosal Nonunion of MRONJ by Regulating SIRT1 Signaling When Treated with an Oncologic Dose of Zoledronate","authors":"Siqi Zhu, Yajun Cui, Weidong Zhang, Yu Ji, Lingshuang Li, Shenglei Luo, Jing Cui, Minqi Li","doi":"10.2147/dddt.s456811","DOIUrl":null,"url":null,"abstract":"Purpose: Zoledronate (ZA) stands as a highly effective antiresorptive agent known to trigger medication-related osteonecrosis of the jaw (MRONJ). Its clinical dosages primarily encompass those used for oncologic and osteoporosis treatments. While inflammation is recognized as a potential disruptor of mucosal healing processes associated with ZA, prior research has overlooked the influence of varying ZA dosages on tissue adaptability. Therefore, a deeper understanding of the specific mechanisms by which inflammation exacerbates ZA-induced MRONJ, particularly when inflammation acts as a risk factor, remains crucial. Methods: Cell proliferation and migration of human oral keratinocytes (HOK) was analyzed after treatment with different doses of ZA and/or lipopolysaccharide (LPS) to assess their possible effect on mucosal healing of extraction wounds. Mouse periodontitis models were established using LPS, and histological changes in extraction wounds were observed after the administration of oncologic dose ZA. Hematoxylin and eosin (HE) staining and immunofluorescence were used to evaluate mucosal healing. Results: In vitro, LPS did not exacerbate the effects of osteoporosis therapeutic dose of ZA on the proliferation and migration of HOK cells, while aggravated these with the oncologic dose of ZA treatment by inducing mitochondrial dysfunction and oxidative stress via regulating SIRT1 expression. Furthermore, SIRT1 overexpression can alleviate this process. In vivo, local injection of LPS increased the nonunion of mucous membranes in MRONJ and decreased the expression of SIRT1, PGC-1α, and MnSOD. Conclusion: Inflammation aggravates oncologic dose of ZA-induced mitochondrial dysfunction and oxidative stress via a SIRT1-dependent pathway, enhancing the risk of impaired mucosal healing in MRONJ. Our study implies that inflammation becomes a critical risk factor for MRONJ development at higher ZA concentrations. Elucidating the mechanisms of inflammation as a risk factor for mucosal non-healing in MRONJ could inform the development of SIRT1-targeted therapies. Keywords: MRONJ, mucosal healing, inflammation, oxidative stress, mitochondrial dysfunction, SIRT1 ","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":null,"pages":null},"PeriodicalIF":4.7000,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Drug Design, Development and Therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.2147/dddt.s456811","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}

引用次数: 0

Abstract

Purpose: Zoledronate (ZA) stands as a highly effective antiresorptive agent known to trigger medication-related osteonecrosis of the jaw (MRONJ). Its clinical dosages primarily encompass those used for oncologic and osteoporosis treatments. While inflammation is recognized as a potential disruptor of mucosal healing processes associated with ZA, prior research has overlooked the influence of varying ZA dosages on tissue adaptability. Therefore, a deeper understanding of the specific mechanisms by which inflammation exacerbates ZA-induced MRONJ, particularly when inflammation acts as a risk factor, remains crucial.
Methods: Cell proliferation and migration of human oral keratinocytes (HOK) was analyzed after treatment with different doses of ZA and/or lipopolysaccharide (LPS) to assess their possible effect on mucosal healing of extraction wounds. Mouse periodontitis models were established using LPS, and histological changes in extraction wounds were observed after the administration of oncologic dose ZA. Hematoxylin and eosin (HE) staining and immunofluorescence were used to evaluate mucosal healing.
Results: In vitro, LPS did not exacerbate the effects of osteoporosis therapeutic dose of ZA on the proliferation and migration of HOK cells, while aggravated these with the oncologic dose of ZA treatment by inducing mitochondrial dysfunction and oxidative stress via regulating SIRT1 expression. Furthermore, SIRT1 overexpression can alleviate this process. In vivo, local injection of LPS increased the nonunion of mucous membranes in MRONJ and decreased the expression of SIRT1, PGC-1α, and MnSOD.
Conclusion: Inflammation aggravates oncologic dose of ZA-induced mitochondrial dysfunction and oxidative stress via a SIRT1-dependent pathway, enhancing the risk of impaired mucosal healing in MRONJ. Our study implies that inflammation becomes a critical risk factor for MRONJ development at higher ZA concentrations. Elucidating the mechanisms of inflammation as a risk factor for mucosal non-healing in MRONJ could inform the development of SIRT1-targeted therapies.

Keywords: MRONJ, mucosal healing, inflammation, oxidative stress, mitochondrial dysfunction, SIRT1

查看原文

微信好友朋友圈 QQ好友复制链接

本刊更多论文

使用肿瘤剂量的唑来膦酸钠治疗时，炎症可通过调节 SIRT1 信号转导成为 MRONJ 粘膜不愈合的高危因素

目的：唑来膦酸钠（ZA）是一种高效抗骨质吸收剂，已知会引发药物性颌骨坏死（MRONJ）。其临床剂量主要用于肿瘤和骨质疏松症治疗。虽然炎症被认为是与ZA相关的粘膜愈合过程的潜在干扰因素，但之前的研究忽略了不同剂量的ZA对组织适应性的影响。因此，深入了解炎症加剧ZA诱导的MRONJ的具体机制，尤其是当炎症作为一种风险因素时，仍然至关重要：方法：分析了不同剂量的ZA和/或脂多糖（LPS）处理后人口腔角质细胞（HOK）的细胞增殖和迁移，以评估它们对拔牙创粘膜愈合可能产生的影响。使用 LPS 建立了小鼠牙周炎模型，并在使用肿瘤剂量的ZA后观察了拔牙伤口的组织学变化。采用血红素和伊红（HE）染色法和免疫荧光法评估粘膜愈合情况：结果：在体外，LPS不会加剧骨质疏松症治疗剂量ZA对HOK细胞增殖和迁移的影响，但会通过调节SIRT1的表达诱导线粒体功能障碍和氧化应激，从而加剧肿瘤剂量ZA治疗对HOK细胞增殖和迁移的影响。此外，SIRT1 的过表达可以缓解这一过程。在体内，局部注射 LPS 会增加 MRONJ 粘膜的不愈合，并降低 SIRT1、PGC-1α 和 MnSOD 的表达：炎症通过 SIRT1 依赖性途径加重肿瘤剂量ZA诱导的线粒体功能障碍和氧化应激，增加了 MRONJ 中粘膜愈合受损的风险。我们的研究表明，当ZA浓度较高时，炎症成为MRONJ发病的关键风险因素。阐明炎症作为MRONJ粘膜不愈合风险因素的机制，可为开发SIRT1靶向疗法提供依据：MRONJ、粘膜愈合、炎症、氧化应激、线粒体功能障碍、SIRT1

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文去求助

来源期刊

Drug Design, Development and Therapy CHEMISTRY, MEDICINAL-PHARMACOLOGY & PHARMACY

CiteScore

9.00

自引率

0.00%

发文量

382

审稿时长

>12 weeks

期刊介绍： Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications. The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas. Specific topics covered by the journal include: Drug target identification and validation Phenotypic screening and target deconvolution Biochemical analyses of drug targets and their pathways New methods or relevant applications in molecular/drug design and computer-aided drug discovery* Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes) Structural or molecular biological studies elucidating molecular recognition processes Fragment-based drug discovery Pharmaceutical/red biotechnology Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products** Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing) Preclinical development studies Translational animal models Mechanisms of action and signalling pathways Toxicology Gene therapy, cell therapy and immunotherapy Personalized medicine and pharmacogenomics Clinical drug evaluation Patient safety and sustained use of medicines.