Lin Hui, Shi Fuli, Gao Jiayu, Hua Ping
Jiangxi Province Key Laboratory of Tumor Pathogens and Molecular Pathology and Department of Pathophysiology, School of Basic Medicine Sciences, Nanchang University Medical College, Nanchang, China
Jiangxi Province Key Laboratory of Tumor Pathogens and Molecular Pathology and Department of Pathophysiology, School of Basic Medicine Sciences, Nanchang University Medical College, Nanchang, China.
Biosci Rep. 2019 Aug 2;39(8). doi: 10.1042/BSR20190377. Print 2019 Aug 30.
Heterotopic ossification (HO) is the aberrant formation of mature, lamellar bone in nonosseous tissue. Fibrodysplasia ossificans progressiva (FOP) is a rare and devastating genetic disorder that causes progressive HO in the ligaments, tendons, and muscles throughout the body. FOP is attributed to an autosomal mutation in activin receptor-like kinase 2 (ALK2), a bone morphogenetic protein (BMP) type I receptor. Initial studies show that mutant ALK2 drives HO by constitutively activating the BMP signaling pathway. Recently, mutant ALK2 has been shown to transduce Smad1/5 signaling and enhance chondrogenesis, calcification in response to Activin A, which normally signals through Smad2/3 and inhibits BMP signaling pathway. Furthermore, Activin A induces heterotopic bone formation via mutant ALK2, while inhibition of Activin A blocks spontaneous and trauma-induced HO. In this manuscript, we describe the molecular mechanism of the causative gene in FOP, mainly focusing on the prominent role of Activin A in HO. It reveals a potential strategy for prevention and treatment of FOP by inhibition of Activin A. Further studies are needed to explore the cellular and molecular mechanisms of Activin A in FOP in more detail.
异位骨化（HO）是指在非骨组织中异常形成成熟的板层骨。进行性骨化性纤维发育不良（FOP）是一种罕见且严重的遗传性疾病，可导致全身韧带、肌腱和肌肉中出现进行性HO。FOP归因于激活素受体样激酶2（ALK2）的常染色体突变，ALK2是一种骨形态发生蛋白（BMP）I型受体。初步研究表明，突变型ALK2通过持续激活BMP信号通路来驱动HO。最近研究发现，突变型ALK2可转导Smad1/5信号，并增强软骨生成、响应激活素A时的钙化，激活素A通常通过Smad2/3信号传导并抑制BMP信号通路。此外，激活素A通过突变型ALK2诱导异位骨形成，而抑制激活素A可阻断自发性和创伤性HO。在本论文中，我们描述了FOP致病基因的分子机制，主要聚焦于激活素A在HO中的突出作用。它揭示了通过抑制激活素A预防和治疗FOP的潜在策略。需要进一步研究以更详细地探索激活素A在FOP中的细胞和分子机制。
