Mechanotransduction Approach to Improve Bone Quality in Osteogenesis Imperfecta

改善成骨不全患者骨质量的力传导方法

• 批准号: 7886189
• 负责人: CHARLOTTE L PHILLIPS
• 金额: $ 32.64万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7886189
• 关键词: Adolescence; Adult; Affect; Age; Age-Months; Area; Biomechanics; Bone Density; COL1A2 gene; Chemical Structure; Chemistry; Child; Childhood; Contracts; Data; Development; Disease; Dominant-Negative Mutation; Elderly; Environment; Exercise; Exercise Tolerance; Failure; Fatigue; Fiber; Fracture; Human; Individual; Life Style; Maintenance; Mechanics; Microscopy; Minerals; Modeling; Molecular; Molecular Structure; Mus; Muscle; Muscle Weakness; Osteogenesis; Osteogenesis Imperfecta; Osteoporosis; Pathology; Patients; Physical activity; Physiological; Property; Regimen; Relative (related person); Reporting; Running; Scanning Acoustic Microscopy; Skeleton; Spectroscopy, Fourier Transform Infrared; Structure; Swimming; Therapeutic Effect; Time; Weight; Weight-Bearing state; bone; bone geometry; bone health; bone mass; bone quality; bone strength; experience; heritable connective tissue disorder; improved; mouse model; muscle form; muscle strength; postnatal; public health relevance; response; sedentary; skeletal

DESCRIPTION (provided by applicant): Peak bone mass is a major determinant of osteoporosis. The bone mineral acquired during childhood and adolescence is critical to attaining maximal peak bone mass. During the critical two year pubertal window surrounding peak bone accrual about 26% of final adult bone mass is acquired; children whom are physically active are known to accrue 10-40% more bone (region specific) than inactive children. Bone is inherently mechanosensitive, responding and adapting to its mechanical environment. Bone formation occurs in response to high mechanical loads; often changing geometry to strengthen the skeleton. The largest physiological loads bones typically experience are from muscles, and bone strength is proportional to muscle mass. Osteogenesis imperfecta (OI) is a heritable connective tissue disorder characterized by small stature, reduced bone mineral density and frequent fractures. OI patients reportedly have muscle weakness. In a single study OI children were found to have reduced muscle strength and decreased exercise tolerance relative to healthy age-matched children. It is unclear though, if the reduced muscle strength and exercise tolerance are a consequence of sedentary lifestyles or inherent to the pathology of OI. Preliminary studies of oim mice (osteogenesis imperfecta model) suggest that the reduced muscle mass in oim/oim mice is a reflection of their reduced size and physical activity, and that the relative contractile generating capacity [peak tetanic tension (Po)/g of muscle] is not significantly different from age-matched wildtype mice. Exercise and physical activity during childhood and adolescence are essential for an individual to attain their full peak bone mass potential; the lack of physical activity in OI children particularly during this critical window of maximal bone accrual is setting OI patients up for even poorer bone health as adults. We propose to utilize two mouse models of osteogenesis imperfecta: the oim mouse which models mild and severe OI due to haploinsufficiency [oim/+ (models human type I OI) and oim/oim (human OI type III)] and the new G610C COL1A2 mouse which models dominant negative molecular mechanisms [G610C/+ (models human type I and IV OI)] to investigate the impact of non-weight bearing (swimming) and weight bearing (treadmill) exercise on muscle strength and bone quality and strength. Specifically, in Aim 1 we will evaluate activity and selected muscles in 6 week old (adolescence-baseline and age of initiation of treatment) and 4 month old (age of peak bone mass) mice to determine if oim and/or G610C mice have an inherent muscle weakness or pathology (reduced muscle mass, fiber cross-sectional area and/or contractile generating capacity) that may contribute to bone weakness and whether physical activity is altered relative to wildtype littermates. In Aim 2, we will evaluate femoral geometry (uCT) and biomechanics (torsional loading to failure) of 6 week and 4 month old oim and G610C mice in relation to mineral and matrix, physicochemical and mechanical properties of the bone by multi-scale analyses ( FTIR, Raman and scanning acoustic microscopy) to determine the structure/chemistry/biomechanical relationship at the multi-scale level. In Aim 3 we will determine if swimming (non-weight bearing) and/or running on a treadmill (weight bearing) exercise regimens will increase muscle contractile generating capacity and endurance, alter the molecular structure of bone mineral and matrix, and improve bone physicochemical properties/biomechanical integrity in oim and G610C mouse bones. PUBLIC HEALTH RELEVANCE: Osteogenesis imperfecta is a heritable connective tissue disorder characterized by muscle weakness and skeletal fragility. We will evaluate the potential therapeutic effects of increasing muscle strength and endurance, and concomitantly bone quality and strength by weight-bearing and non-weight bearing exercise regimens using two distinct osteogenesis imperfecta mouse models.

描述（由申请人提供）：峰值骨量是骨质疏松症的主要决定因素。在儿童和青少年时期获得的骨矿物质是达到最大峰值骨量的关键。在关键的两年青春期窗口期，骨量峰值周围约26%的最终成人骨量获得；据了解，经常运动的儿童比不运动的儿童多积累10-40%的骨质（具体地区）。骨骼天生具有机械敏感性，能够对其机械环境做出反应和适应。骨形成是对高机械负荷的反应；经常改变几何形状以加强骨架。骨骼通常承受的最大生理负荷来自肌肉，而骨骼强度与肌肉质量成正比。成骨不全症（Osteogenesis imperfecta， OI）是一种遗传性结缔组织疾病，其特征是身材矮小、骨密度降低和经常骨折。据报道，成骨不全患者有肌肉无力。在一项单独的研究中发现，与健康的同龄儿童相比，成骨不全症儿童的肌肉力量和运动耐受性降低。然而，目前尚不清楚，肌肉力量和运动耐受性的降低是久坐生活方式的结果，还是成骨不全症的固有病理。对oim小鼠（成骨不全模型）的初步研究表明，oim/oim小鼠肌肉质量的减少是其体型和体力活动减少的反映，相对收缩生成能力[肌肉的峰值破伤风张力(Po)/g]与年龄匹配的野生型小鼠没有显著差异。儿童和青少年时期的锻炼和体育活动对于个体达到骨量潜力的最大峰值至关重要；成骨不全儿童，尤其是在骨量最大的关键时期，缺乏身体活动，会使成骨不全患者成年后的骨骼健康状况更差。我们建议利用两种成骨不全小鼠模型：模拟单倍不全导致的轻度和重度成骨不全的oim小鼠[oim/+（人类I型成骨不全模型）和oim/oim（人类III型成骨不全模型）]和模拟显性负分子机制的新型G610C COL1A2小鼠[G610C/+（人类I型和IV型成骨不全模型）]来研究非负重（游泳）和负重（跑步机）运动对肌肉力量和骨质量和强度的影响。具体来说，在目标1中，我们将评估6周龄（青春期基线和开始治疗的年龄）和4个月大（骨量峰值年龄）小鼠的活动和选定的肌肉，以确定oim和/或G610C小鼠是否具有固有的肌肉无力或病理（肌肉质量、纤维横截面积和/或收缩生成能力减少），这可能导致骨无力，以及相对于野生型幼崽，身体活动是否发生了改变。在Aim 2中，我们将通过多尺度分析（FTIR、拉曼和扫描声学显微镜）评估6周龄和4个月大的oim和G610C小鼠的股骨几何形状（uCT）和生物力学（扭转载荷至失效）与骨骼矿物和基质、物理化学和力学特性的关系，以确定多尺度水平上的结构/化学/生物力学关系。在Aim 3中，我们将确定游泳（非负重）和/或在跑步机上跑步（负重）运动方案是否会增加肌肉收缩产生能力和耐力，改变骨矿物质和基质的分子结构，并改善oim和G610C小鼠骨骼的物理化学性质/生物力学完整性。