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.
Highlights
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
After treatment for 72 h, we examined the www.nature.com/scientificreports expression in primary osteoblasts of each group. (B) ALP staining images of primary osteoblasts in WT and db/db groups. (C) Immunofluorescence of NIPA2 in primary osteoblasts of WT and db/db groups. (D) Detection of magnesium fluorescence in primary osteoblasts of WT and db/db groups. (E) Transmission electron microscopy (TEM) shows the number of mitophagosomes in primary osteoblasts of WT and db/db groups
We found significant NIPA2 downregulation in db/db mice and in primary culture osteoblast-derived from db/ db mice
Summary
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. Our study was performed to determine the effect of intracellular magnesium deficiency induced by NIPA2 deletion on type 2 diabetes osteoporosis and to investigate the possible pathological mechanism. The involvement of autophagy in the pathological mechanism underlying type 2 diabetes osteoporosis has been widely investigated in recent studies, but the results remain controversial[13,14,15,16]. These different conclusions may be due to the combined effect of autophagy on specific organelles. We aimed to investigate the specific mechanism of NIPA2 regulating mitophagy and osteogenic capability of osteoblasts
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