Osteoporosis and osteoblast differentiation in mouse models of accelerated aging

加速衰老小鼠模型中的骨质疏松症和成骨细胞分化

• 批准号: 7877955
• 负责人: ROBERT JOHN PIGNOLO
• 金额: $ 31.33万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7877955
• 关键词: Age; Age-Related Bone Loss; Aging; Animals; Architecture; Bone Density; Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; Cell Aging; Characteristics; Clinical; Cultured Cells; DNA; Defect; Disease; Dyskeratosis Congenita; Elderly; Fracture; Functional disorder; Genetic Models; Genome; Hematopoietic stem cells; Homeostasis; Human; Impairment; In Vitro; Individual; Knockout Mice; Longevity; Maintenance; Mesenchymal; Mesenchymal Stem Cells; Minerals; Modeling; Mus; Mutant Strains Mice; Mutation; Osteoblasts; Osteogenesis; Osteoporosis; Pathogenesis; Phenotype; Premature aging syndrome; RNA; Relative (related person); Research Personnel; Role; Senile Osteoporosis; Stem cells; System; Telomerase; Telomere Shortening; Testing; Tissues; Werner Syndrome; age related; bone; bone mass; bone strength; cell type; helicase; high risk; human tissue; impaired capacity; mouse model; osteoblast differentiation; osteogenic; overexpression; premature; prevent; progenitor; programs; senescence; telomere

DESCRIPTION (provided by applicant): A fundamental aspect of age-related bone loss is the decreased proliferative capacity and impaired differentiation of osteoblasts in the bone of older individuals. Telomeres shorten with age in most human tissues, including bone, and since telomere shortening is a cause of cellular replicative senescence in cultured cells, including osteoblasts and mesenchymal stem cells (MSCs), it is likely that telomere status in MSCs is a critical component of bone formation. Osteoporosis is common in the Werner (Wrn) and Dyskeratosis congenita (DC) premature aging syndromes. One of the targets of the Wrn helicase is telomeric DNA, but the long telomeres and abundant telomerase in mice minimize the need for WRN at telomeres, and thus Wrn knockout mice are healthy. In a model of accelerated aging that combines the Wrn mutation with the shortened telomeres of telomerase (Terc) knockout mice, synthetic defects in proliferative tissues, including bone, have been observed. It is hypothesized that deficiencies in genome maintenance molecules such as TERC and WRN cause a low bone mass phenotype and microarchitectural abnormalities of bone by impairing the ability of MSCs to differentiate into osteoblasts. It is further hypothesized that effective osteoblast differentiation depends on the presence of functional MSCs and hematopoietic stem cells (HSCs). Using micro-CT analysis and bone histomorphometry, this proposal will establish the relationship between the WRN and TERC molecules and structural bone fidelity, including microarchitecture and bone density. We will determine if age-related bone abnormalities in Wrn-/-, Terc-/- and Wrn -/- Terc-/- mice are related to deficiencies in osteoblast differentiation and/or increased osteoclastogenic potential, and will examine whether anabolic defects due to MSC impairment in mutant mice are associated with replicative senescence and/or telomere shortening/uncapping. We will also assess the contributions of MSCs and HSCs to osteoblast differentiation by selective and nonselective bone marrow transplantation of these cellular progenitors and analysis of their ability to reduce age-related osteoporotic changes. A consequence and major clinical challenge in the elderly is osteoporosis and associated high risk of fracture. The Wrn-/-Terc -/- mutant mouse recapitulates senile osteoporosis characterized by decreased bone-forming capacity and provides a system to test stem cell replacement for amelioration of age-related osteoporosis.

描述（由申请人提供）：与年龄相关的骨质流失的基本方面是增殖能力的降低和老年人骨骼中成骨细胞分化的分化受损。在包括骨骼在内的大多数人体组织中，端粒随着年龄的增长而缩短，并且由于端粒缩短是培养细胞中细胞复制性衰老的原因，包括成骨细胞和间质干细胞（MSC），因此MSC中的端粒状态可能是MSC的关键成分。骨质疏松症在Werner（WRN）和症状症状症状（DC）早熟综合症中很常见。 WRN解旋酶的一个靶标之一是端粒DNA，但在小鼠中，长的端粒和丰富的端粒酶可以最大程度地减少端粒中WRN的需求，因此WRN敲除小鼠很健康。在将WRN突变与端粒酶（TERC）基因敲除小鼠缩短的加速衰老模型中，已经观察到包括骨骼在内的增殖组织中的合成缺陷。假设基因组维持分子（例如TERC和WRN）的缺陷会导致骨骼质量表型低，而骨骼的微体系构型异常则通过损害MSC分化为骨细胞的能力。进一步假设有效的成骨细胞分化取决于功能性MSC和造血干细胞（HSC）的存在。使用Micro-CT分析和骨骼组形态计量学，该建议将建立WRN和TERC分子与结构性骨骼忠诚之间的关系，包括微体系结构和骨密度。 We will determine if age-related bone abnormalities in Wrn-/-, Terc-/- and Wrn -/- Terc-/- mice are related to deficiencies in osteoblast differentiation and/or increased osteoclastogenic potential, and will examine whether anabolic defects due to MSC impairment in mutant mice are associated with replicative senescence and/or telomere shortening/uncapping.我们还将通过选择性和非选择性的骨髓移植对这些细胞祖细胞的选择性和非选择性骨髓移植以及减少与年龄相关的骨质疏松变化的能力进行分析，以评估MSC和HSC对成骨细胞分化的贡献。老年人的后果和重大临床挑战是​​骨质疏松症和骨折的高风险。 WRN - / - TERC - / - 突变小鼠概括了老年骨质疏松症，其特征是骨形成能力降低，并提供了一种测试干细胞替代的系统，以改善与年龄相关的骨质疏松症。