Mitochondrial genetics as a determinant of bone health

摘要 线粒体在骨组织生理学和病理学中的作用仍然研究不足。我们的长期目标 是填补这一知识空白，而这一高风险提案是朝着这一目标迈出的一步。它将测试线粒体 遗传学（mtDNA单倍型）影响成骨细胞（OB）及其前体的骨表型和功能， 骨髓基质细胞（也称为间充质干细胞（BMSCs）。这里的科学前提是：1） 线粒体氧化磷酸化（OxPhos）是成骨分化所必需的; 2）线粒体 功能障碍在骨老化中起着重要作用; 3）线粒体疾病患者具有脆弱的骨骼; 4） 为适应寒冷气候，线粒体DNA单倍型群“效率较低”的欧亚人种， 与具有“更高效”mtDNA单倍群L的非洲人后裔相比， (C3H)具有更有效mtDNA单倍型的小鼠也比具有更少mtDNA单倍型的C57 BL/6 J（C57）小鼠具有更强壮的骨骼。 有效mtDNA单倍型。为了研究核基因组与mtDNA基因组对表型的贡献，我们将使用 一种精细的新遗传模型，线粒体/核交换（MNX）小鼠。这些MNX小鼠具有C57或C3 H 核背景，但C3 H和C57 mtDNA分别（C57 n; C3 Hmt和C3 Hn; C57 mt）。这些小鼠体内的细胞 显示OxPhos活性根据其mtDNA单倍型而不是其核背景。我们的试点数据 结果显示，C57 n; C3 Hmt BMSCs成骨能力高于C3 Hn; C57 mt BMSCs，而C3 Hn; C57 mt BMSCs成骨能力低于C3 Hn; C57 mt BMSCs， 分别为相应的对照C57和C3 H。我们还观察到3月龄F小鼠的骨增长， C3Hn; C57mt < C3H）。我们的核心假设是 线粒体遗传学是BMSC成骨潜能、OB骨形成功能和成骨能力的重要决定因素。 骨表型为了测试它，我们将确定MNX小鼠是否具有改变的骨表型（Aim 1）和改变的骨表型（Aim 1）。 BMSC成骨和OB骨形成功能和髓核通讯（目的2）， 与野生型对照相比。如果成功，该项目将为我们的新方向奠定坚实的基础。 研究和骨领域的一般，骨线粒体遗传学。

Abstract The role of mitochondria in bone tissue physiology and pathology remains understudied. Our long-term goal is to fill this gap of knowledge and this high risk proposal is a step towards this goal. It will test if mitochondrial genetics (mtDNA haplotype) influences bone phenotype and function of osteoblasts (OB) and their precursors, bone marrow stromal (a.k.a. mesenchymal stem) cells (BMSCs). The scientific premise here is that: 1) mitochondrial oxidative phosphorylation (OxPhos) is required for osteogenic differentiation; 2) mitochondrial dysfunction plays a significant role in bone aging; 3) patients with mitochondrial diseases have fragile bones; 4) Eurasians with ‘less efficient’ mtDNA haplogroups developed as an adaptation to cold climate, also have weaker bones when compared to people of African descent with ‘more efficient’ mtDNA haplogroup L; and 5) C3H/HeN (C3H) mice with more efficient mtDNA haplotype, also have stronger bones then C57BL/6J (C57) mice with less efficient mtDNA haplotype. To study contributions of nuclear vs mtDNA genome to a phenotype, we will use a delicate new genetic model, mitochondrial/nuclear exchange (MNX) mice. These MNX mice have C57 or C3H nuclear background but C3H and C57 mtDNA, respectively (C57n;C3Hmt and C3Hn;C57mt). Cells in these mice show OxPhos activity according to their mtDNA haplotype rather than their nuclear background. Our pilot data show that C57n;C3Hmt BMSCs have higher, while C3Hn;C57mt BMSCs have lower osteogenic potential than their corresponding controls, C57 and C3H, respectively. We also observed that bone accrual in 3 mo old F mice reflected their mtDNA haplogroup (C57n;C3Hmt > C57 while C3Hn;C57mt < C3H). Our central hypothesis that mitochondrial genetics is a strong determinant of BMSC osteogenic potential, OB bone-forming function, and bone phenotype. To test it, we will determine if MNX mice have altered bone phenotype (Aim 1) and altered BMSC osteogenic and OB bone-forming function and mitochondrio-nuclear communication (Aim 2) when compared to their wild type controls. If successful, this project will lay strong foundation for a new direction in our research and bone field in general, mitochondrial genetics of bone.