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Retuning Mitochondrial Apoptosis/Mitophagy Balance via SIRT3-Energized and Microenvironment-Modulated Hydrogel
Xiaowei Xia1,2, Yang Liu1,2, Yingjie Lu1,2
1Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215006, China.
Abstract:
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.
Insights
This study reveals that activating sirtuin 3 (SIRT3) protects cartilage by regulating mitochondrial apoptosis and mitophagy. A novel hydrogel microsphere delivery system (DMY@HGP) effectively treated post-traumatic osteoarthritis (PTOA) in vivo.
Area of Science:
- Biomedical Engineering
- Cell Biology
- Orthopedics
Background:
- Osteoarthritis (OA) progression is linked to mitochondrial dysfunction in chondrocytes.
- The role of sirtuin 3 (SIRT3) in regulating mitochondrial dynamics and chondrocyte fate during OA remains unclear.
Purpose of the Study:
- To investigate the protective effects of SIRT3 activation on chondrocytes and cartilage extracellular matrix (ECM) preservation.
- To develop and evaluate a novel drug delivery system for OA treatment targeting mitochondrial dynamics.
Main Methods:
- Chondrocytes were treated with SIRT3 agonist (dihydromyricetin, DMY) or antagonist (3-TYP).
- A dual-responsive hydrogel microsphere (DMY@HAMA-GelMA-PBA, DMY@HGP) was fabricated using microfluidic technology.
- In vivo studies utilized a post-traumatic OA (PTOA) rat model to assess the therapeutic efficacy of DMY@HGP.
Main Results:
- SIRT3 activation preserved cartilage ECM by inhibiting mitochondrial apoptosis (mtApoptosis) and promoting mitophagy.
- DMY@HGP effectively ameliorated cartilage damage and subchondral bone sclerosis in the PTOA model.
- Treatment with DMY@HGP promoted motor function recovery in PTOA rats.
Conclusions:
- Targeting mitochondrial dynamics via SIRT3 activation presents a promising therapeutic strategy for OA.
- The developed DMY@HGP hydrogel microsphere system demonstrates significant therapeutic potential for PTOA treatment.
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