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The obligatory role of Activin A in the formation of heterotopic bone in Fibrodysplasia Ossificans Progressiva.

ABSTRACT: Fibrodysplasia Ossificans Progressiva (FOP) is a rare genetic disorder that presents at birth with only minor patterning defects, but manifests its debilitating pathology early in life with episodic, yet progressive and cumulative, heterotopic ossification (HO) of ligaments, tendons, and a subset of major skeletal muscles. The resulting HO lesions are endochondral in nature, and appear to be linked to inflammatory stimuli arising in association with known injuries, or from inflammation linked to normal tissue repair. FOP is caused by gain-of-function mutations in ACVR1, which encodes a type I BMP receptor. Initial studies on the pathogenic mechanism of FOP-causing mutations in ACVR1 focused on the enhanced function of this receptor in response to certain BMP ligands, or independently of ligands, but did not directly address the fact that HO in FOP is episodic and inflammation-driven. Recently, we and others demonstrated that Activin A is an obligate factor for the initiation of HO in FOP, signaling aberrantly via mutant ACVR1 to transduce osteogenic signals and trigger heterotopic bone formation (Hatsell et al., 2015; Hino et al., 2015). Subsequently, we identified distinct tissue-resident mesenchymal progenitor cells residing in muscles and tendons that recognize Activin A as a pro-osteogenic signal (solely in the context of FOP-causing mutant ACVR1), and give rise to the cartilaginous anlagen that form heterotopic bone (Dey et al., 2016). During the course of these studies, we also found that the activity of FOP-causing ACVR1 mutations does not by itself explain the triggered or inflammatory nature of HO in FOP, suggesting the importance of other, inflammation-introduced, factors or processes. This review presents a synthesis of these findings with a focus on the role of Activin A and inflammation in HO, and lays out perspectives for future research.

SUBMITTER: Alessi Wolken DM

PROVIDER: S-EPMC6706059 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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The obligatory role of Activin A in the formation of heterotopic bone in Fibrodysplasia Ossificans Progressiva.

Alessi Wolken Dana M DM Idone Vincent V Hatsell Sarah J SJ Yu Paul B PB Economides Aris N AN

Bone 20170616

Fibrodysplasia Ossificans Progressiva (FOP) is a rare genetic disorder that presents at birth with only minor patterning defects, but manifests its debilitating pathology early in life with episodic, yet progressive and cumulative, heterotopic ossification (HO) of ligaments, tendons, and a subset of major skeletal muscles. The resulting HO lesions are endochondral in nature, and appear to be linked to inflammatory stimuli arising in association with known injuries, or from inflammation linked to ...[more]

PMID: 28629737

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Project description:RATIONALE AND OBJECTIVES:Severe progressive multifocal heterotopic ossification (HO) is a rare occurrence seen predominantly in patients who have fibrodysplasia ossificans progressiva (FOP) and is difficult to quantitate owing to patient-, disease-, logistical-, and radiation-related issues. The purpose of this study was to develop and validate a scoring system based on plain radiographs for quantitative assessment of HO lesions in patients with FOP. MATERIALS AND METHODS:Institutional review board approval was obtained from the University of Pennsylvania, and all data comply with Health Insurance Portability and Accountability Act regulations. The University of Pennsylvania Institutional Animal Care and Use Committee approved the use of mice in this study. First, we used a mouse model of FOP-like HO to validate a semiquantitative analog scale for estimating relative heterotopic bone volume. Second, we used this validated scale to estimate the relative amount of HO from a retrospective analysis of plain radiographs from 63 patients with classic FOP. Finally, the scale was applied to a retrospective analysis of computed tomographic images from three patients with FOP. RESULTS:In the FOP-mouse model, the observed rating on the analog scale is highly correlated to heterotopic bone volumes measured by microcomputed tomography (R2?=?0.89). The scoring system that was applied to radiographs of patients with FOP captured the clinical range of HO typically present at all axial and appendicular sites. Analysis of computed tomographic scans of patients with FOP found that observed radiograph ratings were highly correlated with HO volume (R2?=?0.80). CONCLUSIONS:The scoring system described here could enable practical, quantitative assessment of HO in clinical trials to evaluate new treatment modalities, especially for FOP. The development of the six-point analog scale described here provides and validates a much-needed, reproducible, and quantifiable method for describing and assessing HO in patients with FOP. This scale has the potential to be a key descriptor that can inform patients with FOP and clinicians about disease progression and response of HO lesions to interventions and treatments.

Dataset Information

The obligatory role of Activin A in the formation of heterotopic bone in Fibrodysplasia Ossificans Progressiva.

Publications

The obligatory role of Activin A in the formation of heterotopic bone in Fibrodysplasia Ossificans Progressiva.

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