Urinary biomarkers to assess linear bone growth velocity

项目摘要 测量骨骼生长速度是管理骨骼生长障碍的基本但具有挑战性的部分。 这在很大程度上是因为需要数月的时间来准确测量骨骼长度的增量变化，这 反映了骨骼生长天生缓慢的本质。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， 通过分析其副产物作为骨生长的生物标志物，直接检查骨生长过程。 因为它针对的是骨骼生长，而不是骨骼生长的结果，所以它潜在地提供了 更短的周转时间，可以显著缩短临床测量骨生长所需的时间间隔 速度。我们将通过测量软骨内骨化的直接读数来分析软骨翻转率 尿中II型和X型胶原的终末降解产物。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性，为该方法建立概念验证，但在 在关节炎罕见的发育期儿童，结果应该几乎完全反映软骨内骨骼的生长， 尤其是当结合X型胶原片段的分析时。我们将开发化验方法，关联 结果以骨生长速度为评价和监测骨生长速度及量化提供了手段 生长速度不足及其对促生长疗法的反应。更具体地说，我们将适应 用于检测II型胶原新表位(CTX-II)的商业ELISA试剂盒，并开发一种可供比较的检测方法 X型胶原片段，我们将其命名为CXM，并将它们应用于 目标1。在目标2中，我们将把生物标记物水平与1岁以上健康儿童的生长(身高)速度联系起来 制定可用于临床的标准，以根据生物标记物的测量来衡量生长速度。生物标志物 为实现这一目标，将优化采样和数据报告协议。将评估骨生长生物标记物 患有软骨发育不良和生长激素反应型矮小的儿童 生长激素治疗的后一组将在目标3中通过生物标记物进行监测。我们相信 这一新的方法可以在比目前更短的时间内评估线状骨生长速度 可能会对儿童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.