1α,25-Dihydroxyvitamin D3 increases implant osseointegration in diabetic mice partly through FoxO1 inactivation in osteoblasts
Abstract Oral implant osseointegration is delayed by hyperglycemia-generated oxidative stress (OS). Forkhead transcription factor 1 (FoxO1) is known to be viewed as a sensor to OS since reactive oxide species like H 2 O 2 regulates its activity. We previously demonstrated that 1,25(OH) 2 D 3 favored glucose homeostasis and implant osseointegration in diabetic rats. In this study, we investigated the role of FoxO1 OB in the regulation process of 1,25(OH) 2 D 3 on glycometabolism and bone metabolism. We show herein that, with the treatment of 1,25(OH) 2 D 3 , mice lacking FoxO1 in osteoblasts (FoxO1 OB −/- ) exhibited decreased serum glucose that was gradually elevated in untreated diabetic mice. An optimal increase of bone mass and bone-implant contact (BIC) was observed in 1,25(OH) 2 D 3 treated FoxO1 OB −/- mice after 2-month healing. Surprisingly, FoxO1 OB −/- mice without 1,25(OH) 2 D 3 treatment also 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 1,25(OH) 2 D 3 treated FoxO1 OB −/- mice as compared to untreated WT mice. In addition, in vitro study showed that high glucose induced FoxO1 nuclear localization while the effect was ameliorated by 1,25(OH) 2 D 3 treatment. These results suggest that FoxO1 OB might be involved in the regulation of 1,25(OH) 2 D 3 on glucose homeostasis and bone formation, and that FoxO1 OB might act as a key modulator of the capacity of the skeleton regulating metabolic homeostasis. Our study also provides a new idea that a combination of systemic 1,25(OH) 2 D 3 and local FoxO1 inhibitor may be a new approach to enhance implant osseointegration. Highlights FoxO1 ablation in osteoblasts favors glucose homeostasis in diabetic mice. 1,25(OH) 2 D 3 regulates glucose and bone metabolism partly through inactivation of FoxO1. FoxO1 inhibitor may be a novel approach to enhance implant osseointegration.
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