Mechanotransduction Approach to Improve Bone Quality in Osteogenesis Imperfecta

描述(申请人提供)：峰值骨量是骨质疏松症的主要决定因素。儿童和青春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期间，大约26%的最终成人骨量是在青春期高峰期获得的；众所周知，经常锻炼的儿童比不锻炼的儿童增加了10%-40%的骨量(特定于地区)。骨骼天生对机械敏感，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(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，骨折频繁。据报道，OI患者肌肉无力。在一项单独的研究中，研究发现，与年龄匹配的健康儿童相比，OI儿童的肌肉力量和运动耐力都有所下降。然而，目前尚不清楚肌肉力量和运动耐量的降低是久坐不动的生活方式的结果，还是OI的病理所固有的。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积和体力活动的减少，相对收缩产生能力[强直性最大张力(Po)/g肌肉]与年龄匹配的野生型小鼠没有显著差异。儿童和青春期的锻炼和体力活动对于个人充分发挥其峰值骨量潜力是必不可少的；OI儿童缺乏体育活动，特别是在这个最大限度增加骨骼的关键窗口期间，使OI患者成年后的骨骼健康状况更加糟糕。我们建议利用两种成骨不全的小鼠模型：OIM小鼠[OIM/+(模型人类I型OI)和OIM/OIM(人类OI III型)]和新的G610C COL1A2小鼠[G610C/+(模型人类I型和IV型OI)]来研究不负重(游泳)和负重(跑步机)运动对肌肉力量和骨骼质量和力量的影响。具体地说，在目标1中，我们将评估6周大(青春期-治疗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小鼠是否有可能导致骨骼无力的固有肌肉无力或病理(肌肉质量减少、纤维横截面积和/或收缩生成能力)，以及相对于野生型小鼠，体力活动是否发生改变。在目标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周和4个月龄OIM和G610C小鼠的股骨几何形状(UCT)和生物力学(从扭转载荷到破坏)与骨的矿物质和基质、理化和力学性能的关系，以确定多尺度水平上的结构/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(负重)上跑步是否会增加OIM和G610C小鼠骨骼的肌肉收缩生成能力和耐力，改变骨骼矿物和基质的分子结构，并改善骨的物理化学性质/生物力学完整性。 公共卫生相关性：成骨不全是一种遗传性结缔组织疾病，以肌肉无力和骨骼脆性为特征。我们将使用两种不同的成骨缺陷小鼠模型来评估负重和非负重运动方案在增加肌肉力量和耐力以及伴随而来的骨骼质量和强度方面的潜在治疗效果。

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.