Plasma-Soluble Biomarkers for Fibrodysplasia Ossificans Progressiva (FOP) Reflect Acute and Chronic Inflammatory States

Abstract

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 R206H mutation and 40 ageand 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.

Suppression of heterotopic ossification in fibrodysplasia ossificans progressiva using AAV gene delivery

“…FOP patients have chronically elevated levels of hyperinflammatory immune cells and pro-inflammatory cytokines 35,55,56 . FOP macrophages and mast cells are primed toward inflammatory responses 57 , and depletion of these cells reduces HO in mice 44 .…”

Diminished muscle integrity in patients with fibrodysplasia ossificans progressiva assessed with at-home electrical impedance myography

“…Localized or systemic myopathy, chronic inflammation, atrophy, HO, prolonged immobilization or combination of factors could modulate the bioelectric properties of muscle tissue. An opportunity for further research may entail evaluation of EIM with other objective and more established methods such as imaging ( 18 F-NaF PET/CT, CT, X-Ray, and MRI) or quantification of circulating markers 18 , 33 – 35 .…”

“…Moreover, soft tissue edema on MRI and 18 F-NaF-PET/CT activity are respectively associated with localized tissue inflammation and osteogenic activity typically associated with flares, but do not always correlate with the clinical course or predict sites of future HO 15 . To complement clinical and imaging data, recent studies have sought to identify disease and flare-up-associated biomarkers in plasma samples derived from patients with FOP 18 , which if validated in subsequent work, may provide a novel means to classify disease stages of FOP or further the understanding of mechanistic pathways implicated in FOP.…”

Immunologic Aspects in Fibrodysplasia Ossificans Progressiva

“…Our own research has revealed a significant increase in different cytokine levels, such as IL-3, IL-7, and IL-8 in the blood of patients with FOP [ 20 ] and has also shown that NF- κ B activation is a key factor for inflammation in FOP. Additionally, we have found that blood samples obtained from FOP individuals have high levels of proinflammatory interleukins even in the absence of flare-up symptoms [ 29 , 64 ]. We also found increased monocyte production of TGF-β in patients with FOP, consistent with findings in mouse models [ 63 ].…”