Bone Material Properties in Osteogenesis Imperfecta : BONE MATERIAL PROPERTIES IN OI

The attainment of both strength and toughness is a vital requirement for most structural materials; unfortunately these properties are generally mutually exclusive. Although the quest continues for stronger and harder materials, these have little to no use as bulk structural materials without appropriate fracture resistance. It is the lower-strength, and hence higher-toughness, materials that find use for most safety-critical applications where premature or, worse still, catastrophic fracture is unacceptable. For these reasons, the development of strong and tough (damage-tolerant) materials has traditionally been an exercise in compromise between hardness versus ductility. Drawing examples from metallic glasses, natural and biological materials, and structural and biomimetic ceramics, we examine some of the newer strategies in dealing with this conflict. Specifically, we focus on the interplay between the mechanisms that individually contribute to strength and toughness, noting that these phenomena can originate from very different lengthscales in a material's structural architecture. We show how these new and natural materials can defeat the conflict of strength versus toughness and achieve unprecedented levels of damage tolerance within their respective material classes.

In humans, low peak bone mass is a significant risk factor for osteoporosis. We report that LRP5, encoding the low-density lipoprotein receptor-related protein 5, affects bone mass accrual during growth. Mutations in LRP5 cause the autosomal recessive disorder osteoporosis-pseudoglioma syndrome (OPPG). We find that OPPG carriers have reduced bone mass when compared to age- and gender-matched controls. We demonstrate LRP5 expression by osteoblasts in situ and show that LRP5 can transduce Wnt signaling in vitro via the canonical pathway. We further show that a mutant-secreted form of LRP5 can reduce bone thickness in mouse calvarial explant cultures. These data indicate that Wnt-mediated signaling via LRP5 affects bone accrual during growth and is important for the establishment of peak bone mass.

An epidemiological and genetical study of osteogenesis imperfecta (OI) in Victoria, Australia confirmed that there are at least four distinct syndromes at present called OI. The largest group of patients showed autosomal dominant inheritance of osteoporosis leading to fractures and distinctly blue sclerae. A large proportion of adults had presenile deafness or a family history of presenile conductive hearing loss. A second group, who comprised the majority of newborns with neonatal fractures, all died before or soon after birth. These had characteristic broad, crumpled femora and beaded ribs in skeletal x-rays. Autosomal recessive inheritance was likely for some, if not all, of these cases. A third group, two thirds of whom had fractures at birth, showed severe progressive deformity of limbs and spine. The density of scleral blueness appeared less than that seen in the first group of patients and approximated that seen in normal children and adults. Moreover, the blueness appeared to decrease with age. All patients in this group were sporadic cases. The mode of inheritance was not resolved by the study, but it is likely that the group is heterogeneous with both dominant and recessive genotypes responsible for the syndrome. The fourth group of patients showed dominant inheritance of osteoporosis leading to fractures, with variable deformity of long bones, but normal sclerae.