Urinary biomarkers to assess linear bone growth velocity

描述(申请人提供)：测量骨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，这主要是因为准确测量骨长度的增量变化需要数月时间，这反映了骨生长固有的缓慢性质。虽然显然不太理想，但目前的做法被接受，因为缺乏产生更快结果的方法。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。由于它针对的是骨生长而不是骨生长的结果，因此它可能提供更短的周转时间，从而大大缩短临床测量骨生长速度所需的时间间隔。我们将通过检测尿液中II型和X型胶原的末端降解产物来分析软骨周转率作为软骨内骨化的直接读数。已经对II型胶原片段进行了测量，以评估成人骨关节炎的严重程度，为该方法建立了概念验证，但在关节炎罕见的I型成长儿童中，结果应该几乎完全反映软骨内骨的生长，特别是在结合X型胶原片段的分析时。我们将开发这些分析方法，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手段，并量化不足的生长速度及其对促生长疗法的反应。更具体地说，我们将采用商业ELISA试剂盒来测量II型胶原新表位(CTX-II)，并开发一种类似的X型胶原片段检测方法，我们将其命名为CXM，并将其应用于目标1中的正常生长儿童。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)速度相关联，并开发可用于临床使用的标准，通过生物标记物的测量来衡量生长速度。生物标记物采样和数据报告协议将在这一目标中得到优化。骨生长生物标记物将在软骨发育不良儿童中进行评估，生长激素反应型矮小儿童和生长激素治疗组的反应将通过目标3中的生物标记物进行监测。我们相信，这一新方法的发展将对儿童矮小的评估和治疗产生重大影响。

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.