EXT 1 gene mutation induces chondrocyte cytoskeletal abnormalities and defective collagen expression in the exostoses

Hereditary multiple exostoses (HME), an autosomal skeletal disorder charact erized by cartilage-capped excrescences, has been ascribed to mutations in EXT 1 and EXT 2, two tumor suppressor-related genes encoding glycosyltransf erases involved in the heparan sulfate proteoglycan (HSPG) biosynthesis, Ta king advantage of the availability of three different exostoses from a pati ent with HME harboring a premature termination codon in the EXT 1 gene, mor phological, immunologic, and biochemical analyses of the samples were carri ed out. The cartilaginous exostosis, when compared with control cartilage, exhibited alterations in the distribution and morphology of chondrocytes wi th abundant bundles of actin filaments indicative of cytoskeletal defects, Chondrocytes in the exostosis were surrounded by an extracellular matrix co ntaining abnormally high amounts of collagen type X, The unexpected presenc e of collagen type I unevenly distributed in the cartilage matrix further s uggested that some of the hypertrophic chondrocytes detected in the cartila ginous caps of the exostoses underwent accelerated differentiation, The two mineralized exostoses presented lamellar bone arrangement undergoing inten se remodeling as evidenced by the presence of numerous reversal lines. The increased electrophoretic mobility of chondroitin sulfate and dermatan sulf ate proteoglycans (PGS) extracted from the two bony exostoses was ascribed to an absence of the decorin core protein. Altogether, these data indicate that EXT mutations might induce a defective endochondral ossification proce ss in exostoses by altering actin distribution and chondrocyte differentiat ion and by promoting primary calcification through decorin removal.