Osteogenesis imperfecta and therapeutics

Abstract

Osteogenesis imperfecta, or brittle bone disease, is a congenital disease that primarily causes low bone mass and bone fractures but it can negatively affect other organs. It is usually inherited in an autosomal dominant fashion, although rarer recessive and X-chromosome-linked forms of the disease have been identified. In addition to type I collagen, mutations in a number of other genes, often involved in type I collagen synthesis or in the differentiation and function of osteoblasts, have been identified in the last several years. Seldom, the study of a rare disease has delivered such a wealth of new information that have helped our understanding of multiple processes involved in collagen synthesis and bone formation. In this short review I will describe the clinical features and the molecular genetics of the disease, but then focus on how OI dysregulates all aspects of extracellular matrix biology. I will conclude with a discussion about OI therapeutics.

Keywords: Bone; Collagen; Fragility; Genetics; Mineralization; Osteogenesis imperfecta; Proteoglycans.

Figure 1

Radiographic images of lower extremities of patients affected with different types of OI, demonstrating the wide range of severity that affects the skeleton in this disease. A. One-year-old infant diagnosed with severe type III OI. Note the severe bowing of the legs and the lack of bone modeling in both femurs and tibiae. B. A nine-month-old infant with moderately severe type IV OI. C. A 12-year-old patient with type I OI. Note the relative constriction of the femur diaphysis and the flaring of the distal metaphysis which is known as Erlenmeyer flask deformity. Metaphyseal bands due to cyclical bisphosphonate treatment are also visible. D. Same patient shown in B at 7 years of age and after years of medical and surgical management. Note the telescoping rods implanted in both femurs and tibiae, a common surgical procedure in OI patients that have significant long bone deformities. All the radiographic images are a courtesy of Dr. Paul W. Esposito and Maegen Wallace (University of Nebraska Medical Center).

Figure 2

Representative transmission electron micrograph of dermal collagen from WT (A) and CrtapKO (B) mouse, showing decreased amount of collagen and increased space among collagen bundles in this murine model of recessive OI. This translates into skin laxity and reduced dermal thickness. C = cross section of collagen fibrils; L = longitudinal section of collagen fibrils; E = empty space.

Figure 3

Schematic diagram illustrating essential processes of type I collagen synthesis, its assembly in the matrix, interaction with other matrix components, and mineralization. Some of the proteins that regulate these processes and that are mutated in various types of OI are also indicated. Alterations of one or more of these key steps in the formation of ECM represent major pathogenetic mechanisms in OI.