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  2. NIPA2 regulates osteoblast function by modulating mitophagy in type 2 diabetes osteoporosis

NIPA2 regulates osteoblast function by modulating mitophagy in type 2 diabetes osteoporosis

  • Sci Rep. 2020 Feb 20;10(1):3078. doi: 10.1038/s41598-020-59743-4.
Wei Zhao  # 1 Weilin Zhang  # 1 Hongdong Ma 2 Maowei Yang 3
Affiliations

Affiliations

  • 1 Department of Orthopedics, the Fourth Hospital of China Medical University, Shenyang, Liaoning, China.
  • 2 Department of Orthopedics, the First Hospital of China Medical University, Shenyang, Liaoning, China.
  • 3 Department of Orthopedics, the First Hospital of China Medical University, Shenyang, Liaoning, China. mwyang@cmu.edu.cn.
  • # Contributed equally.
Abstract

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.

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