Genovese F, Siebuhr A S, Musa K, Gallagher J A, Milan A M, Karsdal M A, Rovensky J, Bay-Jensen A C, Ranganath L R
Nordic Bioscience, Herlev Hovedgade 205, 2730, Herlev, Denmark.
Department of Musculoskeletal Biology, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, L69 3GE, UK.
JIMD Rep. 2015;24:29-37. doi: 10.1007/8904_2015_430. Epub 2015 Mar 19.
Alkaptonuria (AKU) clinical manifestations resemble severe arthritis. The Suitability of Nitisinone in Alkaptonuria 1 (SONIA 1) study is a dose-finding trial for nitisinone treatment of AKU patients. We tested a panel of serum and urinary biomarkers reflecting extracellular matrix remodelling (ECMR) of cartilage, bone and connective tissue in SONIA 1 patients to identify non-invasive and diagnostic biomarkers of tissue turnover in AKU.
Fasted serum and urine were retrieved from 40 SONIA 1 patients and 44 healthy controls. Established biomarkers of bone remodelling (CTX-I, P1NP, OC), cartilage remodelling (CTX-II, C2M, AGNx1) and inflammation (CRPM) as well as exploratory biomarkers of ECMR (C6M, VCANM, MIM, TIM) were measured at baseline in serum and urine by means of enzyme-linked immunosorbent assays (ELISAs) or automated systems (Elecsys 2010).
The levels of bone resorption (CTX-I) and cartilage degradation (C2M) were elevated in AKU patients as compared to controls (p > 0.0001 and p = 0.03, respectively). Also tissue inflammation (CRPM) was elevated in AKU patients (p = 0.01). In addition all four exploratory biomarkers of ECMR (C6M, VCANM, MIM, TIM) were elevated in AKU patients compared to healthy controls. CTX-II was the only biomarker to be reduced in AKU patients. TIM was the only marker that showed a higher concentration than the normal assay range in AKU patients.
We have identified new potential biomarkers for assessment of cartilage, bone and cardiovascular remodelling in AKU and demonstrated the robustness of the assays used to measure the biomarker concentration in biological fluids.
黑尿症（AKU）的临床表现类似于严重关节炎。黑尿症1型中尼替西农的适用性（SONIA 1）研究是一项关于尼替西农治疗AKU患者的剂量探索试验。我们检测了一组反映SONIA 1患者软骨、骨骼和结缔组织细胞外基质重塑（ECMR）的血清和尿液生物标志物，以确定AKU中组织更新的非侵入性诊断生物标志物。
从40例SONIA 1患者和44例健康对照者中采集空腹血清和尿液。通过酶联免疫吸附测定（ELISA）或自动化系统（Elecsys 2010）在基线时测量血清和尿液中已确定的骨重塑生物标志物（I型胶原交联羧基末端肽（CTX-I）、I型前胶原氨基端前肽（P1NP）、骨钙素（OC））、软骨重塑生物标志物（II型胶原交联羧基末端肽（CTX-II）、C2M、聚集蛋白聚糖片段1（AGNx1））和炎症生物标志物（C反应蛋白修饰物（CRPM））以及ECMR探索性生物标志物（C6M、硫酸软骨素6含量修饰物（VCANM）、微小整合素结合蛋白1（MIM）、含血小板反应蛋白基序的解聚素样金属蛋白酶（TIM））。
与对照组相比，AKU患者的骨吸收（CTX-I）和软骨降解（C2M）水平升高（分别为p > 0.0001和p = 0.03）。AKU患者的组织炎症（CRPM）也升高（p = 0.01）。此外，与健康对照相比，AKU患者的所有四种ECMR探索性生物标志物（C6M、VCANM、MIM、TIM）均升高。CTX-II是AKU患者中唯一降低的生物标志物。TIM是唯一在AKU患者中浓度高于正常检测范围的标志物。
我们已确定了用于评估AKU中软骨、骨骼和心血管重塑的新的潜在生物标志物，并证明了用于测量生物体液中生物标志物浓度的检测方法的稳健性。
