Urinary biomarkers to assess linear bone growth velocity

项目摘要 测量骨骼生长速度是治疗骨骼生长障碍的一个重要但具有挑战性的部分 这主要是由于需要数月来精确测量骨长度的增量变化， 反映了骨骼生长缓慢的本质。虽然显然不太理想，但目前的做法是 因为缺乏产生更快结果的方法而被接受。 我们提出了一种全新的方法， 通过分析其作为骨生长生物标志物的副产物，直接检查骨生长过程。 因为它解决了骨生长而不是骨生长的后果，它潜在地提供了一个很大的 更短的周转时间，可以大大减少临床测量骨生长所需的时间间隔 速度 我们将分析软骨周转作为软骨内骨化的直接读数，通过测量 尿中II型和X型胶原的末端降解产物。II型胶原蛋白片段已经被 测量以评估成人骨关节炎的严重程度，为该方法建立概念验证，但在 生长中的儿童关节炎是罕见的，结果应反映软骨内骨生长几乎完全， 特别是当与X型胶原片段的分析结合时。我们将开发检测方法， 结果与骨生长速度，以提供评估和监测骨生长速度和量化 生长速度不足及其对生长促进疗法的反应。更具体地说，我们将适应 商业ELISA试剂盒，以测量II型胶原蛋白新表位（CTX-II），并开发用于 型胶原蛋白片段，我们已经指定CXM，并将其应用于正常生长的儿童， 目标1.在目标2中，我们将在健康儿童中将生物标志物水平与1年以上的生长（身高）速度相关联， 制定可用于临床的标准，以根据生物标志物测量来衡量生长率。 生物标志 为此，将优化取样和数据报告程序。 将评估骨生长生物标志物 在患有软骨发育不良和生长发育反应型身材矮小的儿童中， 后一组生长激素治疗将通过目标3中的生物标志物进行监测。 我们相信， 这种在比目前更短的时间内评估线性骨生长速度的新方法 可能会对儿童身材矮小的评估和管理产生重大影响。

Project Summary Measuring bone growth velocity is an essential but challenging part of managing disorders of skeletal growth due largely to the many months needed to accurately gauge incremental changes of bone length, which reflects the inherently slow nature of bone growth. While clearly less than ideal, the current practice is accepted because of the lack of methods that yield faster results. We propose a completely new approach that examines the bone growth process directly by analyzing its byproducts as biomarkers of bone growth. Because it addresses bone growth rather than the consequence of bone growth, it potentially offers a much shorter turn around time that could dramatically reduce the interval needed to clinically measure bone growth velocity. We will analyze cartilage turnover as a direct readout of endochondral ossification by measuring terminal degradation products of types II and X collagen in urine. Type II collagen fragments have been measured to assess severity of osteoarthritis in adults establishing proof-of-concept for this approach, but in growing children in whom arthritis is rare, results should reflect endochondral bone growth almost exclusively, especially when coupled with analysis of type X collagen fragments. We will develop the assays, correlate results with bone growth velocity to provide means to assess and monitor bone growth velocity and quantify deficient growth rate and its response to growth promoting therapies. More specifically, we will adapt commercial ELISA kits to measure a type II collagen neoepitope (CTX-II) and develop a comparable assay for type X collagen fragments, which we have designated CXM, and apply them to normally growing children in Aim 1. In Aim 2 we will correlate biomarker levels with growth (height) velocity over 1 yr in healthy children and develop norms that can be used clinically to gauge growth rate from biomarker measurements. Biomarker sampling and data reporting protocols will be optimized in this aim. Bone growth biomarkers will be assessed in children with chondrodysplasias and growth hormone-responsive forms of short stature and response of the latter group to growth hormone therapy will be monitored by biomarkers in Aim 3. We believe development of this novel approach to assessing linear bone growth velocity in a much shorter time frame than is currently possible will have a major impact on the evaluation and management of pediatric short stature.