Abstract：
A thorough comprehension of age-related variances in orthodontic tooth movement (OTM) and bone remodeling response to mechanical force holds significant implications for enhancing orthodontic treatment. Mitophagy plays a crucial role in bone metabolism and various age-related diseases. However, the impact of mitophagy on the bone remodeling process during OTM remains elusive. Using adolescent (6 weeks old) and adult (12 months old) rats, we established OTM models and observed that orthodontic force increased the expression of the mitophagy proteins PTEN-induced putative kinase 1 (PINK1) and Parkin, as well as the number of tartrate-resistant acid phosphatase-positive osteoclasts and osteocalcin-positive osteoblasts. These biological changes were found to be age-related. In vitro, compression force loading promoted PINK1/Parkin-dependent mitophagy in periodontal ligament stem cells (PDLSCs) derived from adolescents (12-16 years old) and adults (25-35 years old). Furthermore, adult PDLSCs exhibited lower levels of mitophagy, impaired mitochondrial function, and a decreased ratio of RANKL/OPG compared to young PDLSCs after compression. Transfection of siRNA confirmed that inhibition of mitophagy in PDLSC resulted in decreased mitochondrial function and reduced RANKL/OPG ratio. Application of mitophagy inducer Urolithin A enhanced bone remodeling and accelerated OTM in rats, while the mitophagy inhibitor Mdivi-1 had the opposite effect. These findings indicate that force-stimulated PDLSC mitophagy contributes to alveolar bone remodeling during OTM, and age-related impairment of mitophagy negatively impacts the PDLSC response to mechanical stimulus. Our findings enhance the understanding of mitochondrial mechanotransduction and offer new targets to tackle current clinical challenges in orthodontic therapy.
摘要：
全面了解正畸牙齿移动（OTM）和骨骼重塑对机械力的反应与年龄相关的差异，对于加强正畸治疗具有重要意义。线粒体自噬在骨代谢和各种与年龄相关的疾病中起着至关重要的作用。然而,在OTM过程中，线粒体自噬对骨重建过程的影响仍然难以捉摸。使用青少年（6周龄）和成年（12月龄）大鼠，我们建立了OTM模型，观察到正畸力增加了线粒体自噬蛋白PTEN诱导的推定激酶1（PINK1）和Parkin的表达，以及抗酒石酸酸性磷酸酶阳性破骨细胞和骨钙蛋白阳性成骨细胞的数量。发现这些生物学变化与年龄有关。体外，压力负荷可促进青少年（12-16岁）和成人（25-35岁）牙周膜干细胞（PDLSCs）中PINK1/Parkin依赖性线粒体自噬。此外，成年PDLSCs表现出较低水平的线粒体自噬，线粒体功能受损，压缩后与年轻的PDLSCs相比，RANKL/OPG比率降低。转染siRNA证实PDLSC中线粒体自噬的抑制导致线粒体功能降低和RANKL/OPG比率降低。应用线粒体自噬诱导剂尿石素A增强大鼠骨重建和加速OTM,而线粒体自噬抑制剂Mdivi-1具有相反的作用。这些发现表明，力刺激的PDLSC线粒体自噬有助于OTM期间的牙槽骨重建，与年龄相关的线粒体自噬损害会对PDLSC对机械刺激的反应产生负面影响。我们的发现增强了对线粒体机械传导的理解，并为应对正畸治疗中当前的临床挑战提供了新的靶标。
