Hereditary multiple exostoses (HME), an autosomal skeletal disorder characterized by cartilage-capped excrescences, has been ascribed to mutations in EXT 1 and EXT 2, two
tumor suppressor-related genes encoding
glycosyltransferases involved in the
heparan sulfate proteoglycan (
HSPG) biosynthesis. Taking advantage of the availability of three different
exostoses from a patient with HME harboring a
premature termination codon in the EXT 1 gene, morphological, immunologic, and biochemical analyses of the samples were carried out. The
cartilaginous exostosis, when compared with control cartilage, exhibited alterations in the distribution and morphology of chondrocytes with abundant bundles of actin filaments indicative of cytoskeletal defects. Chondrocytes in the
exostosis were surrounded by an extracellular matrix containing abnormally high amounts of
collagen type X. The unexpected presence of
collagen type I unevenly distributed in the cartilage matrix further suggested that some of the hypertrophic chondrocytes detected in the cartilaginous caps of the
exostoses underwent accelerated differentiation. The two mineralized
exostoses presented lamellar bone arrangement undergoing intense remodeling as evidenced by the presence of numerous reversal lines. The increased electrophoretic mobility of
chondroitin sulfate and
dermatan sulfate 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 process in
exostoses by altering actin distribution and chondrocyte differentiation and by promoting primary calcification through
decorin removal.