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: 8076265
• 负责人: CHARLOTTE L PHILLIPS
• 金额: $ 32.4万
• 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/8076265
• 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-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）：峰值骨骼质量是骨质疏松症的主要决定因素。在儿童期和青春期获得的骨矿物质对于达到最大峰值骨质至关重要。在关键的两年中，围绕峰值应计的峰值的青春期窗口，约有26％的最终成人骨骼质量；众所周知，身体活跃的儿童比不活跃的儿童高出10-40％的骨头（特定区域）。骨骼本质上具有机械敏感性，对其机械环境做出反应和适应。骨骼形成是响应高机械负荷而发生的。经常改变几何形状以增强骨骼。最大的生理负荷骨骼通常来自肌肉，骨骼强度与肌肉质量成正比。成骨不完美（OI）是一种可遗传的结缔组织障碍，其特征是身材较小，骨矿物质密度降低和频繁裂缝。据报道，OI患者的肌肉无力。在一项研究中，发现儿童相对于健康年龄匹配的儿童，儿童的肌肉力量降低，运动耐受性降低。不过，尚不清楚，是否降低了肌肉力量和运动耐受性是久坐的生活方式或OI病理学固有的结果。 OIM小鼠的初步研究（成骨不完美模型）表明，OIM/OIM小鼠中肌肉质量的减少反映了它们的大小和体育活动的降低，并且相对收缩的产生能力[峰值四抗张力（PO）肌肉/g]与年龄段的野生野生型野生型小鼠没有显着差异。儿童期和青春期的运动和体育锻炼对于个人获得全部峰值骨骼质量潜力至关重要。 OI儿童缺乏体育锻炼，特别是在最大骨骼造成的关键窗口中，使OI患者成为成年人的骨骼健康。我们建议利用两种骨生成不完美的小鼠模型：OIM鼠标，该模型是由于单倍不足而导致的轻度和重度OI模型[oim/+（型号I oi OI）和OIM/OIM（人类OI型III型）]和新的G610C Col1a2和新的G610C COL1A2鼠标的新型Modelains Mandiv of Modelast of Mandure Inflosim of Humans Inflosim Inflosim of Humans Indiv（G610C/+）（G610C/+）（g610c/+）在肌肉强度，骨骼质量和力量上进行非重量轴承（游泳）和体重轴承（跑步机）。具体而言，在目标1中，我们将评估6周大的活动和选定的肌肉（青春期 - 基线和治疗开始的年龄）和4个月大的小鼠（峰值骨质量年龄），以确定OIM和/或G610C小鼠是否具有固有的肌肉无力或病理学（肌肉质量，肌肉质量较低的能力，以及对野生的骨骼和疾病的造成较低的肌肉质量，并且造成野生型的肌肉差异）是否具有较低同窝工人。 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多尺度级别。在AIM 3中，我们将确定游泳（非重量轴承）和/或在跑步机（负重轴承）运动方案上是否会增加肌肉收缩的产生能力和耐力，改变骨矿物质和基质的分子结构，并改善OIM和G610C小鼠的骨骼理学/生物力学特性/生物力学特性。 公共卫生相关性：成骨不完美是一种可遗传的结缔组织障碍，其特征是肌肉无力和骨骼脆弱性。我们将使用两种不同的成骨不合情的小鼠模型来评估增加肌肉力量和耐力的潜在治疗作用，以及通过体重和非重量轴承运动方案的骨骼质量和强度。