The ultrastructural changes in bone of patients with osteogenesis imperfecta

Osteogenesis Imperfecta (OI) is a heterogeneous, heritable disorder affecting mineralised and non-mineralised connective tissues, resulting in bone fragility. Over 200 mutations in procollagen genes have now been identified in OI patients. This study aimed to identify the morphological manifestations of collagen abnormalities in OI bone and to determine whether changes in mineral composition and collagen structure correlate with clinical types. Bone specimens from 43 OI patients and 25 normal controls were examined using a variety of techniques. The morphological and ultrastructural alterations observed in OI bone correlate well with clinical severity, mildest forms showing the least disturbed changes with severe forms showing the greatest disorganisation. The Ca/P ratio of OI bone mineral as measured by electron probe X-ray microanalysis was lower than normal in both resin and cryo-sections, and mirrored the severity of disease. OI type II gave the lowest ratio (Ca/P = 1.49) compared with normal age- and site-matched controls (Ca/P = 1.69). Histomorphometric measurements revealed collagen fibrils of reduced diameter in the osteoid of all OI types. The smallest mean diameter was found in OI type II (45 nm compared with 67 nm for age- and site-matched controls). OI type II also revealed a shorter collagen D-period (45 nm); the periodicity in other OI types was comparable to normal (63 nm). Immunogold localisation of collagen types in OI bone demonstrated type III collagen for the first time at an ultrastructural level. The labelling intensity for type I collagen was reduced when compared with that of normal controls. Other observations include a reduced alkaline phosphatase activity in OI bone, the abnormal presence of proteoglycans in the osteocytic lacunae of type II/III bone and increased levels of proteoglycans between the collagen fibres of OI osteoid. The abnormalities in mineral composition, collagen structure and proteoglycan distribution demonstrated in this study may be important factors contributing to the fragility of OI bone