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。与其他领域，如心血管和肌肉生理学和神经科学，到目前为止， 在骨骼领域，很少有人致力于线粒体的研究。这呈现了一个巨大的 知识差距和开发新的线粒体靶向骨骼病理策略的关键障碍， 如衰老和创伤，已知与线粒体功能障碍有关。这也给了我们 对我们的以线粒体为中心的提议具有特殊的意义。我们在这里的目标是确定 在骨髓基质细胞(BMSC)成骨分化过程中控制线粒体活性， 又名。骨髓间充质干细胞)，并测试旨在改善线粒体代谢的策略- LISM刺激成骨细胞分化和骨形成。我们公布的和新的未公布的数据表明 在卵母细胞分化过程中，线粒体融合成一个网络，这种现象可以最大限度地提高 氧化磷酸化(OxPhos)。活性OxPhos的一个危险副产品是氧化应激，它促进 微尘打开一个大的线粒体通透性转换孔(MPTP)。MPTP开放损害有丝分裂- 软骨的完整性和功能。亲环素D(CypD)是MPTP的关键正性调节因子。因此，它是有益的 对于正在向氧化代谢转变的细胞，例如分化为OB的BMSCs，使其失活 CypD/MPTP。我们确实发现，随着线粒体在OB分化过程中融合和激活， CypD在mRNA水平下调，确保对氧化应激的保护和支持OxPhos 和OB计划的进展。此外，我们的数据表明，在基因敲除(KO)小鼠中，CypD基因缺失 在以下情况下，药物抑制在支持OB氧化和骨形成功能方面尤其有效 病理性应激，如在衰老和骨折中。我们最近报道了CypD KO小鼠受到很好的保护 防止衰老过程中的骨质流失。这与文献中显示的大脑、心脏和肾脏组织 CypD KO小鼠在衰老或缺血损伤中受到保护，免受退化。所有这些都让我们提出了一个假设 线粒体融合和CypD下调导致OxPhos激活和MPTP抑制 OB的分化，是OB分化的关键。为了验证这一假设并实现我们的目标，我们将： 1)描述线粒体在OB分化过程中被激活的机制，重点是有丝分裂- 线粒体融合；2)CypD/MPTP在OB分化过程中的作用和调节；3)评估。 ATE CypD作为治疗靶点，在骨折愈合和衰老过程中改善骨形成。这些研究将 全面了解OB分化和分化过程中线粒体代谢的调节 开发新的骨骼线粒体靶向治疗策略的理论基础。

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