Retuning Mitochondrial Apoptosis/Mitophagy Balance via SIRT3-Energized and Microenvironment-Modulated Hydrogel Microspheres to Impede Osteoarthritis,Advanced Healthcare Materials

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Retuning Mitochondrial Apoptosis/Mitophagy Balance via SIRT3-Energized and Microenvironment-Modulated Hydrogel Microspheres to Impede Osteoarthritis
Advanced Healthcare Materials ( IF 10.0 ) Pub Date : 2023-09-11 , DOI: 10.1002/adhm.202302475
Xiaowei Xia _{1,

2} , Yang Liu _{1,

2} , Yingjie Lu _{1,

2} , Junlin Liu _{1,

2} , Yaoge Deng _{1,

2} , Yubin Wu _{1,

2} , Mingzhuang Hou _{1,

2} , Fan He _{1,

2} , Huilin Yang _{1,

2} , Yong Xu _{1,

2} , Yijian Zhang _{1,

2} , Xuesong Zhu _{1,

2}

Affiliation

Full-range therapeutic regimens for osteoarthritis (OA) should consider organs (joints)-tissues (cartilage)-cells (chondrocytes)-organelles cascade, of which the subcellular mitochondria dominate eukaryotic cells' fate, and thus causally influence OA progression. However, the dynamic regulation of mitochondrial rise and demise in impaired chondrocytes and the exact role of mitochondrial metronome sirtuins 3 (SIRT3) is not clarified. Herein, chondrocytes are treated with SIRT3 natural agonist dihydromyricetin (DMY) or chemical antagonist 3-TYP, respectively, to demonstrate the positive action of SIRT3 on preserving cartilage extracellular matrix (ECM). Molecular mechanical investigations disclose that SIRT3-induced chondroprotection depended on the repression of mitochondrial apoptosis (mtApoptosis) and the activation of mitophagy. Inspired by the high-level matrix proteinases and reactive oxygen species (ROS) in the OA environment, by anchoring gelatin methacrylate (GelMA) and benzenediboronic acid (PBA) to hyaluronic acid methacrylate (HAMA) with microfluidic technology, a dual-responsive hydrogel microsphere laden with DMY is tactfully fabricated and named as DMY@HAMA-GelMA-PBA (DMY@HGP). In vivo injection of DMY@HGP ameliorated cartilage abrasion and subchondral bone sclerosis, as well as promoted motor function recovery in post-traumatic OA (PTOA) model via recouping endogenous mtApoptosis and mitophagy balance. Overall, this study unveils a novel mitochondrial dynamic-oriented strategy, holding great promise for the precision treatment of OA.

中文翻译：

通过 SIRT3 供电和微环境调节的水凝胶微球重新调整线粒体凋亡/线粒体自噬平衡以阻止骨关节炎

骨关节炎（OA）的全方位治疗方案应考虑器官（关节）-组织（软骨）-细胞（软骨细胞）-细胞器级联，其中亚细胞线粒体主导真核细胞的命运，从而影响OA的进展。然而，受损软骨细胞中线粒体上升和消亡的动态调节以及线粒体节拍器 Sirtuins 3 (SIRT3) 的确切作用尚不清楚。在此，分别用SIRT3天然激动剂二氢杨梅素（DMY）或化学拮抗剂3-TYP处理软骨细胞，以证明SIRT3对保存软骨细胞外基质（ECM）的积极作用。分子力学研究表明，SIRT3 诱导的软骨保护作用取决于线粒体凋亡 (mtApoptosis) 的抑制和线粒体自噬的激活。受OA环境中高级基质蛋白酶和活性氧（ROS）的启发，通过微流控技术将甲基丙烯酸明胶（GelMA）和苯二硼酸（PBA）锚定到透明质酸甲基丙烯酸酯（HAMA）上，形成双响应水凝胶微球满载 DMY 被巧妙地制造并命名为 DMY@HAMA-GelMA-PBA (DMY@HGP)。体内注射 DMY@HGP 可改善软骨磨损和软骨下骨硬化，并通过恢复内源性线粒体凋亡和线粒体自噬平衡，促进创伤后 OA (PTOA) 模型的运动功能恢复。总体而言，这项研究揭示了一种新颖的线粒体动态导向策略，为 OA 的精准治疗带来了巨大希望。

更新日期：2023-09-11

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