Smad3 Deficiency Leads to Mandibular Condyle Degradation via the Sphingosine 1-Phosphate (S1P)/S1P3 Signaling Axis

• Material Type: 博士論文
• Title: Smad3 Deficiency Leads to Mandibular Condyle Degradation via the Sphingosine 1-Phosphate (S1P)/S1P3 Signaling Axis
• Author/Editor: Mori, Hiroki; Izawa, Takashi; Tanaka, Eiji
• Author Heading: Mori, Hiroki; Izawa, Takashi; Tanaka, Eiji
• Publication, Distribution, etc.: American Society for Investigative Pathology|Elsevier
• Publication Date: 2015-08-10
• Publication Date (W3CDTF): 2015-08-10
• Alternative Title: Smad3の欠損はS1P/S1P3シグナル経路を介して下顎頭軟骨変性を生じる; Chondrocyte Migration Mediated by Smad3/S1P3
• Periodical title: The American Journal of Pathology
• No. or year of volume/issue: 185 10
• Volume: 185
• Issue: 10
• Pages: 2742-2756
• ISSN (Periodical Title): ISSN : 0002-9440
• Degree grantor/type: 徳島大学
• Date Granted: 2016-03-23
• Dissertation Number: 甲第2940号
• Degree Type: 博士（歯学）
• Text Language Code: eng
• Subject Heading: TMJ-OA; Smad3; S1P; migration; S1P3
• Target Audience: 一般
• Note (General): Temporomandibular joint osteoarthritis is a degenerative disease that is characterized by permanent cartilage destruction. Transforming growth factor (TGF)-β is one of the most abundant cytokines in the bone matrix and is shown to regulate the migration of osteoprogenitor cells. It is hypothesized that TGF-β/Smad3 signaling affects cartilage homeostasis by influencing sphingosine 1-phosphate (S1P)/ S1P receptor signaling and chondrocyte migration. We therefore investigated the molecular mechanisms by which crosstalk may occur between TGF-β/Smad3 and S1P/S1P receptor signaling to maintain condylar cartilage and to prevent temporomandibular joint osteoarthritis. Abnormalities in the condylar subchondral bone, including dynamic changes in bone mineral density and microstructure, were observed in Smad3-/- mice by microcomputed tomography. Cell-free regions and proteoglycan loss characterized the cartilage degradation present, and increased numbers of apoptotic chondrocytes and matrix metalloproteinase 13+ chondrocytes were also detected. Furthermore, expression of S1P receptor 3 (S1P3), but not S1P1 or S1P2, was significantly down-regulated in the condylar cartilage of Smad3-/- mice. By using RNA interference technology and pharmacologic tools, S1P was found to transactivate Smad3 in an S1P3/TGF-β type II receptor-dependent manner, and S1P3 was found to be required for TGF-β-induced migration of chondrocyte cells and downstream signal transduction via Rac1, RhoA, and Cdc42. Taken together, these results indicate that the Smad3/S1P3 signaling pathway plays an important role in the pathogenesis of temporomandibular joint osteoarthritis.
• Format (IMT): application/pdf
• Access Restrictions: インターネット公開
• Related Material (DOI): 10.1016/j.ajpath.2015.06.015
• Data Provider (Database): 国立情報学研究所 : 学術機関リポジトリデータベース（IRDB）（機関リポジトリ）; https://irdb.nii.ac.jp
• Original Data Provider (Database): 徳島大学 : 徳島大学機関リポジトリ

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