PATHOLOGY OF INBORN SKELETAL DISEASES

该主题是对影响胶原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变。重点是软骨胶原，特别是II型、IX型和XI型胶原及其相关基质分子的异聚组合。通过研究蛋白质水平上的结构变化及其对原纤维蛋白水解易感性的潜在影响，这些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正在得到解决。随着分子技术迅速揭示导致或易感骨骼疾病的突变和多态性，人们越来越需要了解疾病发病机制。在这里，该方法是研究在手术或尸检中获得的影响软骨基质结构的遗传性软骨发育不良组织中的蛋白质缺陷。它们包括由COL2A1（胶原II）突变引起的严重疾病奈斯特发育不良；多发性骨骺发育不良（MED），一种轻至中度骨骼发育不良伴膝和髋关节早发性骨关节炎，由胶原IX或COMP突变引起；家族性骨关节炎，伴或不伴由COL2A1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）。分子的原因，倾向于关节退行性变在这些条件正在寻求。一种假设是突变的等位基因产物沉积在细胞外原纤维中，并促进通常不能攻击原纤维的蛋白酶的破坏，目前正在进行测试。II型、III型、IX型和XI型胶原降解产物在遗传性疾病中与正常软骨和受获得性OA影响的关节中产生的产物进行了比较。越来越多的胶原基因突变的报道导致关节早衰（滑膜关节和椎间关节），这推动了这项研究的方向。通过定义分子机制，遗传因素导致关节失败导致新的治疗和预防措施的预期。

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.