非凡疾病恢复力的单例研究可能会提供对尚无明确治疗方法的条件的治疗见解。原本健康的35岁男性(patient-R)具有典型的致病性ACVR1R206H变异体和典型的先天性大脚趾畸形的纤维发育不全骨化性进行性(FOP),其出生后异位骨化(HO)和几乎正常的活动性极为缺乏。我们假设患者-R缺乏足够的出生后HO炎症触发因素。血浆生物标志物调查显示,与健康对照和具有静止FOP的个体相比,总基质金属蛋白酶-9(MMP-9)减少。全外显子组测序鉴定了MMP-9中的复合杂合变体(c.59C>T,p.A20V和c.493G>A,p.D165N)。D165N变体的结构分析预测了通过ELISA和明胶酶谱证实的MMP-9分泌和活性的降低。Further,表达MMP-9变体的人促炎性M1样巨噬细胞产生的激活素A显着减少,FOP中HO的专性配体,与野生型对照相比。重要的是,通过遗传抑制MMP-9,生物学,或多种FOP小鼠模型中的药理学手段废除了创伤诱导的HO,激活素A在细胞外基质中螯合,并诱导受损骨骼肌的再生。我们的数据表明,MMP-9是将炎症与HO联系起来的可药用节点,编排在FOP发病机理中的存在作用,并说明单个患者的临床表型可以揭示疾病的关键分子机制,从而揭示新的治疗策略。
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.
A healthy 35-year-old man (patient-R) with the classic fibrodysplasia ossificans progressiva (FOP) mutation and the congenital great toe malformation of FOP had extreme lack of heterotopic ossification (HO) and nearly normal mobility. We hypothesized that patient-R lacked a sufficient inflammatory trigger for HO. Blood tests revealed a reduction in the level of an inflammatory protein called matrix metalloproteinase-9 (MMP-9) compared to other individuals with FOP as well as healthy controls. DNA analysis in patient-R identified mutations in MMP-9, one of which predicted decreased activity of MMP-9 which was confirmed by further testing. Inflammatory cells (macrophages) expressing the MMP-9 mutations identified in patient-R produced significantly less Activin A, an obligate stimulus for HO in FOP. In order to determine if MMP-9 deficiency was a cause of HO prevention in FOP, we inhibited MMP-9 activity by genetic, biologic, or pharmacologic means in FOP mouse models and showed that MMP-9 inhibition prevented or dramatically decreased trauma-induced HO in FOP, locked-up Activin A in the extracellular matrix, and induced regeneration of injured skeletal muscle. Our data show that MMP-9 links inflammation to HO and illustrate that one patient’s clinical picture can reveal critical molecular mechanisms of disease that unveil new treatment strategies.