Mutations in collagen genes resulting in metaphyseal and epiphyseal dysplasias.

Genetic mapping and positional cloning of genes, in which mutations lead to osteochondrodysplasias in humans and mice, combined with studies of transgenic mice with mutations in cloned genes, is providing novel and exciting insights into the molecular mechanisms of cartilage and bone development and growth as well as the basis for a variety of osteochondrodysplasias. Studies of mice with targeted disruption of c-src and c-fos have shown that these two genes have essential roles in the function and differentiation of osteoclasts. Combined mouse and human studies demonstrate that a unique extracellular matrix molecule (collagen X) in the mineralizing hypertrophic zone of growth plates is essential for normal growth plate function. Mutations in this molecule cause metaphyseal chondrodysplasia type Schmid (MCDS) in humans. Identification of the gene causing autosomal recessive chondrodysplasia in mice demonstrates that the quantitatively minor fibrillar collagen XI is essential for the cohesive properties of cartilage and the normal differentiation and spatial organization of chondrocytes in growth plates. Finally, mutations in all three collagen components of cartilage fibrils, collagens II, IX, and XI, have been found to cause a spectrum of clinical disorders, ranging from severe, perinatal lethal, osteochondrodysplasias to extremely mild conditions presenting themselves as a genetic predisposition to osteoarthritis.