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The role of FoxO1 in the regulation of 1,25(OH)2D3 on implant osseointegration in diabetic mice
EAO Online Library. Xiong Y. Oct 9, 2018; 232521
Yi Xiong
Yi Xiong
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Our previous study found that 1α+,25-Dihydroxyvitamin D3 (1,25(OH)2D3) was involved in the regulation of glucose metabolism and implant osseointegration in diabetic rats via regulating osteocalcin (OCN) secretion and its uncarboxylated level (GluOC). More research demonstrated that forkhead transcription factor O1 (FoxO1) in osteoblasts could bind the promoter of OCN and inhibit its transcription, thus regulating glucose metabolism and bone metabolism.We hypothesis that 1,25(OH)2D3 improves glucose metabolism and implant osseointegration in diabetic mice through the regulation of FoxO1 and OCN activity.Diabetic mouse models were established with streptozotocin (40mg kg). Titanium implants were placed in femurs in the following 5 groups, Control- WT mice (WT group)+ the diabetic groups- DB-WT group and DB-KO group+ the treatment group- VD3-DB-WT group and VD3-DB-KO group. 1,25(OH)2D3 was given at a dose of 5μ+g kg via intraperitoneal injection every other day for 4 weeks. Serum glucose was estimated every week, and ITT assay was conducted before sacrifice. 2 months post-operation, blood samples and femur samples were collected for molecular biological detection and histomorphometric analysis. Group set in vitro study was familiar with in vivo study. BrdU assay, Alizarin Red staining, Alkaline phosphatase assay, RT-PCR, Western blot and immunofluorescence were conducted to evaluate osteoblasts proliferation, mineralization, osteogenic differentiation, and its underlying mechanism in different cultural conditions.VD3-DB-KO mice exhibited remarkably decreased serum glucose and a favorable insulin sensitivity. Results also showed that FoxO1 knockout promoted glucose control and insulin secretion in DB-KO mice when compared with DB-WT mice. Besides, an optimal increase of bone mass and bone-implant contact (BIC) was observed in VD3-DB-KO mice after 2-month healing. Of note, DB-KO mice showed an improvement on bone formation and BIC. Same effect could be found in the expression of bone-related markers Runx2, Osterix and BSP, which elevated in VD3-DB-KO mice as compared to DB-WT mice. Moreover, VDR and p-Akt detected by immunohistochemistry, and OCN and GluOC level detected by Elisa assay were elevated in VD3-DB-KO when compared with other groups. In vitro study also showed that 1,25(OH)2D3 promotes osteoblasts proliferation, mineralization and osteogenic differentiation, and promoted FoxO1 nuclear exclusion in high glucose condition.1,25(OH)2D3 facilitated glucose metabolism and bone metabolism through FoxO1 nuclear exclusion resulted from the activation of PI3K Akt signaling.
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