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This process is insufficiently understood, cannot be efficiently counteracted and calls for novel means of treatment. The endocytic collagen receptor, <jats:styled-content style=\"fixed-case\">uPARAP<\/jats:styled-content>\/Endo180, is expressed on various mesenchymal cell types and is involved in bone matrix turnover during normal bone growth. Human osteosarcoma specimens showed strong expression of this receptor on tumour cells, along with the collagenolytic metalloprotease, <jats:styled-content style=\"fixed-case\">MT1\u2013MMP<\/jats:styled-content>. In advanced tumours with ongoing bone degeneration, sarcoma cells positive for these proteins formed a contiguous layer aligned with the degradation zones. Remarkably, osteoclasts were scarce or absent from these regions and quantitative analysis revealed that this scarcity marked a strong contrast between osteosarcoma and bone metastases of carcinoma origin. This opened the possibility that sarcoma cells might directly mediate bone degeneration. To examine this question, we utilized a syngeneic, osteolytic bone tumour model with transplanted <jats:styled-content style=\"fixed-case\">NCTC<\/jats:styled-content>\u20102472 sarcoma cells  in mice. When analysed <jats:italic>in vitro<\/jats:italic>, these cells were capable of degrading the protein component of surface\u2010labelled bone slices in a process dependent on <jats:styled-content style=\"fixed-case\">MMP<\/jats:styled-content> activity and <jats:styled-content style=\"fixed-case\">uPARAP<\/jats:styled-content>\/Endo180. Systemic treatment of the sarcoma\u2010inoculated mice with a mouse monoclonal antibody that blocks murine <jats:styled-content style=\"fixed-case\">uPARAP<\/jats:styled-content>\/Endo180 led to a strong reduction of bone destruction. Our findings identify sarcoma cell\u2010resident <jats:styled-content style=\"fixed-case\">uPARAP<\/jats:styled-content>\/Endo180 as a central player in the bone degeneration of advanced tumours, possibly following an osteoclast\u2010mediated attack on bone in the early tumour stage. This points to <jats:styled-content style=\"fixed-case\">uPARAP<\/jats:styled-content>\/Endo180 as a promising therapeutic target in osteosarcoma, with particular prospects for improved neoadjuvant therapy. Copyright \u00a9 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/path.4661","type":"journal-article","created":{"date-parts":[[2015,10,15]],"date-time":"2015-10-15T05:06:37Z","timestamp":1444885597000},"page":"120-133","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Targeting a novel bone degradation pathway in primary bone cancer by inactivation of the collagen receptor uPARAP\/Endo180"],"prefix":"10.1002","volume":"238","author":[{"given":"Lars H","family":"Engelholm","sequence":"first","affiliation":[{"name":"Finsen Laboratory\/Biotech Research and Innovation Centre (BRIC) Rigshospitalet and University of Copenhagen  Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria C","family":"Melander","sequence":"additional","affiliation":[{"name":"Finsen Laboratory\/Biotech Research and Innovation Centre (BRIC) Rigshospitalet and University of Copenhagen  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Z","family":"Ingvarsen","sequence":"additional","affiliation":[{"name":"Finsen Laboratory\/Biotech Research and Innovation Centre (BRIC) Rigshospitalet and University of Copenhagen  Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas","family":"Kj\u00e6r","sequence":"additional","affiliation":[{"name":"Department of Clinical Physiology, Nuclear Medicine and PET and Cluster for Molecular Imaging Rigshospitalet and University of Copenhagen  Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clement S","family":"Trovik","sequence":"additional","affiliation":[{"name":"Department of Oncology\/Orthopaedics Haukeland University Hospital  Bergen Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ole D","family":"L\u00e6rum","sequence":"additional","affiliation":[{"name":"Finsen Laboratory\/Biotech Research and Innovation Centre (BRIC) Rigshospitalet and University of Copenhagen  Denmark"},{"name":"Department of Clinical 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