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HME is caused by mutations in heparan sulfate (HS)\u2010synthesizing enzymes EXT1 or EXT2. Seemingly paradoxically, osteochondromas were found to contain excessive extracellular heparanase (Hpse) that could further reduce HS levels and exacerbate pathogenesis. To test <jats:italic>Hpse<\/jats:italic> roles, we asked whether its ablation would protect against osteochondroma formation in a conditional HME model consisting of mice bearing floxed <jats:italic>Ext1<\/jats:italic> alleles in <jats:italic>Agr\u2010CreER<\/jats:italic> background (<jats:italic>Ext1<\/jats:italic><jats:sup><jats:italic>f\/f<\/jats:italic><\/jats:sup><jats:italic>;Agr\u2010CreER<\/jats:italic> mice). Mice were crossed with a new global <jats:italic>Hpse<\/jats:italic>\u2010null (<jats:italic>Hpse<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>) mice to produce compound <jats:italic>Hpse<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup><jats:italic>;Ext1<\/jats:italic><jats:sup><jats:italic>f\/f<\/jats:italic><\/jats:sup><jats:italic>;Agr\u2010CreER<\/jats:italic> mice. Tamoxifen injection of standard juvenile <jats:italic>Ext1<\/jats:italic><jats:sup><jats:italic>f\/f<\/jats:italic><\/jats:sup><jats:italic>;Agr\u2010CreER<\/jats:italic> mice elicited stochastic <jats:italic>Ext1<\/jats:italic> ablation in growth plate and perichondrium, followed by osteochondroma formation, as revealed by microcomputed tomography and histochemistry. When we examined companion conditional <jats:italic>Ext1<\/jats:italic>\u2010deficient mice lacking <jats:italic>Hpse<\/jats:italic> also, we detected no major decreases in osteochondroma number, skeletal distribution, and overall structure by the analytical criteria above. The <jats:italic>Ext1<\/jats:italic> mutants used here closely mimic human HME pathogenesis, but have not been previously tested for responsiveness to treatments. To exclude some innate therapeutic resistance in this stochastic model, tamoxifen\u2010injected <jats:italic>Ext1<\/jats:italic><jats:sup><jats:italic>f\/f<\/jats:italic><\/jats:sup><jats:italic>;Agr\u2010CreER<\/jats:italic> mice were administered daily doses of the retinoid Palovarotene, previously shown to prevent ectopic cartilage and bone formation in other mouse disease models. This treatment did inhibit osteochondroma formation compared with\u00a0vehicle\u2010treated mice. Our data indicate that heparanase is not a major factor in osteochondroma initiation and accumulation in mice. Possible roles of heparanase upregulation in disease severity in patients are discussed.<\/jats:p>","DOI":"10.1002\/jor.25260","type":"journal-article","created":{"date-parts":[[2022,1,7]],"date-time":"2022-01-07T23:25:31Z","timestamp":1641597931000},"page":"2391-2401","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Osteochondroma formation is independent of heparanase expression as revealed in a mouse model of hereditary multiple exostoses"],"prefix":"10.1002","volume":"40","author":[{"given":"Christina","family":"Mundy","sequence":"first","affiliation":[{"name":"Translational Research Program in Pediatric Orthopaedics, Division of Orthopaedic Surgery The Children's Hospital of Philadelphia Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliet","family":"Chung","sequence":"additional","affiliation":[{"name":"Translational Research Program in Pediatric Orthopaedics, Division of Orthopaedic Surgery The Children's Hospital of Philadelphia Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eiki","family":"Koyama","sequence":"additional","affiliation":[{"name":"Translational Research Program in Pediatric Orthopaedics, Division of Orthopaedic Surgery The Children's Hospital of Philadelphia Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart","family":"Bunting","sequence":"additional","affiliation":[{"name":"BioMarin Pharmaceutical, Inc. Novato California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajeev","family":"Mahimkar","sequence":"additional","affiliation":[{"name":"BioMarin Pharmaceutical, Inc. 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