COLLAGEN METABOLISM IN O. IMPERFECTA OSTEOBLASTS

成骨不全是一种遗传性出生缺陷，其 主要特征是骨脆性，从轻微到 很严重。将该病分为四种主要表型 是基于临床和遗传标准。青蒿素的生化研究 OI真皮成纤维细胞培养发现了多种I型 胶原蛋白结构、合成和翻译后 异常现象。然而，这些成纤维细胞的研究提出了三个 重要问题；1)没有直接关联出现在 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 调查显示没有明显的I型胶原突变，以及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-没有充分解决缺陷有多大的问题 I型胶原导致OI骨骼发育异常。 最近，成骨细胞培养系统已经开发出来 合成骨特异性和相关蛋白，并指导 矿化ECM的组装。因此，成骨细胞培养是 显然，一个比真皮更相关的细胞外基质发育模型 成纤维细胞。我们假设培养的OI成骨细胞将有助于 阐明I型胶原缺陷症与 骨骼有机基质异常。I型胶原出现的地方 结构正常的，其他骨骼特异的和相关的蛋白质(即。 骨钙素、骨磷蛋白和碱性磷酸酶)可能是 与异常的基质发育有关。因此，我们建议 利用培养的人OI成骨细胞研究骨组织 AS的特异性合成、ECM发育和矿化 异常基质形成的功能指标。我们有 以前的特征是类似的胚胎雏鸡和骨质疏松 人成骨小梁细胞培养。我们建议研究其他投资项目 L(I)或阿尔法患者的成骨细胞培养 2(I)基因突变(先前在成纤维细胞中确定) 细胞外胚层发育异常。他们将被与年龄进行比较 配对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.