PATHOLOGY OF INBORN SKELETAL DISEASES

该主题是对影响胶原蛋白和其他细胞外蛋白并导致遗传性骨骼疾病的突变的分子效应的基础研究。 一个关键的目标是了解分子事件在关节软骨，易患和伴随关节退行性变。 重点是软骨胶原蛋白，特别是胶原蛋白II型，IX型和Xi及其相关基质分子的杂聚体组装。 通过研究蛋白质水平的结构变化及其影响纤维对蛋白水解的敏感性的潜力，正在解决关于这种基因缺陷如何转化为组织发病机制和临床疾病的知识缺口。随着分子生物学技术迅速发现导致或易患骨骼疾病的突变和多态性，人们越来越需要了解疾病的发病机制。 在这里，该方法是研究从影响软骨基质结构的遗传性软骨发育不良的手术或尸检中获得的组织中的蛋白质缺陷。 它们包括最严重的发育不良，一种由COL 2A 1（胶原II）突变引起的严重疾病;多发性骨骺发育不良（MED），一种由胶原IX或COMP突变引起的轻度至中度骨骼发育不良伴膝关节和髋关节早发性骨关节炎;家族性骨关节炎，伴或不伴由COL 2A 1突变或胶原IX和Xi基因突变引起的轻度脊椎骨骺发育不良（SED）。 在这些条件下，关节退行性变的易感性的分子原因正在寻找。 突变等位基因产物沉积在细胞外原纤维中，并促进蛋白酶通常不能攻击原纤维的损伤，这一假说正在接受检验。 II、III、IX和Xi型胶原降解产物在遗传性疾病中与在正常软骨和受获得性OA影响的关节中产生的降解产物进行比较。 越来越多的胶原基因突变的报告，使关节过早衰竭（滑膜和椎间关节）驱动的方向，这项研究。 通过定义遗传因素导致关节失败的分子机制，可以预期新的治疗和预防措施。

The topic is basic research on the molecular effects of mutations that affect collagens and other extracellular proteins and cause heritable skeletal disorders. A key goal is to understand molecular events in articular cartilage that predispose to and accompany joint degeneration. The focus is on cartilage collagens, in particular the heteropolymeric assemblage of collagen types II, IX and XI and their associated matrix molecules. By studying structural changes at the protein level and their potential to affect the susceptibility of fibrils to proteolysis, the knowledge gap on how such gene defects translate into tissue pathogenesis and clinical disease is being addressed. As molecular techniques rapidly uncover mutations and polymorphisms that cause or predispose to skeletal disorders, there is a growing need to know that mechanisms of disease pathogenesis. Here, the approach is to study the protein defects in tissues obtained at surgery or autopsy from heritable chondrodysplasias that affect cartilage matrix structure. They include Kniest dysplasia, a severe disorder caused by COL2A1 (collagen II) mutations; multiple epiphyseal dysplasia (MED), a mild-to-moderate skeletal dysplasia with early-onset osteoarthritis of knees and hips, caused by collagen IX or COMP mutations; familial osteoarthritis, with or without mild spondyloepiphyseal dysplasia (SED) caused by COL2A1 mutations or mutations in collagens IX and XI genes. Molecular reasons for the predisposition to joint degeneration in these conditions are being sought. A hypothesis that mutant allelic products are deposited in extracellular fibrils and promote damage by proteases normally incapable of attacking fibrils, is being tested. Collagen type II, III, IX and XI degradation products are being compared in heritable disease to those generated in normal cartilage and in joints affected by acquired OA. The growing number of reports of mutations in collagen genes that predispose to premature joint failure (synovial and intervertebral joints) drive the direction of this research. By defining molecular mechanisms whereby genetic factors cause joints to fail leads on novel therapeutic and preventive measures are anticipated.