Ectopic ossification.

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Abstract

[Indexed for MEDLINE] 9. Trends Mol Med. 2025 Feb;31(2):106-116. doi: 10.1016/j.molmed.2024.08.010. Epub 2024 Sep 18. Fibrodysplasia ossificans progressiva emerges from obscurity. Kaplan FS(1), Shore EM(2), Pignolo RJ(3). Author information: (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. 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. Copyright © 2024 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.molmed.2024.08.010