Genetic Analysis of Bone Structure and Strength

骨骼结构和强度的遗传分析

• 批准号: 7429790
• 负责人: CHARLES H TURNER
• 金额: $ 40.85万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-08 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7429790
• 关键词: Adult; Affect; Bone Density; Bone Growth; Calcium; Calvaria; Cellular Mechanotransduction; Chromosomes; Complex; Congenic Mice; Congenic Strain; Cultured Cells; Disease; Female; Femur; Gene Expression; Genes; Genetic; Inbred C3H Mice; Inbred Mouse; Link; Liquid substance; Location; Maps; Measures; Mechanics; Modeling; Molecular Profiling; Mouse Strains; Mus; Osteoblasts; Osteoporosis; Pathway interactions; Phenotype; Prostaglandins; Quantitative Trait Loci; Skeletal system; Stimulus; Structure; Tissue-Specific Gene Expression; Work; bone; congenic; genetic analysis; in vivo; interest; long bone; male; mouse model; progenitor; response; shear stress; size; trait; ulna

DESCRIPTION (provided by applicant): Osteoporosis is a complex disease, from a genetics standpoint. Bone mass and structure are highly heritable traits, but there are probably many genes that contribute to these traits. We have identified quantitative trait loci (QTL) in B6C3F2 mice that are linked to bone structure and strength. In addition, we have developed 11 congenic mouse lines, each of which contains a bone structure/strength QTL. Our preliminary studies demonstrate that the progenitor mouse strains (C57BL/6 and C3H/He) differ considerably in their skeletal response to mechanical loading. Furthermore, we demonstrated in a congenic mouse line, B6.C3H-4T, a significantly enhanced skeletal responsiveness to mechanical loading. Not surprisingly, B6.C3H-4T femurs have significantly larger cross-sectional size compared to B6 control femurs. This finding suggests that congenic mice can be used to identify genes that affect cellular mechanotransduction in bone. We have identified four congenic mouse lines (in addition to B6.C3H-4T) that have altered femoral crosssectional size. We propose to determine which of these congenic lines differ in skeletal mechanical loading response. We will then develop congenic sublines and complete fine mapping of the QTLs to isolate genes contributing to altered mechanotransduction. We will develop multiple sublines of congenic mice to genetically dissect each QTL region to better pinpoint the location on the chromosome contributing to femoral BMD and/or structure/strength phenotypes. In addition we will study osteoblasts isolated from congenic mouse lines to determine their responsiveness to mechanical stimuli and we will examine gene expression profiles in bones from congenic mice and in isolated osteoblasts in order to determine the genetic pathways that differ among the congenic lines.

描述（由申请人提供）：从遗传学的角度来看，骨质疏松症是一种复杂的疾病。骨质和结构是高度遗传的特征，但可能有许多基因促成这些特征。我们已经在 B6C3F2 小鼠中鉴定出与骨骼结构和强度相关的数量性状基因座 (QTL)。此外，我们还培育了11个同源小鼠品系，每个品系都包含一个骨骼结构/强度QTL。我们的初步研究表明，祖代小鼠品系（C57BL/6 和 C3H/He）在骨骼对机械负荷的反应方面存在很大差异。此外，我们在同系小鼠 B6.C3H-4T 中证明了骨骼对机械负荷的反应性显着增强。毫不奇怪，与 B6 对照股骨相比，B6.C3H-4T 股骨具有明显更大的横截面尺寸。这一发现表明，同源小鼠可用于识别影响骨骼细胞机械转导的基因。我们已经鉴定出四种同源小鼠系（除了 B6.C3H-4T 之外），它们改变了股骨横截面尺寸。我们建议确定这些同源系中哪些在骨骼机械负荷响应方面有所不同。然后，我们将开发同源亚系并完成 QTL 的精细定位，以分离有助于改变机械转导的基因。我们将开发多个同源小鼠亚系，对每个 QTL 区域进行基因剖析，以更好地查明染色体上有助于股骨 BMD 和/或结构/强度表型的位置。此外，我们将研究从同源小鼠品系中分离的成骨细胞，以确定它们对机械刺激的反应性，并且我们将检查同源小鼠骨骼和分离的成骨细胞中的基因表达谱，以确定同源品系之间不同的遗传途径。

项目成果

Numerical modeling of long bone adaptation due to mechanical loading: correlation with experiments.

由于机械载荷而导致的长骨适应的数值模型：与实验相关。

• DOI: 10.1007/s10439-009-9861-4
• 发表时间: 2010-03
• 期刊: ANNALS OF BIOMEDICAL ENGINEERING
• 影响因子: 3.8
• 作者: Kumar, Natarajan Chennimalai;Dantzig, Jonathan A.;Jasiuk, Iwona M.;Robling, Alex G.;Turner, Charles H.
• 通讯作者: Turner, Charles H.

The skeletal responsiveness to mechanical loading is enhanced in mice with a null mutation in estrogen receptor-beta.

雌激素受体-β 无效突变的小鼠的骨骼对机械负荷的反应性增强。

• DOI: 10.1152/ajpendo.00189.2007
• 发表时间: 2007
• 期刊: American journal of physiology. Endocrinology and metabolism
• 作者: Saxon,LK;Robling,AG;Castillo,AB;Mohan,S;Turner,CH
• 通讯作者: Turner,CH

Rapamycin impairs trabecular bone acquisition from high-dose but not low-dose intermittent parathyroid hormone treatment.

• DOI: 10.1002/jcp.21887
• 发表时间: 2009-12
• 期刊: JOURNAL OF CELLULAR PHYSIOLOGY
• 影响因子: 5.6
• 作者: Niziolek, P. J.;Murthy, S.;Ellis, S. N.;Sukhija, K. B.;Hornberger, T. A.;Turner, C. H.;Robling, A. G.
• 通讯作者: Robling, A. G.

Mechanical signaling for bone modeling and remodeling.

• DOI: 10.1615/critreveukargeneexpr.v19.i4.50
• 发表时间: 2009
• 期刊: Critical reviews in eukaryotic gene expression
• 影响因子: 1.6
• 作者: Robling AG;Turner CH
• 通讯作者: Turner CH

Gene expression patterns in bone following mechanical loading.

• DOI: 10.1002/jbmr.193
• 发表时间: 2011-01
• 期刊: JOURNAL OF BONE AND MINERAL RESEARCH
• 影响因子: 6.2
• 作者: Roosa, Sara M. Mantila;Liu, Yunlong;Turner, Charles H.
• 通讯作者: Turner, Charles H.