Heterotopic ossification (HO) is a disorder characterised by the formation of ectopic bone in soft tissue. Acquired HO typically occurs in response to trauma and is relatively common, yet its aetiology remains poorly understood. Genetic forms, by contrast, are very rare, but provide insights into the mechanisms of HO pathobiology. Fibrodysplasia ossificans progressiva (FOP) is the most debilitating form of HO. All patients reported to date carry heterozygous gain-of-function mutations in the gene encoding activin A receptor type I (ACVR1). These mutations cause dysregulated bone morphogenetic protein (BMP) signalling, leading to HO at extraskeletal sites including, but not limited to, muscles, ligaments, tendons and fascia. Ever since the identification of the causative gene, developing a cure for FOP has been a focus of investigation, and studies have decoded the pathophysiology at the molecular and cellular levels, and explored novel management strategies. Based on the established role of BMP signalling throughout HO in FOP, therapeutic modalities that target multiple levels of the signalling cascade have been designed, and some drugs have entered clinical trials, holding out hope of a cure. A potential role of other signalling pathways that could influence the dysregulated BMP signalling and present alternative therapeutic targets remains a matter of debate. Here, we review the recent FOP literature, including pathophysiology, clinical aspects, animal models and current management strategies. We also consider how this research can inform our understanding of other types of HO and highlight some of the remaining knowledge gaps.

中文翻译：

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进展性骨化纤维发育不良：从工作台到床边的当前概念。

异位骨化 (HO) 是一种以软组织中异位骨形成为特征的疾病。获得性 HO 通常发生在对创伤的反应中，并且相对常见，但其病因仍知之甚少。相比之下，遗传形式非常罕见，但提供了对 H2O 病理生物学机制的见解。进展性骨化纤维发育不良 (FOP) 是 H2O 最虚弱的形式。迄今为止报道的所有患者在编码激活素 A 受体类型 I (ACVR1) 的基因中都携带杂合的功能获得性突变。这些突变导致骨形态发生蛋白 (BMP) 信号传导失调，导致骨骼外部位的 H2O，包括但不限于肌肉、韧带、肌腱和筋膜。自从确定致病基因以来，开发治疗 FOP 的方法一直是研究的重点，研究已经在分子和细胞水平上解码了病理生理学，并探索了新的管理策略。基于 BMP 信号在 FOP 中整个 HO 中的既定作用，已经设计了针对多个级别的信号级联反应的治疗方式，并且一些药物已经进入临床试验，有望治愈。其他信号通路可能影响 BMP 信号失调并提供替代治疗靶点的潜在作用仍然是一个有争议的问题。在这里，我们回顾了最近的 FOP 文献，包括病理生理学、临床方面、动物模型和当前的管理策略。我们还考虑了这项研究如何帮助我们了解其他类型的 HO，并强调一些剩余的知识差距。