PDF(Pubmed)
Abstract：
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
摘要：
■唑来膦酸盐（ZA）是一种高效的抗吸收剂，已知可引发药物相关的颌骨坏死（MRONJ）。其临床剂量主要包括用于肿瘤和骨质疏松症治疗的剂量。虽然炎症被认为是与ZA相关的粘膜愈合过程的潜在干扰物，先前的研究忽视了不同ZA剂量对组织适应性的影响。因此,更深入地了解炎症加剧ZA诱导的MRONJ的具体机制，特别是当炎症作为危险因素时，仍然至关重要。
在用不同剂量的ZA和/或脂多糖(LPS)处理后,分析人口腔角质形成细胞(HOK)的细胞增殖和迁移,以评估它们对拔牙伤口的粘膜愈合的可能影响。用LPS建立小鼠牙周炎模型,并观察到肿瘤剂量ZA给药后拔除伤口的组织学变化。使用苏木精和伊红（HE）染色和免疫荧光来评估粘膜愈合。
■体外，LPS并未加重骨质疏松治疗剂量的ZA对HOK细胞增殖和迁移的影响,而肿瘤剂量的ZA治疗通过调节SIRT1表达诱导线粒体功能障碍和氧化应激加重了这些。此外，SIRT1过表达可以缓解这一过程。在体内,局部注射LPS增加MRONJ粘膜骨不连，降低SIRT1、PGC-1α的表达，和MnSOD。
■炎症通过SIRT1依赖性途径加重ZA诱导的线粒体功能障碍和氧化应激的肿瘤剂量，增加MRONJ粘膜愈合受损的风险。我们的研究表明，在较高的ZA浓度下，炎症成为MRONJ发育的关键风险因素。阐明炎症机制是MRONJ粘膜不愈合的危险因素，可以为SIRT1靶向治疗的发展提供信息。
在用不同剂量的ZA和/或脂多糖(LPS)处理后,分析人口腔角质形成细胞(HOK)的细胞增殖和迁移,以评估它们对拔牙伤口的粘膜愈合的可能影响。用LPS建立小鼠牙周炎模型,并观察到肿瘤剂量ZA给药后拔除伤口的组织学变化。使用苏木精和伊红（HE）染色和免疫荧光来评估粘膜愈合。
■体外，LPS并未加重骨质疏松治疗剂量的ZA对HOK细胞增殖和迁移的影响,而肿瘤剂量的ZA治疗通过调节SIRT1表达诱导线粒体功能障碍和氧化应激加重了这些。此外，SIRT1过表达可以缓解这一过程。在体内,局部注射LPS增加MRONJ粘膜骨不连，降低SIRT1、PGC-1α的表达，和MnSOD。
■炎症通过SIRT1依赖性途径加重ZA诱导的线粒体功能障碍和氧化应激的肿瘤剂量，增加MRONJ粘膜愈合受损的风险。我们的研究表明，在较高的ZA浓度下，炎症成为MRONJ发育的关键风险因素。阐明炎症机制是MRONJ粘膜不愈合的危险因素，可以为SIRT1靶向治疗的发展提供信息。
