Urinary biomarkers to assess linear bone growth velocity

描述（由申请人提供）：测量骨生长速度是管理骨骼生长障碍的一个重要但具有挑战性的部分，这主要是因为需要数月来准确测量骨长度的增量变化，这反映了骨生长的固有缓慢性质。目前的做法虽然显然不够理想，但由于缺乏能更快取得结果的方法，因此得到了接受。我们提出了一种全新的方法，通过分析其副产物作为骨生长的生物标志物来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，所以它可能提供更短的周转时间，从而可以显著减少临床测量骨生长速度所需的时间间隔。我们将通过测量尿液中II型和X型胶原的终末降解产物来分析软骨转换，作为软骨内骨化的直接读数。已测量II型胶原片段以评估成人中骨关节炎的严重程度，建立该方法的概念验证，但在关节炎罕见的生长中的儿童中，结果应几乎完全反映软骨内骨生长，特别是当结合X型胶原片段分析时。我们将开发检测方法，将结果与骨生长速度相关联，以提供评估和监测骨生长速度的方法，并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，我们将采用商业ELISA试剂盒来测量II型胶原蛋白新表位（CTX-II），并开发一种可比较的X型胶原蛋白片段测定法，我们将其命名为CXM，并将其应用于目标1中正常生长的儿童。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，并制定可用于临床的标准，以通过生物标志物测量来衡量生长速度。生物标志物采样和数据报告协议将在这一目标进行优化。将在软骨发育不良和生长激素反应型身材矮小儿童中评估骨生长生物标志物，并将通过目标3中的生物标志物监测后一组对生长激素治疗的反应。我们相信，这种新方法的发展，以评估线性骨生长速度在一个更短的时间框架比目前可能的将有一个重大影响的评估和管理的儿科身材矮小。

DESCRIPTION (provided by applicant): 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 i 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.