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

• Published in: Endocrine reviews Vol. 43; no. 1; pp. 61 - 90
• Main Authors: Jovanovic, Milena, Guterman-Ram, Gali, Marini, Joan C
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 01-02-2022
• Subjects: Biological response modifiers; Bone dysplasia; Bone growth; Bone mass; Bone strength; Bones; Cholesterol; Collagen; Collagen (type I); Collagen - genetics; Collagen Type I - genetics; Collagen Type I - metabolism; Defects; Density; Epithelium; Extracellular matrix; Fragility; Genes; Humans; Interferon; Interferons - genetics; Lipid metabolism; Mineralization; Mutation; Osteoblastogenesis; Osteogenesis; Osteogenesis imperfecta; Osteogenesis Imperfecta - genetics; Osteogenesis Imperfecta - metabolism; Physiological aspects; Pigment epithelium-derived factor; Post-translational modification; Procollagen; Proteases; Proteins; Proteolysis; Review; Signal Transduction; Skeleton; bone mass; PEDF; collagen synthesis; osteogenesis imperfecta; regulated intramembrane proteolysis; BRIL; bone mineralization; IFITM5/BRIL; MBTPS2
• ISSN: 0163-769X; 1945-7189
• DOI: 10.1210/endrev/bnab017

Abstract
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.
Graphical Abstract
Graphical Abstract