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

• 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
• 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

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.

摘要 令人信服的临床证据已经将糖尿病与骨折风险增加和骨愈合受损联系起来。 抑制骨转换是I型和II型糖尿病的共同特征。因此，使用 二膦酸盐是治疗骨质疏松症的主要药物，但会进一步抑制骨转换， 从长远来看，会加剧骨质恶化。然而，目前的骨合成代谢药物有限， 糖尿病患者，特别是糖尿病儿童，由于黑盒警告。因此， 对安全有效的骨合成代谢药物的巨大未满足的需求。深入了解细胞 糖尿病骨代谢对于合理设计新的骨疗法是必不可少的，但这一领域的研究 由于对骨细胞的正常代谢缺乏足够的了解，近年来 我们和其他人已经发现了关于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， 糖尿病的背景。由于1型糖尿病（T1 D）是最常见的新诊断糖尿病形式， 童年，我们集中我们目前的研究T1 D雇用秋田小鼠，窝藏一个自发点 Ins 2基因突变导致出生后胰腺癌细胞凋亡。我们建议测试中央 假设I型糖尿病破坏正常成骨细胞代谢， 成骨细胞中的葡萄糖代谢可以减轻糖尿病性骨缺损。我们在三个方面测试这个假设 明确的目标。目的1将在细胞水平上表征糖尿病小鼠的骨缺损。目标2将 详细介绍了糖尿病引起的成骨细胞代谢缺陷，并具体探讨了胰岛素的作用。 最后，在目标3中，我们将从遗传学上测试糖酵解的刺激是否改善了骨缺损。 糖尿病小鼠。该提案的成功完成可能会为骨骼开发开辟一条新的途径- 增强药物。

项目成果

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

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

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.

• DOI: 10.7554/elife.85714
• 发表时间: 2023-05-05
• 期刊: eLife
• 影响因子: 7.7
• 作者: Song F;Lee WD;Marmo T;Ji X;Song C;Liao X;Seeley R;Yao L;Liu H;Long F
• 通讯作者: Long F