COLLAGEN METABOLISM IN O. IMPERFECTA OSTEOBLASTS

成骨不全（OI）是一种遗传性出生缺陷， 主要特征是骨脆性， 严重。 将疾病分类为四种主要表型 是基于临床和遗传标准的。 的生化学研究 OI真皮成纤维细胞培养揭示了多种I型 胶原蛋白结构、合成和翻译后 异常 然而，这些成纤维细胞研究提出了三个 重要问题; 1）没有直接的相关性之间出现 特异性I型胶原缺陷与OI患者的临床 表型，2）我们拥有的某些成纤维细胞培养物 研究显示没有明显I型胶原突变，3） 成纤维细胞模型缺乏组织特异性， 细胞外基质（ECM）发育。 成纤维细胞培养 数据-没有充分解决如何缺陷的问题， I型胶原导致OI中异常的骨骼发育。 最近，已经开发了成骨细胞培养系统， 合成骨特异性和相关蛋白质， 矿化ECM的组装。 因此，成骨细胞培养物 这显然是一个比真皮更相关的ECM发育模型， 成纤维细胞 我们假设培养的成骨细胞有助于 为了阐明I型胶原蛋白缺陷与 异常的骨骼有机基质 I型胶原蛋白出现的地方 结构正常，其他骨特异性和相关蛋白质（即， 骨钙素、骨磷蛋白和碱性磷酸酶）可以是 与异常基质发育有关。 因此，我们建议 利用培养的人成骨细胞研究骨组织 特异性合成、ECM发育和矿化， 异常基质形成的功能指标。 我们有 先前描述的相似的鸡胚和胚胎 人骨小梁成骨细胞培养物。 我们建议审查其他机构 来自具有确定的α I（I）或α I（II）的患者的成骨细胞培养物 2（I）基因突变（先前在成纤维细胞中确定）， ECM发育异常。 他们将与年龄进行比较 匹配的正常对照成骨细胞。

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.