2010 Fiscal Year Final Research Report
Elucidation of the mechanism of aggrecan degradation and epigenetic regulation of aggrecanase expression in osteoarthritic cartilage
| Project/Area Number |
20591780
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Orthopaedic surgery
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| Research Institution | Okayama University |
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Principal Investigator |
NISHIDA Keiichiro Okayama University, 大学院・医歯薬学総合研究科, 准教授 (80284058)
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| Research Collaborator |
鉄永 智紀 岡山大学, 大学院・医歯薬学総合研究科整形外科学
古松 毅之 岡山大学, 大学院・医歯薬学総合研究科整形外科学
吉田 晶 岡山大学, 大学院・医歯薬学総合研究科整形外科学
尾崎 敏文 岡山大学, 大学院・医歯薬学総合研究科整形外科学
成瀬 恵治 岡山大学, 大学院・医歯薬学総合研究科システム生理学
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| Project Period (FY) |
2008 – 2010
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| Keywords | 変形性関節症 / 軟骨破壊 / アグリカナーゼ / メカニカルストレス |
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| Research Abstract |
We investigated the mechanism of mechanical stress-induced expression and regulation of aggrecanases and examined the role of runt-related transcription factor 2 (RUNX-2) in chondrocyte-like cells. A uni-axial cyclic tensile strain (CTS) (0.5 Hz, 10% stretch) induced expression of RUNX-2, MMP-13, ADAMTS-4, -5, and -9 by SW1353 cells. Overexpression of RUNX-2 up-regulated expression of MMP-13 and ADAMTS-5, whereas RUNX-2 siRNA resulted in significant downregulation of mechanically-induced MMP-13 and ADAMTS-5 expression. CTS induced activation of p38 MAPK, and CTS induction of RUNX-2, MMP-13 and ADAMTS-5 mRNA was down-regulated by the selective p38 MAPK inhibitor SB203580 but not by the p44/42 MAPK inhibitor U0126, or the JNK MAPK inhibitor JNK inhibitor II. These results suggested that RUNX-2 might have a role as a key downstream mediator of p38's ability to regulate mechanical stress-induced MMP-13 and ADAMTS-5 expression. Furthermore, histone deacetylase (HDAC) inhibitor, trichostatin A and MS-275 downregulated the expression of mechanically-induced RUNX-2 and ADAMTS-5. The epigenetic regulation of RUNX-2 transcriptional factor by HDAC inhibitor might be beneficial for the suppression of cartilage degeneration of early phase of osteoarthritis.
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