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: 8277100
• 负责人: CHARLOTTE L PHILLIPS
• 金额: $ 32.39万
• 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 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8277100
• 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）：峰值骨量是骨质疏松症的主要决定因素。儿童期和青春期获得的骨矿物质对于获得最大峰值骨量至关重要。在骨增长峰值周围的关键的两年青春期窗口期间，获得了最终成人骨量的约 26%；据了解，经常运动的儿童比不运动的儿童会多积 10-40% 的骨质（特定区域）。骨骼本质上是机械敏感的，能够响应并适应其机械环境。骨形成是响应高机械负荷而发生的；经常改变几何形状来强化骨骼。骨骼通常承受的最大生理负荷来自肌肉，骨骼强度与肌肉质量成正比。成骨不全症 (OI) 是一种遗传性结缔组织疾病，其特征是身材矮小、骨矿物质密度降低和频繁骨折。据报道，成骨不全患者有肌肉无力的症状。在一项研究中发现，与健康年龄匹配的儿童相比，成骨不全儿童的肌肉力量下降，运动耐量下降。但目前尚不清楚肌肉力量和运动耐量下降是否是久坐生活方式的结果，还是成骨不全症固有的病理机制。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反映了它们体型和体力活动的减少，并且相对收缩产生能力 [峰值强直张力 (Po)/g 肌肉] 与年龄匹配的野生型小鼠没有显着差异。儿童期和青春期的锻炼和体力活动对于个人充分发挥骨量峰值潜力至关重要；成骨不全儿童缺乏体力活动，特别是在最大骨质增生的关键时期，导致成骨不全患者成年后骨骼健康状况更差。我们建议使用两种成骨不全症小鼠模型：oim 小鼠，由于单倍剂量不足而模拟轻度和重度 OI [oim/+（模型人类 I 型 OI）和 oim/oim（人类 III 型 OI）] 和新的 G610C COL1A2模拟显性负分子机制的小鼠 [G610C/+（人类 I 型和 IV 型 OI 模型）]，以研究非负重（游泳）和负重（跑步机）锻炼对肌肉力量、骨骼质量和力量的影响。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年龄）和 4 个月龄（骨量峰值年龄）小鼠的活动和选定肌肉，以确定 oim 和/或 G610C 小鼠是否具有可能导致骨无力的固有肌肉无力或病理学（肌肉质量、纤维横截面积和/或收缩产生能力减少）以及身体活动是否相对于野生型同窝动物发生改变。在目标 2 中，我们将通过多尺度分析评估 6 周和 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）与骨骼的矿物质和基质、物理化学和机械特性的关系（FTIR、拉曼和扫描声学显微镜）确定多尺度水平的结构/化学/生物力学关系。在目标 3 中，我们将确定游泳（非负重）和/或在跑步机上跑步（负重）锻炼方案是否会增加肌肉收缩能力和耐力，改变骨矿物质和基质的分子结构，并改善骨理化oim 和 G610C 小鼠骨骼的特性/生物力学完整性。 公众健康相关性：成骨不全症是一种遗传性结缔组织疾病，其特征是肌肉无力和骨骼脆弱。我们将使用两种不同的成骨不全症小鼠模型，通过负重和非负重运动方案来评估增加肌肉力量和耐力以及随之而来的骨质量和强度的潜在治疗效果。

项目成果

Gender-dependence of bone structure and properties in adult osteogenesis imperfecta murine model.

• DOI: 10.1007/s10439-013-0793-7
• 发表时间: 2013-06
• 期刊: ANNALS OF BIOMEDICAL ENGINEERING
• 影响因子: 3.8
• 作者: Yao, Xiaomei;Carleton, Stephanie M.;Kettle, Arin D.;Melander, Jennifer;Phillips, Charlotte L.;Wang, Yong
• 通讯作者: Wang, Yong

Myostatin deficiency partially rescues the bone phenotype of osteogenesis imperfecta model mice.

• DOI: 10.1007/s00198-015-3226-7
• 发表时间: 2016-01
• 期刊: Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA
• 作者: Oestreich AK;Carleton SM;Yao X;Gentry BA;Raw CE;Brown M;Pfeiffer FM;Wang Y;Phillips CL
• 通讯作者: Phillips CL

Decreasing maternal myostatin programs adult offspring bone strength in a mouse model of osteogenesis imperfecta.

在成骨不全小鼠模型中，母体肌生长抑制素的减少会影响成年后代的骨强度。

• DOI: 10.1073/pnas.1607644113
• 发表时间: 2016
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Oestreich,ArinK;Kamp,WilliamM;McCray,MarcusG;Carleton,StephanieM;Karasseva,Natalia;Lenz,KristinL;Jeong,Youngjae;Daghlas,SalahA;Yao,Xiaomei;Wang,Yong;Pfeiffer,FerrisM;Ellersieck,MarkR;Schulz,LauraC;Phillips,CharlotteL
• 通讯作者: Phillips,CharlotteL