Heparan sulfate (HS) is an essential component of cell surface and matrix-associated
proteoglycans. Due to their sulfation patterns, the HS chains interact with numerous signaling
proteins and regulate their distribution and activity on target cells. Many of these
proteins, including
bone morphogenetic protein family members, are expressed in the growth plate of developing skeletal elements, and several skeletal phenotypes are caused by mutations in those
proteins as well as in HS-synthesizing and modifying
enzymes. The disease we discuss here is
hereditary multiple exostoses (HME), a disorder caused by mutations in HS synthesizing
enzymes EXT1 and EXT2, leading to HS deficiency. The
exostoses are benign cartilaginous-bony outgrowths, form next to growth plates, can cause growth retardation and
deformities,
chronic pain and impaired motion, and progress to
malignancy in 2-5% of patients. We describe recent advancements on HME pathogenesis and
exostosis formation deriving from studies that have determined distribution, activities and roles of signaling
proteins in wild-type and HS-deficient cells and tissues. Aberrant distribution of signaling factors combined with aberrant responsiveness of target cells to those same factors appear to be a major culprit in
exostosis formation. Insights from these studies suggest plausible and cogent ideas about how HME could be treated in the future.