Osteogenesis imperfecta (OI) is a phenotypically and genetically heterogeneous skeletal dysplasia characterized by bone fragility, growth deficiency and skeletal deformity. Previously known to be caused by defects in type I collagen, the major protein of extracellular matrix, it is now also understood to be a collagen-related disorder caused by defects in collagen folding, post-translational modification and processing, bone mineralization and osteoblast differentiation, with inheritance of OI types spanning autosomal dominant and recessive as well as X-linked recessive. This review provides the latest updates on OI, encompassing both classical OI and rare forms, their mechanism and the signaling pathways involved in their pathophysiology. There is a special emphasis on mutations in type I procollagen C-propeptide structure and processing, the later causing OI with strikingly high bone mass. Types V and VI OI, while notably different, are shown to be interrelated by the IFITM5 p.S40L mutation that reveals the connection between the BRIL and PEDF pathways. The function of Regulated Intramembrane Proteolysis has been extended beyond cholesterol metabolism to bone formation by defects in RIP components S2P and OASIS. Several recently proposed candidate genes for new types of OI are also presented. Discoveries of new OI genes add complexity to already-challenging OI management; current and potential approaches are summarized.

中文翻译：

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成骨不全：连接经典和罕见成骨不全类型的机制和信号通路

成骨不全症（OI）是一种表型和遗传异质性骨骼发育不良，其特征是骨脆性、生长缺陷和骨骼畸形。以前已知是由细胞外基质的主要蛋白质 I 型胶原蛋白缺陷引起的，现在也被认为是由胶原蛋白折叠、翻译后修饰和加工、骨矿化和成骨细胞分化缺陷引起的胶原蛋白相关疾病，OI 类型的遗传涵盖常染色体显性和隐性以及 X 连锁隐性。这篇综述提供了成骨不全症的最新进展，包括经典的成骨不全症和罕见的成骨不全症、它们的机制以及涉及其病理生理学的信号通路。特别强调 I 型前胶原 C 前肽结构和加工的突变，后者导致 OI 并伴有惊人的高骨量。V 型和 VI 型 OI 虽然明显不同，但通过 IFITM5 p.S40L 突变相互关联，揭示了 BRIL 和 PEDF 途径之间的联系。通过 RIP 成分 S2P 和 OASIS 的缺陷，调节膜内蛋白水解的功能已从胆固醇代谢扩展到骨形成。还提出了一些最近提出的新型成骨不全症的候选基因。新的成骨不全基因的发现给本已充满挑战的成骨不全管理增添了复杂性；总结了当前和潜在的方法。