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ID 109705
Title Alternative
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
Author
Keywords
TMJ-OA
Smad3
S1P
migration
S1P3
Content Type
Thesis or Dissertation
Description
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.
Journal Title
The American Journal of Pathology
ISSN
00029440
NCID
AA00520990
AA12024839
Publisher
American Society for Investigative Pathology|Elsevier
Volume
185
Issue
10
Start Page
2742
End Page
2756
Published Date
2015-08-10
Remark
内容要旨・審査要旨・論文本文の公開:
内容要旨 : LID201606141004.pdf
審査要旨 : LID201606141005.pdf
論文全文 : k2940_fulltext.pdf
著者の申請により要約(2016-06-15公開)に替えて論文全文を公開(2019-06-05)
本論文は, 著者Hiroki Moriの学位論文として提出され, 学位審査・授与の対象となっている。
EDB ID
DOI (Published Version)
URL ( Publisher's Version )
FullText File
language
eng
TextVersion
ETD
MEXT report number
甲第2940号
Diploma Number
甲口第405号
Granted Date
2016-03-23
Degree Name
Doctor of Dental Science
Grantor
Tokushima University
departments
University Hospital
Oral Sciences