1α,25-Dihydroxyvitamin D3 promotes bone formation by promoting nuclear exclusion of the FoxO1 transcription factor in diabetic mice

Yu, Xiong; Zhang, Yixin; Xin, Na; Yuan, Ying; Zhang, Qin; Gong, Ping; Wu, Yingying

doi:10.1074/jbc.m117.796367

Cited by 32 publications

(23 citation statements)

References 61 publications

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“…1,25(OH) 2 D 3 was also reported to improve calcium metabolism in thalassemic mice, especially to enhance intestinal calcium absorption to supply more calcium for bone formation 5 . Basically, 1,25(OH) 2 D 3 directly affects bone cells by activating osteoblast activities and induces bone formation or mineralization 36 . However, paradoxical actions of 1,25(OH) 2 D 3 on bone are found in both in vivo and in vitro studies 37 .…”

Section: Discussionmentioning

confidence: 99%

Responses of primary osteoblasts and osteoclasts from hemizygous β-globin knockout thalassemic mice with elevated plasma glucose to 1,25-dihydroxyvitamin D3

Charoenphandhu

Aeimlapa

Sooksawanwit

et al. 2019

Sci Rep

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β-thalassemia is often associated with hyperglycemia, osteoporosis and increased fracture risk. However, the underlying mechanisms of the thalassemia-associated bone loss remain unclear. It might result from abnormal activities of osteoblasts and osteoclasts, and perhaps prolonged exposure to high extracellular glucose. Herein, we determined the rate of duodenal calcium transport in hemizygous β-globin knockout thalassemic (BKO) mice. Their bones were collected for primary osteoblast and osteoclast culture. We found that BKO mice had lower calcium absorption than their wild-type (WT) littermates. Osteoblasts from BKO mice showed aberrant expression of osteoblast-specific genes, e.g., Runx2, alkaline phosphatase and osteocalcin, which could be partially restored by 1,25(OH)2D3 treatment. However, the mRNA expression levels of RANK, calcitonin receptor (Calcr), c-Fos, NFATc1, cathepsin K and DMT1 were similar in both BKO and WT groups. Exposure to high extracellular glucose modestly but significantly affected the expression of osteoclast-specific markers in WT osteoclasts with no significant effect on osteoblast-specific genes in WT osteoblasts. Thus, high glucose alone was unable to convert WT bone cells to BKO-like bone cells. In conclusion, the impaired calcium absorption and mutation-related aberrant bone cell function rather than exposure to high blood glucose were likely to be the principal causes of thalassemic bone loss.

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Section: Discussionmentioning

confidence: 99%

Responses of primary osteoblasts and osteoclasts from hemizygous β-globin knockout thalassemic mice with elevated plasma glucose to 1,25-dihydroxyvitamin D3

Charoenphandhu

Aeimlapa

Sooksawanwit

et al. 2019

Sci Rep

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“…Over the past decade, many strategies such as pharmacological agents and implant surface modifications attempted to increase osseointegration of implants in T2DM, but few of them are available as a routine treatment method in clinical settings. [3][4][5] Therefore, it is urgent to develop new treatment strategies to improve the osseointegration of implants in T2DM patients.…”

Section: Introductionmentioning

confidence: 99%

PTPN2 improves implant osseointegration in T2DM via inducing the dephosphorylation of ERK

Wang

Jia

Zhang

et al. 2019

Exp Biol Med (Maywood)

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Type 2 diabetes mellitus (T2DM) is considered to compromise implant osseointegration. Protein tyrosine phosphatase non-receptor type 2 (PTPN2) regulates glucose metabolism, systemic inflammation, and bone regeneration. This study aimed to investigate the role of PTPN2 in implant osseointegration in T2DM and explore the potential mechanisms. Streptozotocin-induced diabetic rats received implant surgery, with or without local overexpression of PTPN2 for three months, and implant osseointegration was examined by histological evaluation, micro-CT analysis, pull-out test, and scanning electron microscope. Rat bone marrow stem cells (RBMSCs) were isolated and exposed to high glucose, and osteogenic differentiation was evaluated by alizarin red staining, ALP assay, and Western blot analysis. Overexpression of PTPN2 could improve impaired implant osseointegration in T2DM rats and promote osteogenic differentiation of RBMSCs in high glucose. In addition, p-ERK level in RBMSCs was increased in high glucose and decreased after PTPN2 overexpression. These results suggest that PTPN2 promotes implant osseointegration in T2DM rats and enhances osteogenesis of RBMSCs in high glucose medium via inducing the dephosphorylation of ERK. PTPN2 may be a novel target for the therapy of impaired implant osseointegration in T2DM patients. Impact statement Using both in vivo and in vitro approaches, we made important findings that PTPN2 promoted implant osseointegration in T2DM rats and enhanced osteogenesis of RBMSCs in high glucose medium. The positive effects of PTPN2 on osteogenesis are related to the dephosphorylation of ERK and the inhibition of MAPK/ERK pathway. PTPN2 may be a novel target for the therapy of impaired implant osseointegration in T2DM patients.

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“…To determine whether PI3K/Akt signaling participates in the effect of 1,25D on the biological function of primary osteoblasts in HG environment, cells were pretreated in a 2-h incubation of PI3K inhibitor LY294002 (LY29, 50 mol/l, Sigma). Given that 1,25D could induce a time-dependent Akt and FoxO1 phosphorylation as previously reported ( 35 ), relevant analysis was detected after a 2-h treatment of 1,25D. It was observed that p-Akt/Akt level increased when 1,25D was added in primary osteoblasts cultured in HG (p-Akt is the active form of Akt via phosphorylation), which implied that PI3K/Akt signaling was activated by 1,25D.…”

Section: Resultsmentioning

confidence: 53%

1α,25-Dihydroxyvitamin D3 ameliorates diabetes-induced bone loss by attenuating FoxO1-mediated autophagy

Jiang

Luo

Wang

et al. 2021

Journal of Biological Chemistry

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Autophagy is vital for maintaining cellular homeostasis through removing impaired organelles. It has recently been found to play pivotal roles in diabetes mellitus (DM), which is associated with increased bone fracture risk and loss of bone density. However, the mechanism whereby autophagy modulates DM-induced bone loss is not fully elucidated. Previous work has shown that 1α,25-Dihydroxyvitamin D3 (1,25D) exerts positive effects on autophagy, thus affecting bone metabolism. Here, we investigated whether autophagy was involved in the regulation of diabetic bone metabolism. Using Micro-CT, Elisa, histology, and histomorphometry analysis, we demonstrated that 1,25D rescues glucose metabolism dysfunction and ameliorates bone loss in diabetic mice. In vitro , 1,25D alleviated primary osteoblast dysfunction and intracellular oxidative stress through reducing prolonged high-glucose-mediated excessive autophagy in primary osteoblasts, reflected by decreased protein level of Beclin1 and LC3. Of note, the autophagy activator rapamycin (RAP) ablated the positive effects of 1,25D in diabetic environment, leading to a marked increase in autolysosomes and autophagosomes, examined by mRFP-GFP-LC3 fluorescence double labeling. The excessive autophagy induced by high glucose was deleterious to proliferation and differentiation of primary osteoblasts. Additionally, biochemical studies identified that PI3K/Akt signaling could be activated by 1,25D, resulting in the inhibition of FoxO1. We confirmed that FoxO1 deficiency alleviated high-glucose-induced autophagy and improved biological functions of primary osteoblasts. Together, our results suggest that the PI3K/Akt/FoxO1 signaling pathway is involved in the osteoprotective effect of 1,25D by attenuating autophagy in diabetes, providing a novel insight for the prevention and treatment of diabetes-caused bone loss.

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1α,25-Dihydroxyvitamin D3 promotes bone formation by promoting nuclear exclusion of the FoxO1 transcription factor in diabetic mice

Cited by 32 publications

References 61 publications

Responses of primary osteoblasts and osteoclasts from hemizygous β-globin knockout thalassemic mice with elevated plasma glucose to 1,25-dihydroxyvitamin D3

Responses of primary osteoblasts and osteoclasts from hemizygous β-globin knockout thalassemic mice with elevated plasma glucose to 1,25-dihydroxyvitamin D3

PTPN2 improves implant osseointegration in T2DM via inducing the dephosphorylation of ERK

1α,25-Dihydroxyvitamin D3 ameliorates diabetes-induced bone loss by attenuating FoxO1-mediated autophagy

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