Osteogenesis Imperfecta: Mechanisms and Signaling Pathways Connecting Classical and Rare OI Types

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, posttranslational 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 interferon-induced transmembrane protein 5 p.S40L mutation that reveals the connection between the bone-restricted interferon-induced transmembrane protein-like protein and pigment epithelium-derived factor pathways. The function of regulated intramembrane proteolysis has been extended beyond cholesterol metabolism to bone formation by defects in regulated membrane proteolysis components site-2 protease and old astrocyte specifically induced-substance. 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.

Automated summary

Osteogenesis imperfecta (OI) is a diverse genetic and phenotypic skeletal disorder characterized by bone fragility, growth deficiency, and skeletal deformity. Research focuses on defects in collagen, abnormal bone mineralization, different inheritance patterns, and various genetic mutations related to OI.