Marini Joan C, Reich Adi, Smith Simone M
Bone and Extracellular Matrix Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
Curr Opin Pediatr. 2014 Aug;26(4):500-7. doi: 10.1097/MOP.0000000000000117.
Osteogenesis imperfecta or 'brittle bone disease' has mainly been considered a bone disorder caused by collagen mutations. Within the last decade, however, a surge of genetic discoveries has created a new paradigm for osteogenesis imperfecta as a collagen-related disorder, where most cases are due to autosomal dominant type I collagen defects, while rare, mostly recessive, forms are due to defects in genes whose protein products interact with collagen protein. This review is both timely and relevant in outlining the genesis, development, and future of this paradigm shift in the understanding of osteogenesis imperfecta.
Bone-restricted interferon-induced transmembrane (IFITM)-like protein (BRIL) and pigment epithelium-derived factor (PEDF) defects cause types V and VI osteogenesis imperfecta via defective bone mineralization, while defects in cartilage-associated protein (CRTAP), prolyl 3-hydroxylase 1 (P3H1), and cyclophilin B (CYPB) cause types VII-IX osteogenesis imperfecta via defective collagen post-translational modification. Heat shock protein 47 (HSP47) and FK506-binding protein-65 (FKBP65) defects cause types X and XI osteogenesis imperfecta via aberrant collagen crosslinking, folding, and chaperoning, while defects in SP7 transcription factor, wingless-type MMTV integration site family member 1 (WNT1), trimeric intracellular cation channel type b (TRIC-B), and old astrocyte specifically induced substance (OASIS) disrupt osteoblast development. Finally, absence of the type I collagen C-propeptidase bone morphogenetic protein 1 (BMP1) causes type XII osteogenesis imperfecta due to altered collagen maturation/processing.
Identification of these multiple causative defects has provided crucial information for accurate genetic counseling, inspired a recently proposed functional grouping of osteogenesis imperfecta types by shared mechanism to simplify current nosology, and has prodded investigations into common pathways in osteogenesis imperfecta. Such investigations could yield critical information on cellular and bone tissue mechanisms and translate to new mechanistic insight into clinical therapies for patients.
成骨不全症或“脆骨病”主要被认为是一种由胶原蛋白突变引起的骨骼疾病。然而，在过去十年中，大量的基因发现为成骨不全症创造了一种新的范式，即作为一种与胶原蛋白相关的疾病，其中大多数病例是由于常染色体显性I型胶原蛋白缺陷，而罕见的、大多为隐性的形式则是由于其蛋白质产物与胶原蛋白相互作用的基因缺陷所致。这篇综述对于概述这种在成骨不全症理解上的范式转变的起源、发展及未来而言，既及时又具有相关性。
骨限制性干扰素诱导跨膜（IFITM）样蛋白（BRIL）和色素上皮衍生因子（PEDF）缺陷通过骨矿化缺陷导致V型和VI型成骨不全症，而软骨相关蛋白（CRTAP）、脯氨酰3-羟化酶1（P3H1）和亲环蛋白B（CYPB）缺陷通过胶原蛋白翻译后修饰缺陷导致VII-IX型成骨不全症。热休克蛋白47（HSP47）和FK506结合蛋白65（FKBP65）缺陷通过异常的胶原蛋白交联、折叠和伴侣作用导致X型和XI型成骨不全症，而SP7转录因子、无翅型MMTV整合位点家族成员1（WNT1）、三聚体细胞内阳离子通道b型（TRIC-B）和老年星形胶质细胞特异性诱导物质（OASIS）缺陷会破坏成骨细胞发育。最后，I型胶原蛋白C-前肽酶骨形态发生蛋白1（BMP1）的缺失由于胶原蛋白成熟/加工改变导致XII型成骨不全症。
这些多种致病缺陷的鉴定为准确的遗传咨询提供了关键信息，激发了最近提出的按共同机制对成骨不全症类型进行功能分组以简化当前疾病分类学的方法，并推动了对成骨不全症常见途径的研究。此类研究可能会产生有关细胞和骨组织机制的关键信息，并转化为对患者临床治疗的新机制性见解。
