进行性骨化性纤维发育不良
促炎细胞因子
异位骨化
基质金属蛋白酶
外显子组测序
发病机制
医学
炎症
细胞外基质
癌症研究
表型
生物
免疫学
遗传学
内科学
基因
解剖
作者
Vitali Lounev,Jay C. Groppe,Niambi Brewer,Kelly L. Wentworth,Victoria Smith,Meiqi Xu,Lutz Schomburg,Pankaj Bhargava,Mona Al Mukaddam,Edward C. Hsiao,Eileen M. Shore,Robert J. Pignolo,Frederick S. Kaplan
摘要
Abstract Single case studies of extraordinary disease resilience may provide therapeutic insight into conditions for which no definitive treatments exist. An otherwise healthy 35-year-old man (patient-R) with the canonical pathogenic ACVR1R206H variant and the classic congenital great toe malformation of fibrodysplasia ossificans progressiva (FOP) had extreme paucity of post-natal heterotopic ossification (HO) and nearly normal mobility. We hypothesized that patient-R lacked a sufficient post-natal inflammatory trigger for HO. A plasma biomarker survey revealed a reduction in total matrix metalloproteinase-9 (MMP-9) compared to healthy controls and individuals with quiescent FOP. Whole exome sequencing identified compound heterozygous variants in MMP-9 (c.59C > T, p.A20V and c.493G > A, p.D165N). Structural analysis of the D165N variant predicted both decreased MMP-9 secretion and activity that were confirmed by enzyme-linked immunosorbent assay and gelatin zymography. Further, human proinflammatory M1-like macrophages expressing either MMP-9 variant produced significantly less Activin A, an obligate ligand for HO in FOP, compared to wildtype controls. Importantly, MMP-9 inhibition by genetic, biologic, or pharmacologic means in multiple FOP mouse models abrogated trauma-induced HO, sequestered Activin A in the extracellular matrix (ECM), and induced regeneration of injured skeletal muscle. Our data suggest that MMP-9 is a druggable node linking inflammation to HO, orchestrates an existential role in the pathogenesis of FOP, and illustrates that a single patient’s clinical phenotype can reveal critical molecular mechanisms of disease that unveil novel treatment strategies.
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