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Targeting thymidine phosphorylase as a potential therapy for bone loss associated with periprosthetic osteolysis

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Title: Targeting thymidine phosphorylase as a potential therapy for bone loss associated with periprosthetic osteolysis
Authors: Matsumae, Gen Browse this author
Shimizu, Tomohiro Browse this author
Tian, Yuan Browse this author
Takahashi, Daisuke Browse this author
Ebata, Taku Browse this author
Alhasan, Hend Browse this author
Yokota, Shunichi Browse this author
Kadoya, Ken Browse this author
Terkawi, Mohamad Alaa Browse this author
Iwasaki, Norimasa Browse this author
Keywords: aseptic loosening
kinase inhibitor
macrophage factors
Issue Date: Sep-2021
Publisher: John Wiley & Sons
Journal Title: Bioengineering & Translational Medicine
Volume: 6
Issue: 3
Start Page: e10232
Publisher DOI: 10.1002/btm2.10232
Abstract: Macrophages are generally thought to play a key role in the pathogenesis of aseptic loosening through initiating periprosthetic inflammation and pathological bone resorption. The aim of this study was to identify macrophage-derived factors that promote osteoclast differentiation and periprosthetic bone destruction. To achieve this, we examined the effects of 12 macrophage-derived factors that were identified by RNA-seq 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-seq for TYMP-induced-osteoclasts 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-induced osteolysis model. Our findings highlight a novel molecular target for therapeutic intervention in periprosthetic osteolysis.
Type: article
Appears in Collections:医学院・医学研究院 (Graduate School of Medicine / Faculty of Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

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