Iyer Srividhya, Han Li, Ambrogini Elena, Yavropoulou Maria, Fowlkes John, Manolagas Stavros C, Almeida Maria
Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.
Barnstable Brown Diabetes and Obesity Center, Department of Pediatrics, University of Kentucky College of Medicine, Lexington, KY, USA.
J Bone Miner Res. 2017 Jan;32(1):60-69. doi: 10.1002/jbmr.2934. Epub 2016 Sep 7.
Type 1 diabetes is associated with osteopenia and increased fragility fractures, attributed to reduced bone formation. However, the molecular mechanisms mediating these effects remain unknown. Insulin promotes osteoblast formation and inhibits the activity of the FoxO transcription factors. FoxOs, on the other hand, inhibit osteoprogenitor proliferation and bone formation. Here, we investigated whether FoxOs play a role in the low bone mass associated with type 1 diabetes, using mice lacking FoxO1, 3, and 4 in osteoprogenitor cells (FoxO1,3,4 ). Streptozotocin-induced diabetes caused a reduction in bone mass and strength in FoxO-intact mice. In contrast, cancellous bone was unaffected in diabetic FoxO1,3,4 mice. The low bone mass in the FoxO-intact diabetic mice was associated with decreased osteoblast number and bone formation, as well as decreased expression of the anti-osteoclastogenic cytokine osteoprotegerin (OPG) and increased osteoclast number. FoxO deficiency did not alter the effects of diabetes on bone formation; however, it did prevent the decrease in OPG and the increase in osteoclast number. Addition of high glucose to osteoblastic cell cultures decreased OPG mRNA, indicating that hyperglycemia in and of itself contributes to diabetic bone loss. Taken together, these results suggest that FoxOs exacerbate the loss of cancellous bone mass associated with type 1 diabetes and that inactivation of FoxOs might ameliorate the adverse effects of insulin deficiency. © 2016 American Society for Bone and Mineral Research.
1型糖尿病与骨质减少和脆性骨折增加有关，这归因于骨形成减少。然而，介导这些效应的分子机制仍不清楚。胰岛素促进成骨细胞形成并抑制FoxO转录因子的活性。另一方面，FoxO抑制骨祖细胞增殖和骨形成。在这里，我们使用在骨祖细胞中缺乏FoxO1、3和4的小鼠（FoxO1,3,4），研究了FoxO是否在与1型糖尿病相关的低骨量中起作用。链脲佐菌素诱导的糖尿病导致FoxO完整小鼠的骨量和骨强度降低。相比之下，糖尿病FoxO1,3,4小鼠的松质骨未受影响。FoxO完整的糖尿病小鼠的低骨量与成骨细胞数量减少、骨形成减少以及抗破骨细胞生成细胞因子骨保护素（OPG）表达降低和破骨细胞数量增加有关。FoxO缺乏并没有改变糖尿病对骨形成的影响；然而，它确实阻止了OPG的减少和破骨细胞数量的增加。向成骨细胞培养物中添加高糖会降低OPG mRNA，表明高血糖本身会导致糖尿病性骨质流失。综上所述，这些结果表明FoxO会加剧与1型糖尿病相关的松质骨量流失，并且FoxO失活可能会改善胰岛素缺乏的不利影响。©2016美国骨与矿物质研究学会。
