Abstract
The clinical hallmarks of osteogenesis imperfecta (OI), often referred to as 'brittle-bone disease', are bone fragility and skeletal deformities that are usually accompanied by extra skeletal manifestations. OI is a family of collagen I-related disorders, currently classified into 23 distinct types and 5 OI-like forms, with variable phenotypic severity ranging from mild to lethal. At the molecular level, the pathophysiology of OI is driven by alterations in collagen I structure, primarily caused by dominant mutations in collagen genes (affecting approximately 85% of patients). It can also result from dominant, recessive, or X-linked defects in proteins involved in collagen biosynthesis, extracellular matrix organization, mineralization, or bone forming cell differentiation and/or activity. This review illustrates the different OI forms from a collagen I perspective, its complex biosynthetic process is first described, followed by a classification of the OI and OI-like causative mutations grouped based on whether the resulting collagen molecule is overmodified, undermodified, or unaltered. The underlying molecular mechanisms and the consequences at cellular and extracellular levels leading to the OI phenotype are discussed. An overview is provided on how newly discovered molecular pathways altered in OI can guide the development of innovative therapies aiming at increasing bone mass and improving bone quality in OI patients.