Osteogenesis imperfecta (OI) is a heritable birth defect whose dominant feature is bone fragility which varies from mild to severe. Classification of the disease into four main phenotypes is based on clinical and genetic criteria. Biochemical study of OI dermal fibroblast cultures has revealed a variety of type I collagen structural, synthetic and post-translational abnormalities. However, these fibroblast studies have raised three important issues; 1) that no direct correlation appears between a specific type I collagen defect and the OI patient's clinical phenotype, 2) that certain of the fibroblast cultures we have investigated show no apparent type I collagen mutation and 3) that the fibroblast model lacks tissue specificity with respect to extracellular matrix (ECM) development. The fibroblast culture data-has not adequately addressed the question of how defective type I collagen results in abnormal skeletal development in OI. Recently, osteoblastic culture systems have been developed that synthesize bone-specific and related proteins and direct the assembly of a mineralized ECM. Thus, the osteoblast cultures are clearly a more relevant model of ECM development than the dermal fibroblasts. We hypothesize that cultured OI osteoblasts will help to clarify the relationship between defective type I collagen and abnormal skeletal organic matrix. Where type I collagen appears structurally normal, other bone-specific and related proteins (ie. osteocalcin, bone phosphoproteins and alkaline phosphatase) may be related to abnormal matrix development. Thus, we propose to utilize cultured human OI osteoblasts to investigate bone tissue specific synthesis, ECM development and mineralization as functional indicators of abnormal matrix formation. We have previously characterized similar embryonic chick and osteoporotic human trabecular osteoblast cultures. We propose to examine OI osteoblast cultures from patients with defined alpha l(I) or alpha 2(I) gene mutations (previously determined in fibroblasts) for abnormalities in ECM development. They will be compared to age matched, normal control osteoblasts.
