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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\u2010synthesizing 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\u2010bony outgrowths, form next to growth plates, can cause growth retardation and deformities, chronic pain and impaired motion, and progress to malignancy in 2\u20135% 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\u2010type and HS\u2010deficient 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. <jats:italic>Developmental Dynamics 242:1021\u20131032, 2013<\/jats:italic>. \u00a9 2013 Wiley Periodicals, Inc.<\/jats:p>","DOI":"10.1002\/dvdy.24010","type":"journal-article","created":{"date-parts":[[2013,7,2]],"date-time":"2013-07-02T12:36:05Z","timestamp":1372768565000},"page":"1021-1032","source":"Crossref","is-referenced-by-count":66,"title":["Heparan sulfate in skeletal development, growth, and pathology: The case of hereditary multiple exostoses"],"prefix":"10.1002","volume":"242","author":[{"given":"Julianne","family":"Huegel","sequence":"first","affiliation":[{"name":"Translational Research Program in Pediatric Orthopaedics, Division of Orthopaedic Surgery The Children's Hospital of Philadelphia Philadelphia 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