Department of Orthodontics, Hospital of Stomatology, Sun Yat-Sen University, Guangzhou, Guangdong, China.
Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-Sen University, Guangzhou, Guangdong, China.
FASEB J. 2024 Aug 15;38(15):e23865. doi: 10.1096/fj.202401280R.
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.
深入理解正畸牙齿移动（OTM）和骨骼重塑对机械力的反应随年龄的变化，对于增强正畸治疗具有重要意义。自噬在骨骼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，自噬对 OTM 期间骨骼重塑过程的影响仍不清楚。我们使用青少年（6 周龄）和成年（12 月龄）大鼠建立了 OTM 模型，观察到正畸力增加了自噬蛋白 PTEN 诱导的假定激酶 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素阳性成骨细胞的数量。这些生物学变化与年龄有关。在体外，压缩力加载促进了来源于青少年（12-16 岁）和成年人（25-35 岁）的牙周膜干细胞（PDLSCs）中 PINK1/Parkin 依赖性自噬。此外，与年轻的 PDLSCs 相比，成年 PDLSCs 的自噬水平较低，线粒体功能受损，RANKL/OPG 比值降低。siRNA 转染证实，PDLSC 中的自噬抑制导致线粒体功能降低和 RANKL/OPG 比值降低。自噬诱导剂 Urolithin A 的应用增强了大鼠的骨骼重塑和 OTM 加速，而自噬抑制剂 Mdivi-1 则产生相反的效果。这些发现表明，力刺激的 PDLSC 自噬有助于 OTM 期间牙槽骨重塑，而与年龄相关的自噬受损会对 PDLSC 对机械刺激的反应产生负面影响。我们的研究结果增强了对线粒体力学转导的理解，并为解决当前正畸治疗中的临床挑战提供了新的靶点。
