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The aim of this study was to identify macrophage\u2010derived factors that promote osteoclast differentiation and periprosthetic bone destruction. To achieve this, we examined the effects of 12 macrophage\u2010derived factors that were identified by RNA\u2010seq analysis of stimulated macrophages on osteoclast differentiation. Surprisingly, thymidine phosphorylase (TYMP) was found to trigger significant number of osteoclasts that exhibited resorbing activities on dentine slices. Functionally, TYMP knockdown reduced the number of osteoclasts in macrophages that had been stimulated with polyethylene debris. TYMP were detected in serum and synovial tissues of patients that had been diagnosed with aseptic loosening. Moreover, the administration of TYMP onto calvariae of mice induced pathological bone resorption that was accompanied by an excessive infiltration of inflammatory cells and osteoclasts. The RNA\u2010seq for TYMP\u2010induced\u2010osteoclasts was then performed in an effort to understand action mode of TYMP. TYMP stimulation appeared to activate the tyrosine kinase FYN signaling associated with osteoclast formation. Oral administration of saracatinib, a FYN kinase inhibitor, significantly suppressed formation of bone osteolytic lesions in a polyethylene debris\u2010induced osteolysis model. Our findings highlight a novel molecular target for therapeutic intervention in periprosthetic osteolysis.<\/jats:p>","DOI":"10.1002\/btm2.10232","type":"journal-article","created":{"date-parts":[[2021,5,19]],"date-time":"2021-05-19T06:17:16Z","timestamp":1621405036000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Targeting thymidine phosphorylase as a potential therapy for bone loss associated with periprosthetic osteolysis"],"prefix":"10.1002","volume":"6","author":[{"given":"Gen","family":"Matsumae","sequence":"first","affiliation":[{"name":"Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine Hokkaido University  Sapporo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomohiro","family":"Shimizu","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine Hokkaido University  Sapporo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuan","family":"Tian","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine Hokkaido University  Sapporo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daisuke","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine Hokkaido University  Sapporo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Taku","family":"Ebata","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine Hokkaido University  Sapporo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hend","family":"Alhasan","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine Hokkaido University  Sapporo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shunichi","family":"Yokota","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine Hokkaido University  Sapporo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ken","family":"Kadoya","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine Hokkaido University  Sapporo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5481-8516","authenticated-orcid":false,"given":"Mohamad Alaa","family":"Terkawi","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine Hokkaido University  Sapporo Japan"},{"name":"Global Institution for Collaborative Research and Education (GI\u2010CoRE), Frontier Research Center for Advanced Material and Life Science Bldg No 2. 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