DOE OSTI2017
Highlights: • FoxO1 ablation in osteoblasts favors glucose homeostasis in diabetic mice. • 1,25(OH){sub 2}D{sub 3} regulates glucose and bone metabolism partly through inactivation of FoxO1. • FoxO1 inhibitor may be a novel approach to enhance implant osseointegration. 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{sub 2}O{sub 2} regulates its activity. We previously demonstrated that 1,25(OH){sub 2}D{sub 3} favored glucose homeostasis and implant osseointegration in diabetic rats. In this study, we investigated the role of FoxO1{sub OB} in the regulation process of 1,25(OH){sub 2}D{sub 3} on glycometabolism and bone metabolism. We show herein that, with the treatment of 1,25(OH){sub 2}D{sub 3}, mice lacking FoxO1 in osteoblasts (FoxO1{sub OB}{sup −/-}) 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){sub 2}D{sub 3} treated FoxO1{sub OB}{sup −/-} mice after 2-month healing. Surprisingly, FoxO1{sub OB}{sup −/-} mice without 1,25(OH){sub 2}D{sub 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){sub 2}D{sub 3} treated FoxO1{sub OB}{sup −/-} 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){sub 2}D{sub 3} treatment. These results suggest that FoxO1{sub OB} might be involved in the regulation of 1,25(OH){sub 2}D{sub 3} on glucose homeostasis and bone formation, and that FoxO1{sub 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){sub 2}D{sub 3} and local FoxO1 inhibitor may be a new approach to enhance implant osseointegration.
60 APPLIED LIFE SCIENCES↗