Serum biomarker profile associated with high bone turnover and BMD in postmenopausal women
Serum biomarker profile associated with high bone turnover and BMD in postmenopausal women
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DOI：
10.1359/jbmr.080235
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发表时间：
2008-07-01
影响因子：
6.2
通讯作者：
Suva, Larry J.
中科院分区：
文献类型：
--
作者：
Bhattacharyya, Sudeepa;Siegel, Eric R.;Suva, Larry J.
骨质疏松症的早期诊断是提供有效治疗的关键。骨转换的生化标志物提供了一种评价骨骼动力学的方法，补充了DXA静态测量BMD。骨转换的常规临床测量，主要是血液或尿液中胶原蛋白及其分解产物的估计，缺乏作为可靠诊断工具的灵敏度和特异性。因此，需要改进的测试，以增加使用BMD测量作为主要的诊断方式。在这项研究中，通过表面增强激光解吸/电离飞行时间质谱法分析了58名绝经后高或低/正常骨转换妇女（训练集）的血清蛋白质组，并使用各种统计和机器学习工具确定了诊断指纹。诊断指纹在一个单独的不同的测试组中得到验证，该测试组由来自同一马约队列的另外59名绝经后妇女的血清样本组成，间隔为2年。鉴别并验证了区分绝经后高或低/正常骨转换患者的特异性蛋白质峰。多种监督学习方法能够以80%的灵敏度和100%的特异性对训练集中的骨转换水平进行分类。此外，在这些患者中，单个蛋白质峰也与BMD测量值显著相关。诊断谱中的4个主要鉴别峰被鉴定为α-胰蛋白酶抑制剂重链H4前体（ITIH 4）的片段，ITIH 4是一种血浆激肽释放酶敏感性糖蛋白，是宿主应答系统的组分。这些数据表明，这些血清蛋白片段是破骨细胞活性增加的血清反映，导致骨转换增加，这与BMD降低相关，并可能增加骨折的风险。结合识别的个别蛋白质，这种蛋白质指纹可能提供一种新的方法来评估高骨转换状态。
Early diagnosis of the onset of osteoporosis is key to the delivery of effective therapy. Biochemical markers of bone turnover provide a means of evaluating skeletal dynamics that complements static measurements of BMD by DXA. Conventional clinical measurements of bone turnover, primarily the estimation of collagen and its breakdown products in the blood or urine, lack both sensitivity and specificity as a reliable diagnostic tool. As a result, improved tests are needed to augment the use of BMD measurements as the principle diagnostic modality. In this study, the serum proteome of 58 postmenopausal women with high or low/normal bone turnover (training set) was analyzed by surface enhanced laser-desorption/ionization time-of-flight mass spectrometry, and a diagnostic fingerprint was identified using a variety of statistical and machine learning tools. The diagnostic fingerprint was validated in a separate distinct test set, consisting of serum samples from an additional 59 postmenopausal women obtained from the same Mayo cohort, with a gap of 2 yr. Specific protein peaks that discriminate between postmenopausal patients with high or low/normal bone turnover were identified and validated. Multiple supervised learning approaches were able to classify the level of bone turnover in the training set with 80% sensitivity and 100% specificity. In addition, the individual protein peaks were also significantly correlated with BMD measurements in these patients. Four of the major discriminatory peaks in the diagnostic profile were identified as fragments of interalpha-trypsin-inhibitor heavy chain H4 precursor (ITIH4), a plasma kallikrein-sensitive glycoprotein that is a component of the host response system. These data suggest that these serum protein fragments are the serum-borne reflection of the increased osteoclast activity, leading to the increased bone turnover that is associated with decreasing BMD and presumably an increased risk of fracture. In conjunction with the identification of the individual proteins, this protein fingerprint may provide a novel approach to evaluate high bone turnover states.