Mitochondrial metabolism and bone formation

线粒体代谢和骨形成

• 批准号: 10321534
• 负责人: Roman Eliseev
• 金额: $ 33.54万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10321534
• 关键词: Adipocytes; Aging; BMP2 gene; Binding Sites; Biological Assay; Biology; Bone Marrow; Brain; Cardiovascular Physiology; Cell Respiration; Cells; Chondrocytes; Cyclophilin A; DNA Binding; Dangerousness; Data; Development; Differentiation Antigens; Down-Regulation; Drug Targeting; Energy Metabolism; Ensure; Event; Fracture; Genes; Genetic; Genetic Transcription; Goals; Heart; Human; IGF1 gene; Impairment; In Vitro; Injury; Kidney; Knock-out; Knockout Mice; Knowledge; Lead; Literature; Messenger RNA; Metabolic; Mission; Mitochondria; Mus; Neurosciences; Osteoblasts; Osteogenesis; Oxidative Phosphorylation; Oxidative Stress; Pathologic; Pathology; Pharmacology; Phosphorylation Inhibition; Physiology; Public Health; Publishing; Regulation; Reporter; Reporting; Research; Role; Stress; Stromal Cells; Testing; Therapeutic; Tissues; Transcription Repressor; Trauma; United States National Institutes of Health; base; biomechanical test; bone; bone fracture repair; bone loss; bone marrow mesenchymal stem cell; bone marrow stromal stem cell; bone strength; conditional knockout; cortical bone; cyclophilin D; disability; improved; in vivo; indexing; inhibitor; ischemic injury; loss of function; mitochondrial dysfunction; mitochondrial metabolism; mitochondrial permeability transition pore; muscle physiology; novel; osteoblast differentiation; osteogenic; programs; promoter; sensor; stem cell differentiation; subcutaneous; substantia spongiosa; targeted treatment; therapeutic target

Our long-term goal is to understand the role and regulation of mitochondrial metabolism in bone physiology and pathology. Unlike other fields, such as cardiovascular and muscle physiology and neuroscience, to date very little effort has been directed towards mitochondrial research in the bone field. This presents an immense knowledge gap and a critical barrier to developing novel mitochondria-targeted strategies for bone pathologies, such as aging and trauma which are known to be associated with mitochondrial dysfunction. This also gives special significance to our mitochondria-centered proposal. Our objective here is to determine the mechanism controlling mitochondrial activity during osteoblastic (OB) differentiation of bone marrow stromal cells (BMSC, a.k.a. bone marrow mesenchymal stem cells) and test if strategies aimed at improving mitochondrial metabo- lism stimulate OB differentiation and bone formation. Our published and new unpublished data indicate that during OB differentiation, mitochondria fuse into a network, a phenomenon known to maximize the fidelity for oxidative phosphorylation (OxPhos). A dangerous byproduct of active OxPhos is oxidative stress which pro- motes opening of a large Mitochondrial Permeability Transition Pore (MPTP). MPTP opening impairs mito- chondrial integrity and function. Cyclophilin D (CypD) is a key positive regulator of MPTP. It is, thus beneficial for cells undergoing a shift towards oxidative metabolism, e.g. BMSCs differentiating into OBs, to inactivate CypD/MPTP. We indeed found that as mitochondria become fused and activated during OB differentiation, CypD is downregulated at the mRNA level ensuring protection against oxidative stress and supporting OxPhos and progression of OB program. Moreover, our data indicate that CypD genetic deletion in knockout (KO) mice or pharmacological inhibition is especially efficient in supporting OB oxidative and bone forming function under pathological stress, such as in aging and fracture. We recently reported that CypD KO mice are well protected against bone loss in aging. This is consistent with the literature showing that brain, heart, and kidney tissues of CypD KO mice are protected against degeneration in aging or ischemic injury. All this led us to hypothesize that mitochondrial fusion and CypD downregulation leading to activation of OxPhos and inhibition of MPTP dur- ing OB differentiation, are critical for OB differentiation. To test this hypothesis and fulfill our objective, we will: 1) characterize the mechanism by which mitochondria are activated during OB differentiation focusing on mito- chondrial fusion; 2) characterize the role and regulation of CypD/MPTP during OB differentiation; and 3) evalu- ate CypD as a therapeutic target to improve bone formation in fracture healing and aging. These studies will provide comprehensive understanding of regulation of mitochondrial metabolism during OB differentiation and a rationale for developing new mitochondria-targeted therapeutic strategies in bone.

我们的长期目标是了解线粒体代谢在骨生理学中的作用和调节 和病理学。迄今为止，与心血管、肌肉生理学和神经科学等其他领域不同 在骨领域的线粒体研究方面所做的努力很少。这呈现出巨大的 知识差距和开发针对骨病理学的新型线粒体靶向策略的关键障碍， 例如已知与线粒体功能障碍有关的衰老和创伤。这也给出了 对我们以线粒体为中心的提案具有特殊意义。我们的目标是确定机制 在骨髓基质细胞（BMSC、 又名骨髓间充质干细胞）并测试是否旨在改善线粒体代谢的策略 lism 刺激 OB 分化和骨形成。我们已发布和新未发布的数据表明 在 OB 分化过程中，线粒体融合成一个网络，这种现象已知可以最大限度地提高 OB 的保真度 氧化磷酸化（OxPhos）。活性 O​​xPhos 的一个危险副产品是氧化应激，它会促进 微粒打开了一个大的线粒体渗透性转换孔（MPTP）。 MPTP 开放损害线粒体 软骨的完整性和功能。亲环蛋白 D (CypD) 是 MPTP 的关键正向调节因子。因此，这是有益的 对于正在向氧化代谢转变的细胞，例如BMSCs 分化为 OB，从而失活 CypD/MPTP。我们确实发现，随着线粒体在 OB 分化过程中融合并激活， CypD 在 mRNA 水平上下调，确保免受氧化应激并支持 OxPhos 和 OB 计划的进展。此外，我们的数据表明敲除（KO）小鼠中的 CypD 基因缺失 或药物抑制在支持 OB 氧化和骨形成功能方面特别有效 病理应激，例如衰老和骨折。我们最近报道 CypD KO 小鼠受到很好的保护 对抗衰老过程中的骨质流失。这与文献表明，大脑、心脏和肾脏组织 CypD KO 小鼠可免受衰老或缺血性损伤引起的退化。所有这一切使我们做出假设 线粒体融合和 CypD 下调导致 OxPhos 激活并抑制 MPTP OB 分化，对于 OB 分化至关重要。为了检验这一假设并实现我们的目标，我们将： 1) 描述 OB 分化过程中线粒体被激活的机制，重点关注线粒体 软骨融合； 2) 表征CypD/MPTP在OB分化过程中的作用和调节； 3）评估- 将 CypD 作为改善骨折愈合和衰老过程中骨形成的治疗靶点。这些研究将 提供对 OB 分化过程中线粒体代谢调节的全面了解 开发新的线粒体靶向骨治疗策略的基本原理。

项目成果

Mitochondrial permeability transition regulator, cyclophilin D, is transcriptionally activated by C/EBP during adipogenesis.

• DOI: 10.1016/j.jbc.2023.105458
• 发表时间: 2023-12
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Yu, Chen;Sautchuk, Rubens Jr;Martinez, John;Eliseev, Roman A
• 通讯作者: Eliseev, Roman A

Bone morphogenic protein-2 signaling in human disc degeneration and correlation to the Pfirrmann MRI grading system.

• DOI: 10.1016/j.spinee.2021.03.002
• 发表时间: 2021-07
• 期刊: The spine journal : official journal of the North American Spine Society
• 作者: Hollenberg AM;Maqsoodi N;Phan A;Huber A;Jubril A;Baldwin AL;Yokogawa N;Eliseev RA;Mesfin A
• 通讯作者: Mesfin A