{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T16:39:33Z","timestamp":1781109573346,"version":"3.54.1"},"reference-count":35,"publisher":"National Academy of Sciences","issue":"24","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2010,6,15]]},"abstract":"<jats:p>\n                    Multiple hereditary exostoses (MHE) is one of the most common skeletal dysplasias, exhibiting the formation of multiple cartilage-capped bony protrusions (osteochondroma) and characteristic bone deformities. Individuals with MHE carry heterozygous loss-of-function mutations in\n                    <jats:italic>Ext1<\/jats:italic>\n                    or\n                    <jats:italic>Ext2<\/jats:italic>\n                    , genes which together encode an enzyme essential for heparan sulfate synthesis. Despite the identification of causative genes, the pathogenesis of MHE remains unclear, especially with regard to whether osteochondroma results from loss of heterozygosity of the\n                    <jats:italic>Ext<\/jats:italic>\n                    genes. Hampering elucidation of the pathogenic mechanism of MHE, both\n                    <jats:italic>\n                      Ext1\n                      <jats:sup>+\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    and\n                    <jats:italic>\n                      Ext2\n                      <jats:sup>+\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    heterozygous mutant mice, which mimic the genetic status of human MHE, are highly resistant to osteochondroma formation, especially in long bones. To address these issues, we created a mouse model in which\n                    <jats:italic>Ext1<\/jats:italic>\n                    is stochastically inactivated in a chondrocyte-specific manner. We show that these mice develop multiple osteochondromas and characteristic bone deformities in a pattern and a frequency that are almost identical to those of human MHE, suggesting a role for\n                    <jats:italic>Ext1<\/jats:italic>\n                    LOH in MHE. Surprisingly, however, genotyping and fate mapping analyses reveal that chondrocytes constituting osteochondromas are mixtures of mutant and wild-type cells. Moreover, osteochondromas do not possess many typical neoplastic properties. Together, our results suggest that inactivation of\n                    <jats:italic>Ext1<\/jats:italic>\n                    in a small fraction of chondrocytes is sufficient for the development of osteochondromas and other skeletal defects associated with MHE. Because the observed osteochondromas in our mouse model do not arise from clonal growth of chondrocytes, they cannot be considered true neoplasms.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0914642107","type":"journal-article","created":{"date-parts":[[2010,6,1]],"date-time":"2010-06-01T20:51:16Z","timestamp":1275425476000},"page":"10932-10937","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":82,"title":["A mouse model of chondrocyte-specific somatic mutation reveals a role for\n                    <i>Ext1<\/i>\n                    loss of heterozygosity in multiple hereditary exostoses"],"prefix":"10.1073","volume":"107","author":[{"given":"Kazu","family":"Matsumoto","sequence":"first","affiliation":[{"name":"Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumitoshi","family":"Irie","sequence":"additional","affiliation":[{"name":"Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Mackem","sequence":"additional","affiliation":[{"name":"Cancer and Developmental Biology Laboratory, National Cancer Institute, Frederick, MD 21702"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Yamaguchi","sequence":"additional","affiliation":[{"name":"Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037; and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2010,6]]},"reference":[{"key":"e_1_3_3_1_2","volume-title":"Pediatric Orthopaedics and Sports Medicine: The Requisites in Pediatrics","author":"Erol B","year":"2004","unstructured":"B Erol, JP Dormans, L States, FS Kaplan, Skeletal dysplasias and metabolic disorders of bone. 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