A zebrafish model of developmental joint dysplasia: Manipulating the larval mechanical environment to drive the malformation and recovery of joint shape
A zebrafish model of developmental joint dysplasia: Manipulating the larval mechanical environment to drive the malformation and recovery of joint shape
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DOI：
10.1101/155911
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发表时间：
2017-06
期刊：
影响因子：
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通讯作者：
K. Roddy;Roderick E. H. Skinner;Lucy H. Brunt;E. Kague;Stephen J. Cross;E. Rayfield;C. Hammond
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文献类型：
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作者：
K. Roddy;Roderick E. H. Skinner;Lucy H. Brunt;E. Kague;Stephen J. Cross;E. Rayfield;C. Hammond
发育性髋关节发育不良(DDH)是髋臼的一种畸形，是早期发病的骨关节炎的常见原因。这种疾病包括一系列严重程度，其中一些更适合治疗。胚胎制动显着损害关节形态的发育，但这种畸形在中短期内对关节功能和生长的影响尚不清楚。我们利用斑马鱼的颌骨关节开发了一种新的发育性关节发育不良模型，以确定调控细胞可塑性和恢复关节形状和功能的机制。斑马鱼幼体被药物固定或通过有针对性的颌肌消融来诱导改变关节形状。在肌肉活动恢复后，我们以细胞分辨率动态监测个体的关节形状和功能，这在其他脊椎动物物种中是不可能的。反映了人类状况的多样性，我们发现，尽管来自基因相同的人群，但一部分关节将恢复其形状和功能，而其他关节则不会。这使我们能够研究是什么控制了恢复的可能性；我们确定了一些预测功能恢复可能性的细胞变化，包括前体细胞的位置，以及关节和相关结缔组织中增殖、迁移和分化的特定模式。这些因素加在一起比单独预测畸形的严重程度更能预测康复。使用有限元分析，我们研究了关节的力学，代表了那些恢复的关节和那些未能识别应变模式差异的关节，这些模式可以解释支撑恢复可能性的细胞行为。因此，该模型将能够研究关节形状改变对功能的短期和长期影响，并有助于识别使个人更容易接受治疗的变化，因此可能潜在地指示长期的关节健康。
Developmental dysplasia of the hip (DDH), a malformation of the acetabulum, is a frequent cause of early onset osteoarthritis. The disease encompasses a spectrum of severities, some of which are more amenable to treatment. Embryonic immobilisation significantly impairs the development of joint shape however the impact of this malformation to the function and growth of the joint in the short to medium term is unclear. We developed a novel model of developmental joint dysplasia using the zebrafish jaw joint to identify the mechanisms regulating cellular plasticity and ability to recover joint shape and function. Larval zebrafish were immobilised either pharmacologically or using targeted ablation of jaw muscles to induce an altered joint shape. Following restoration of muscle activity we dynamically monitored the joint shape and function in individuals at cellular resolution impossible in other vertebrate species. Reflecting the variability of the human condition we found a proportion of joints will recover both their shape and function, while others will not; despite coming from a genetically homogenous population. This allowed us to study what controls likelihood of recovery; we identified a number of cellular changes that predict likelihood of functional recovery, including position of precursor cells, and specific patterns of proliferation, migration and differentiation in joints and associated connective tissues. These factors together predict recovery better than severity of malformation alone. Using Finite Element Analysis we studied the mechanics of joints representative of ones that recover and those that fail to identify differences in patterns of strain that could explain the cellular behaviours that underpin likelihood of recovery. Thus, this model would enable the study of the short to long term impact of altered joint shape on function and could help to identify the changes that render an individual more receptive to treatment and therefore may potentially be indicative of long term joint health.