Matrix metalloproteinase-9 deficiency confers resilience in fibrodysplasia ossificans progressiva in a man and mice

• Published in: Journal of bone and mineral research Vol. 39; no. 4; pp. 382 - 398
• Main Authors: Lounev, Vitali, Groppe, Jay C, Brewer, Niambi, Wentworth, Kelly L, Smith, Victoria, Xu, Meiqi, Schomburg, Lutz, Bhargava, Pankaj, Al Mukaddam, Mona, Hsiao, Edward C, Shore, Eileen M, Pignolo, Robert J, Kaplan, Frederick S
• Format: Journal Article
• Language: English
• Published: England 02-05-2024
• Subjects: Activin Receptors, Type I - deficiency; Activin Receptors, Type I - genetics; Activin Receptors, Type I - metabolism; Adult; Animals; Humans; Male; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - metabolism; Mice; Myositis Ossificans - genetics; Myositis Ossificans - metabolism; Myositis Ossificans - pathology; Ossification, Heterotopic - genetics; Ossification, Heterotopic - metabolism; Ossification, Heterotopic - pathology; ACVR1; heterotopic ossification; Activin A; disease resilience; MMP-9; fibrodysplasia ossificans progressiva (FOP)
• ISSN: 0884-0431; 1523-4681
• DOI: 10.1093/jbmr/zjae029

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.