2017 Fiscal Year Research-status Report
人工股関節置換術後の骨溶解を制御する新規治療法の開発
| Project/Area Number |
17K10993
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| Research Institution | Hokkaido University |
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Principal Investigator |
テルカウィ アラー 北海道大学, 医学研究院, 助教 (00723074)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Keywords | Osteolysis / Inflammation / Osteoclastogenesis / Bone resorption |
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| Outline of Annual Research Achievements |
Transcriptional profiling of human macrophages exposed to ultra-high molecular weight polyethylene (UHMWPE) particles was analyzed using RNA-Seq. A total of 1218 transcripts were differentially expressed in macrophages stimulated with UHMWPE particles as compared with control cultured without particles. Results revealed that macrophages generate a broad and vigorous set of gene expression in response to wear particles, functionally classified in cellular signaling, development, immune response and adhesion. Gene enrichment analysis suggested that macrophages stimulated by UHMWPE particles elicited common gene expression signatures for inflammation and rheumatoid arthritis. These results support the concept that response of macrophages to UHMWPE particles is complex and includes osteolytic factors alongside inflammatory mediators. Among the regulated genes, TNFSF15 was further characterized as molecular target involved pathogenesis of osteolysis. On note, addition of TNFSF15 to the monocyte cultures resulted in an increase in osteoclastogenesis and bone-resorbing osteoclastic activity, suggesting its potential contribution to the implant loosening. Moreover, osteoclastic activity induced by TNFSF15 stimulation was significantly enhanced after addition of CCL20 chemokine, which may indicate synergistic effects of CCL20 in bone loss. These data provide a new insight into the molecular pathogenesis of osteolysis and highlight number of molecular targets with prognostic and therapeutic implications.
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| Current Status of Research Progress |
Current Status of Research Progress
1: Research has progressed more than it was originally planned.
Reason
In this year, transcriptional profiling of human macrophages exposed to UHMWPE particles was performed and several molecular candidates were further selected based on the bioinformatics analysis for in vitro studies. Osteoclastogenesis and bone resorption assays for the selected molecules led to identify number of molecules which might be involved in osteolysis. Based on these reasons, the research plan for this fiscal year has been smoothly progressed as planned.
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| Strategy for Future Research Activity |
Based on the findings in this study that osteolysis and implant loosening might occur in RNAKL-independent mechanism, we aim to continue screening assays in vitro and vitro with the selected molecules to clarify the mechanism of osteolysis and implant loosening. In this fiscal year, we aim also to study the signaling pathways initiated by our identified molecules that leads to osteoclasts differentiation and bone resorption. Moreover, we aim to study the contribution of neutrophils to pathogenesis of osteolysis.
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