The cell metabolism basis for bone complications in type I diabetes

I型糖尿病骨并发症的细胞代谢基础

基本信息

批准号：
10608948
负责人：
Fanxin Long
金额：
$ 45.79万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10608948
关键词：
Adult Anabolic Agents Apoptosis Area Biochemical Markers Bone Formation Stimulation Bone Growth Carbon Cell Lineage Cells Cellular Metabolic Process Child Childhood Childhood diabetes Citric Acid Cycle Clinical Consumption Coupled Data Defect Deterioration Diabetes Mellitus Diabetic mouse Disease model Down-Regulation Doxycycline Energy Metabolism Energy-Generating Resources Fatty Acids Forteo Foundations Galactose Genes Glucose Glutamine Glycolysis Impairment In Vitro Insulin Insulin-Dependent Diabetes Mellitus Knowledge Label Link Metabolic Metabolism Modeling Mus Newly Diagnosed Oleates Osteoblasts Osteoclasts Osteogenesis Osteoporosis Oxidative Phosphorylation Patients Periosteal Cell Periosteum Pharmaceutical Preparations Phenotype Point Mutation Positioning Attribute Potential Energy Predisposition Prevention Regulation Research Role Serum Solid Structure of beta Cell of islet Testing bisphosphonate bone bone cell bone fracture repair bone fragility bone healing bone mass bone quality bone turnover cardiovascular risk factor design diabetic diabetic patient effective therapy fatty acid metabolism fracture risk glucose metabolism in vivo insight long bone metabolic profile mouse model next generation novel osteoblast differentiation osteosarcoma pediatric patients postnatal progenitor rational design single-cell RNA sequencing type I and type II diabetes warning label

项目摘要

Abstract Compelling clinical evidence has linked diabetes with increased fracture risks and impaired bone healing. Suppressed bone turnover is a common feature in both type I and type II diabetes. Therefore, use of bisphosphonates, which are the main stay of osteoporosis treatment but further suppress bone turnover, may exacerbate bone quality deterioration in the long term. The current bone anabolic drugs however have limited use in diabetic patients, particularly diabetic children, due to black box warnings. Thus, there remain tremendous unmet needs for safe and effective bone anabolic drugs. A thorough understanding of cellular metabolism in diabetic bone is essential for rational designs of novel bone therapies, but research in this area has been hampered by the lack of adequate knowledge about normal metabolism in bone cells. In recent years we and others have uncovered new details about the metabolic signatures of osteoblasts and osteoclasts, therefore providing a solid foundation for investigating the potential dysregulation of bone cell metabolism in the context of diabetes. As type 1 diabetes (T1D) is the most common form of newly diagnosed diabetes in childhood, we focus our present study on T1D by employing the Akita mouse that harbors a spontaneous point mutation in the Ins2 gene causing postnatal apoptosis of pancreatic ß cells. We propose to test the central hypothesis that type I diabetes disrupts normal osteoblast metabolism and that enhancement of glucose metabolism in osteoblasts can mitigate diabetic bone defects. We test the hypothesis in three specific aims. Aim 1 will characterize the bone defects at the cellular level in the diabetic mouse. Aim 2 will detail the metabolic defects in osteoblasts caused by diabetes, and specifically investigate the role of insulin. Finally, in Aim 3 we will test genetically whether stimulation of glycolysis ameliorates the bone defect in the diabetic mouse. Successful completion of the proposal is likely to open a new avenue for developing bone- enhancing drugs.

抽象的令人信服的临床证据表明，糖尿病与骨折风险增加和骨愈合受损有关。骨转换受到抑制是 I 型和 II 型糖尿病的共同特征，因此使用。双膦酸盐是骨质疏松症治疗的主要药物，但会进一步抑制骨转换，可能从长远来看，会加剧骨质量恶化，但目前的骨合成代谢药物的作用有限。由于黑匣子警告，糖尿病患者尤其是糖尿病儿童的使用仍然存在。对安全有效的骨合成代谢药物的巨大未满足需求。糖尿病骨骼的代谢对于新型骨疗法的合理设计至关重要，但该领域的研究近年来，由于对骨细胞正常代谢缺乏足够的了解而受到阻碍。我们和其他人发现了有关成骨细胞和破骨细胞代谢特征的新细节，因此为研究骨细胞代谢的潜在失调提供了坚实的基础 1 型糖尿病 (T1D) 是新诊断糖尿病的最常见形式。童年时期，我们目前的研究重点是 T1D，使用具有自发点的秋田小鼠 Ins2 基因突变导致胰腺 ß 细胞出生后凋亡。我们建议测试中枢。假设 I 型糖尿病会破坏正常的成骨细胞代谢，并且增强成骨细胞中的葡萄糖代谢可以减轻糖尿病性骨缺损，我们在三个方面检验了这一假设。目标 1 将在细胞水平上表征糖尿病小鼠的骨缺陷。详细介绍了糖尿病引起的成骨细胞的代谢缺陷，并专门研究了胰岛素的作用。最后，在目标 3 中，我们将从基因角度测试刺激糖酵解是否可以改善骨骼中的骨缺损。糖尿病小鼠的成功完成可能会为骨骼发育开辟一条新途径。增强药物。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Glucose metabolism in skeletal cells.

DOI：
10.1016/j.bonr.2022.101640
发表时间：
2022-12
期刊：
BONE REPORTS
影响因子：
2.5
作者：
Long, Fanxin
通讯作者：
Long, Fanxin

Sexual dimorphism of osteoclast reliance on mitochondrial oxidation of energy substrates in the mouse.

DOI：
10.1172/jci.insight.174293
发表时间：
2023-12-22
期刊：
JCI INSIGHT
影响因子：
8
作者：
Song, Chao;Valeri, Arianna;Song, Fangfang;Ji, Xing;Liao, Xueyang;Marmo, Tyler;Seeley, Rebecca;Rutter, Jared;Long, Fanxin
通讯作者：
Long, Fanxin

Glycemic Control and Bone in Diabetes.

DOI：
10.1007/s11914-022-00747-6
发表时间：
2022-12
期刊：
Current osteoporosis reports
影响因子：
4.3
作者：
通讯作者：

Genetic activation of glycolysis in osteoblasts preserves bone mass in type I diabetes.

成骨细胞糖酵解的基因激活可保护 I 型糖尿病患者的骨量。

DOI：
10.1016/j.chembiol.2023.07.003
发表时间：
2023
期刊：
Cell chemical biology
影响因子：
8.6
作者：
Ji,Xing;Seeley,Rebecca;Li,Ke;Song,Fangfang;Liao,Xueyang;Song,Chao;Angelozzi,Marco;Valeri,Arianna;Marmo,Tyler;Lee,Wen-Chih;Shi,Yu;Long,Fanxin
通讯作者：
Long,Fanxin

Osteoblast-intrinsic defect in glucose metabolism impairs bone formation in type II diabetic male mice.