Fibrodysplasia ossificans progressiva emerges from obscurity

Frederick S Kaplan; Eileen M Shore; Robert J Pignolo

doi:10.1016/j.molmed.2024.08.010

Fibrodysplasia ossificans progressiva emerges from obscurity

Trends Mol Med. 2024 Sep 18:S1471-4914(24)00238-7. doi: 10.1016/j.molmed.2024.08.010. Online ahead of print.

Authors

Frederick S Kaplan¹, Eileen M Shore², Robert J Pignolo³

Affiliations

¹ Department of Orthopaedic Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Center for Research in FOP and Related Disorders, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. Electronic address: frederick.kaplan@pennmedicine.upenn.edu.
² Department of Orthopaedic Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
³ Department of Medicine, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN 55905, USA.

PMID: 39299836
DOI: 10.1016/j.molmed.2024.08.010

Abstract

Fibrodysplasia ossificans progressiva (FOP), a disorder of congenital skeletal malformations and progressive extraskeletal ossification, is the most severe form of heterotopic ossification (HO) in humans. Gain-of-function pathogenic variants in activin A receptor type I (ACVR1), a bone morphogenetic protein (BMP) type 1 receptor, cause FOP by dramatically altering the normal physiologic functions of ACVR1, impacting BMP signaling and other interacting pathways. These alterations affect various systems, including inflammation, innate immunity, hypoxia sensing, wound healing, aging, temperature and mechanical thresholds, pain sensitivity, skeletal growth, diarthrodial joint patterning, joint function and fate, and HO. This article examines the emergent properties of FOP's diverse phenotypes, proposes a schema for targeting these phenotypes, and highlights outstanding questions and knowledge gaps.

Keywords: ACVR1; emergent properties; fibrodysplasia ossificans progressiva (FOP); heterotopic ossification.

Publication types

Review