Kaplan Frederick S, Shore Eileen M, Pignolo Robert J
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.
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.
Trends Mol Med. 2025 Feb;31(2):106-116. doi: 10.1016/j.molmed.2024.08.010. Epub 2024 Sep 18.
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.
进行性骨化性纤维发育不良（FOP）是一种先天性骨骼畸形和进行性骨外骨化疾病，是人类最严重的异位骨化（HO）形式。激活素A受体I型（ACVR1）是一种骨形态发生蛋白（BMP）1型受体，其功能获得性致病变异通过显著改变ACVR1的正常生理功能、影响BMP信号传导和其他相互作用途径而导致FOP。这些改变影响各种系统，包括炎症、先天免疫、缺氧感知、伤口愈合、衰老、温度和机械阈值、疼痛敏感性、骨骼生长、双关节模式、关节功能和命运以及异位骨化。本文研究了FOP多种表型的新特性，提出了针对这些表型的方案，并强调了突出问题和知识空白。
