PATHOLOGY OF INBORN SKELETAL DISEASES

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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.