Kaplan Frederick S, Glaser David L, Pignolo Robert J, Shore Eileen M
University of Pennsylvania School of Medicine, Department of Orthopaedic Surgery, Hospital of the University of Pennsylvania, Silverstein Two, 34th & Spruce Street, Philadelphia, PA 19104, USA.
Expert Opin Biol Ther. 2007 May;7(5):705-12. doi: 10.1517/14712598.7.5.705.
Fibrodysplasia ossificans progressiva (FOP) is a disabling genetic condition that leads to the formation of a second (heterotopic) skeleton, and is the most catastrophic disorder of heterotopic ossification in humans. Throughout childhood and early adult life, FOP progressively immobilizes all of the joints of the normotopic skeleton, rendering movement impossible. At present, there is no effective prevention or treatment. Recently, a recurrent mutation in the glycine-serine activation domain of the activin receptor IA/activin-like kinase-2, a bone morphogenetic protein type I receptor, was reported in all sporadic and familial cases of classic FOP, making this one of the most highly specific disease-causing mutations in the human genome. The discovery of the FOP gene establishes a critical milestone in understanding FOP, reveals a highly conserved druggable target in the TGF-beta/bone morphogenetic protein signaling pathway and compels therapeutic approaches for the development of small molecule signal transduction inhibitors for activin-like kinase-2. Effective therapies for FOP, and possibly for a vast array of more common conditions of heterotopic ossification, will be based on blocking activin-like kinase-2, a critical node in the BMP signaling pathway.
进行性骨化性纤维发育不良（FOP）是一种致残性遗传病，会导致第二（异位）骨骼的形成，是人类异位骨化最严重的疾病。在整个儿童期和成年早期，FOP会逐渐使正常骨骼的所有关节固定，导致无法活动。目前，尚无有效的预防或治疗方法。最近，在所有散发和家族性经典FOP病例中均报告了激活素受体IA/激活素样激酶-2（一种I型骨形态发生蛋白受体）的甘氨酸-丝氨酸激活域中的复发性突变，这使其成为人类基因组中最具特异性的致病突变之一。FOP基因的发现是理解FOP的一个关键里程碑，揭示了转化生长因子-β/骨形态发生蛋白信号通路中一个高度保守的可药物作用靶点，并促使开发针对激活素样激酶-2的小分子信号转导抑制剂的治疗方法。针对FOP以及可能针对大量更常见的异位骨化病症的有效疗法，将基于阻断激活素样激酶-2，它是骨形态发生蛋白信号通路中的一个关键节点。
