MK-4 Ameliorates Diabetic Osteoporosis in Angiogenesis-Dependent Bone Formation by Promoting Mitophagy in Endothelial Cells.

IF 4.7 2区医学 Q1 CHEMISTRY, MEDICINAL

Drug Design, Development and Therapy Pub Date : 2025-03-25 eCollection Date: 2025-01-01 DOI:10.2147/DDDT.S503930

Fan Ding, Weidong Zhang, Ting Liu, Xing Rong, Yajun Cui, Lingxiao Meng, Luxu Wang, Bo Liu, Minqi Li

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引用次数: 0

Abstract

Purpose: Diabetic osteoporosis (DOP), one of the usual complications in diabetic patients, poses a significant threat to bone health. Type H vessels in metaphysis and medial cortical bone are associated with osteogenesis. As a form of Vitamin K_2, menaquinone-4 (MK-4) is a potential treatment for osteoporosis. We aimed to investigate whether MK-4 ameliorates DOP by promoting bone formation through protecting type H vessels and its associated mechanisms.

Methods: High fat diet (HDF) feeding and streptozotocin (STZ) injection were applied to establish a mouse model of type 2 diabetic osteoporosis (T2DOP). Micro-CT, Masson staining, HE staining and IHC staining were applied to observe bone mass and the osteoblastic ability of osteoblasts. Tissue immunofluorescence (IF) staining and flow cytometry were employed to assess alteration of type H blood vessels. In vitro, to evaluate the functional level and mitophagy of ECs under high glucose conditions, wound healing assay, tube formation assay, EdU assay and IF were employed. Osteogenic differentiation ability in vitro was evaluated by ALP staining, AR staining, Western blot and RT-qPCR.

Results: MK-4 alleviated type H vessel injury and angiogenesis-dependent osteogenesis in DOP mice, thereby maintaining the bone mass. The vitro results showed that MK-4 could mitigate the dysfunction of ECs subjected to HG treatment, and further facilitate the osteogenic differentiation of MC3T3-E1 cells. Moreover, mechanism exploration found that PINK1/Parkin-mediated mitophagy was required for the impact of MK-4 on ECs. Meanwhile, ERK signal pathway is necessary for the improvement of MK-4 in PINK1/Parkin-mediated mitophagy.

Conclusion: MK-4 is capable of alleviating the PINK1/Parkin-mediated mitophagy of ECs via the ERK pathway, thereby facilitating angiogenesis-dependent bone formation and further ameliorating DOP.

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MK-4通过促进内皮细胞的有丝分裂改善血管生成依赖性骨形成的糖尿病骨质疏松症。

目的：糖尿病骨质疏松症（DOP）是糖尿病患者常见的并发症之一，对骨骼健康构成严重威胁。干骺端和内侧皮质骨中的 H 型血管与骨生成有关。作为维生素 K2 的一种形式，脑醌-4（MK-4）是治疗骨质疏松症的潜在药物。方法：应用高脂饮食（HDF）喂养和链脲佐菌素（STZ）注射建立 2 型糖尿病骨质疏松症（T2DOP）小鼠模型。应用显微 CT、Masson 染色、HE 染色和 IHC 染色观察骨量和成骨细胞的成骨能力。组织免疫荧光（IF）染色和流式细胞术用于评估H型血管的改变。在体外，为了评估高糖条件下EC的功能水平和有丝分裂，采用了伤口愈合试验、管形成试验、EdU试验和IF。通过 ALP 染色、AR 染色、Western 印迹和 RT-qPCR 评估体外成骨分化能力：结果：MK-4能缓解H型血管损伤和DOP小鼠的血管生成依赖性骨生成，从而维持骨量。体外实验结果表明，MK-4能缓解HG处理下EC的功能障碍，并进一步促进MC3T3-E1细胞的成骨分化。此外，机理研究还发现，MK-4对心肌细胞的影响需要PINK1/Parkin介导的有丝分裂。同时，ERK信号通路是MK-4改善PINK1/Parkin介导的有丝分裂的必要条件：结论：MK-4能够通过ERK通路缓解PINK1/Parkin介导的心肌细胞有丝分裂，从而促进血管生成依赖性骨形成，进一步改善DOP。

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

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.