Diabetic Fracture Healing

简介（由申请人提供）：摘要糖尿病导致骨质减少和骨折风险增加。此外，糖尿病会干扰下颌骨和长骨的骨折修复。我们最近发现，血糖正常的小鼠和糖尿病小鼠之间的一个主要区别是糖尿病组的软骨加速损失。这表明糖尿病性骨折愈合中存在一种以前未被认识到的分解代谢缺陷，并提示快速去除软骨可能会减少软骨内骨形成的基质。此外，糖尿病性骨折老茧的特点是FOXO1活性水平显著升高，软骨细胞中FOXO1核易位增加。提出的研究的目的是验证糖尿病增强FOXO1活性改变软骨细胞基因表达的假设，从而导致糖尿病骨折愈合受损。目的1将研究糖尿病骨折愈合、TNF-1升高、晚期糖基化终产物或高葡萄糖水平刺激软骨细胞中FOXO1激活的机制。这些实验将通过质谱法对FOXO1的翻译后修饰进行评估，因为它调节FOXO1的核定位和DNA结合活性。目的2将确定使用Cre/lox系统对FOXO1进行软骨细胞特异性缺失是否会逆转糖尿病对软骨加速去除的影响。为了研究FOXO1如何影响愈合过程，我们将检测FOXO1缺失对破骨细胞原基因表达、破骨细胞数量和机械强度的影响。Aim 3将利用相同的小鼠来确定在糖尿病骨折愈合过程中，软骨细胞中FOXO1的条件缺失是否逆转糖尿病，增强软骨细胞凋亡和促凋亡基因的表达。

DESCRIPTION (provided by applicant): Abstract Diabetes causes osteopenia and increased fracture risk. Furthermore, diabetes interferes with fracture repair of the mandible and long bones. We have recently found that a major difference between normoglycemic and diabetic mice is the accelerated loss of cartilage in the diabetic group. This points to a previously unrecognized catabolic defect in diabetic fracture healing and suggests that rapid removal of cartilage may reduce the anlage for endochondral bone formation. Furthermore, diabetic fracture calluses are characterized by significantly elevated levels of FOXO1 activity and increased FOXO1 nuclear translocation in chondrocytes. The goal of the proposed studies is to test the hypothesis that diabetes enhanced FOXO1 activity alters gene expression in chondrocytes that contributes to impaired diabetic fracture healing. Aim 1 will investigate mechanisms by which conditions that are present in diabetic fracture healing, elevated TNF-1, advanced glycation end products or high glucose levels stimulate FOXO1 activation in chondrogenic cells. These experiments will FOXO1 post- translational modification assesses by mass spectrometry which is significant since it regulates FOXO1 nuclear localization and DNA binding activity. Aim 2 will establish whether chondrocyte specific deletion of FOXO1 using the Cre/lox system will reverse the impact of diabetes on the accelerated removal of cartilage. To investigate how FOXO1 could affect the healing process we will examine FOXO1 deletion on pro- osteoclastogenic gene expression, osteoclast numbers and mechanical strength. Aim 3 will utilize the same mice to determine whether conditional deletion of FOXO1 in chondrocytes reverses diabetes enhanced chondrocyte apoptosis and pro-apoptotic gene expression during diabetic fracture healing.