Departments of Medicine and Physiology/Biomedical Engineering, Mayo Clinic Alix School of Medicine, Mayo Clinic, Rochester, MN, USA.
Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
J Bone Miner Res. 2022 Mar;37(3):475-483. doi: 10.1002/jbmr.4492. Epub 2022 Jan 24.
Fibrodysplasia ossificans progressiva (FOP) is a progressive, debilitating genetic disease in which skeletal muscle and connective tissue is episodically replaced by heterotopic bone. Discovery of surrogate biomarkers of disease (genotype)-related and flare-up-associated activity of FOP in a readily accessible matrix, such as plasma, would facilitate an understanding of the complex pathophysiology of FOP, aid patient care, and provide a valuable tool for the development and monitoring of potential therapeutics. In a case-control study, using a carefully collected and curated set of plasma samples from 40 FOP patients with the classic ACVR1 mutation and 40 age- and sex-matched controls, we report the identification of disease-related and flare-up-associated biomarkers of FOP using a multiplex analysis of 113 plasma-soluble analytes. Adiponectin (implicated in hypoxia, inflammation, and heterotopic ossification) as well as tenascin-C (an endogenous activator of innate immune signaling through the TLR4 pathway and a substrate for kallikrein-7) were highly correlated with FOP genotype, while kallikrein-7 was highly correlated with acute flare-up status. Plasma-soluble biomarkers for FOP support a flare-up-related acute inflammatory phase of disease activity superimposed on a genotypic background of chronic inflammation. © 2021 American Society for Bone and Mineral Research (ASBMR).
进行性骨化性纤维发育不良（FOP）是一种进行性、使人虚弱的遗传性疾病，其特征是骨骼肌和结缔组织间歇性地被异位骨取代。在易于获得的基质（如血浆）中发现与疾病（基因型）相关的替代生物标志物和 FOP 发作相关的活性，将有助于理解 FOP 的复杂病理生理学，辅助患者护理，并为潜在治疗药物的开发和监测提供有价值的工具。在一项病例对照研究中，我们使用精心收集和精心整理的 40 名携带经典 ACVR1 突变的 FOP 患者和 40 名年龄和性别匹配的对照者的血浆样本，使用对 113 种血浆可溶性分析物的多重分析，报告了 FOP 的与疾病相关和发作相关的生物标志物的鉴定。脂联素（与缺氧、炎症和异位骨化有关）以及 tenascin-C（通过 TLR4 途径激活固有免疫信号的内源性激活剂，也是激肽释放酶-7 的底物）与 FOP 基因型高度相关，而激肽释放酶-7 与急性发作状态高度相关。FOP 的血浆可溶性生物标志物支持疾病活动的发作相关急性炎症相叠加在慢性炎症的基因型背景上。 © 2021 美国骨矿研究学会（ASBMR）。
