Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, 3450 Hamilton Walk, Philadelphia, PA 19104, USA.
Proteomics Core Facility, Children's Hospital of Philadelphia, 3401 Civic Center Blvd, Philadelphia, PA 19104, United States of America.
Mol Genet Metab. 2023 Feb;138(2):107371. doi: 10.1016/j.ymgme.2023.107371. Epub 2023 Jan 4.
Mucopolysaccharidosis I is a lysosomal storage disorder characterized by deficient alpha-L-iduronidase activity, leading to abnormal accumulation of glycosaminoglycans in cells and tissues. Synovial joint disease is prevalent and significantly reduces patient quality of life. There is a critical need for improved understanding of joint disease pathophysiology in MPS I, including specific biomarkers to predict and monitor joint disease progression, and response to treatment. The objective of this study was to leverage the naturally-occurring MPS I canine model and undertake an unbiased proteomic screen to identify systemic biomarkers predictive of local joint disease in MPS I. Synovial fluid and serum samples were collected from MPS I and healthy dogs at 12 months-of-age, and protein abundance characterized using liquid chromatography tandem mass spectrometry. Stifle joints were evaluated postmortem using magnetic resonance imaging (MRI) and histology. Proteomics identified 40 proteins for which abundance was significantly correlated between serum and synovial fluid, including markers of inflammatory joint disease and lysosomal dysfunction. Elevated expression of three biomarker candidates, matrix metalloproteinase 19, inter-alpha-trypsin inhibitor heavy-chain 3 and alpha-1-microglobulin, was confirmed in MPS I cartilage, and serum abundance of these molecules was found to correlate with MRI and histological degenerative grades. The candidate biomarkers identified have the potential to improve patient care by facilitating minimally-invasive, specific assessment of joint disease progression and response to therapeutic intervention.
黏多糖贮积症 I 型是一种溶酶体贮积症，其特征为α-L-艾杜糖苷酸酶活性缺乏，导致糖胺聚糖在细胞和组织中异常积聚。滑膜关节疾病较为普遍，显著降低了患者的生活质量。人们迫切需要深入了解黏多糖贮积症 I 型的关节疾病病理生理学，包括特定的生物标志物，以预测和监测关节疾病的进展以及对治疗的反应。本研究旨在利用天然发生的黏多糖贮积症 I 型犬模型，进行无偏蛋白组学筛选，以鉴定预测黏多糖贮积症 I 型局部关节疾病的全身性生物标志物。在 12 个月大时，从黏多糖贮积症 I 型犬和健康犬中采集滑液和血清样本，并使用液相色谱串联质谱法对蛋白质丰度进行表征。使用磁共振成像（MRI）和组织学对后肢膝关节进行评估。蛋白质组学鉴定了 40 种在血清和滑液之间丰度显著相关的蛋白质，包括炎症性关节疾病和溶酶体功能障碍的标志物。在黏多糖贮积症 I 型软骨中证实了三种候选生物标志物（基质金属蛋白酶 19、α1-微球蛋白和α-1-抗胰蛋白酶重链 3）的表达上调，并且这些分子的血清丰度与 MRI 和组织学退行性分级相关。所鉴定的候选生物标志物具有通过促进对关节疾病进展和治疗干预反应的微创、特异性评估来改善患者护理的潜力。
