Department of Orthopedics, the Fourth Hospital of China Medical University, Shenyang, Liaoning, China.
Department of Orthopedics, the First Hospital of China Medical University, Shenyang, Liaoning, China.
Sci Rep. 2020 Feb 20;10(1):3078. doi: 10.1038/s41598-020-59743-4.
The highly selective magnesium transporter non-imprinted in Prader-Willi/Angelman syndrome region protein 2 (NIPA2) has recently been associated with the development and progression of type 2 diabetes osteoporosis, but the mechanisms involved are still poorly understood. Because mitophagy is involved in the pathology of type 2 diabetes osteoporosis, the present study aimed to explore the relationship among NIPA2, mitophagy and osteoblast osteogenic capacity. NIPA2 expression was reduced in C57BKS background db/db mice and in vitro models of type 2 diabetes osteoporosis, and the activation of mitophagy in primary culture osteoblast-derived from db/db mice and in high glucose-treated human fetal osteoblastic cells (hFOB1.19) was observed. Knockdown, overexpression of NIPA2 and pharmacological inhibition of peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) showed that NIPA2 increased osteoblast function, which was likely regulated by PTEN induced kinase 1 (PINK1)/E3 ubiquitin ligase PARK2 (Parkin)-mediated mitophagy via the PGC-1α/forkhead box O3a(FoxO3a)/mitochondrial membrane potential (MMP) pathway. Furthermore, the negative effect of mitophagy on osteoblast function was confirmed by pharmacological regulation of mitophagy and knockdown of Parkin. Taken together, these results suggest that NIPA2 positively regulates the osteogenic capacity of osteoblasts via the mitophagy pathway in type 2 diabetes.
高度选择性的镁转运蛋白非印记在 Prader-Willi/Angelman 综合征区域蛋白 2（NIPA2）最近与 2 型糖尿病骨质疏松症的发展和进展有关，但涉及的机制仍知之甚少。由于自噬参与了 2 型糖尿病骨质疏松症的病理学，本研究旨在探讨 NIPA2、自噬和成骨细胞成骨能力之间的关系。在 C57BKS 背景 db/db 小鼠和 2 型糖尿病骨质疏松症的体外模型中，NIPA2 的表达减少，并且在 db/db 小鼠原代培养的成骨细胞和高糖处理的人胎成骨细胞（hFOB1.19）中观察到自噬的激活。NIPA2 的敲低、过表达和过氧化物酶体增殖物激活受体 γ 共激活剂 1-α（PGC-1α）的药理学抑制表明，NIPA2 增加了成骨细胞的功能，这可能是通过 PGC-1α/叉头框 O3a（FoxO3a）/线粒体膜电位（MMP）途径调节的 PTEN 诱导激酶 1（PINK1）/E3 泛素连接酶 PARK2（Parkin）介导的自噬来调节的。此外，通过自噬的药理学调节和 Parkin 的敲低证实了自噬对成骨细胞功能的负向影响。总之，这些结果表明，NIPA2 通过 2 型糖尿病中的自噬途径正向调节成骨细胞的成骨能力。
