Trps1 plays a pivotal role downstream of Gdf5 signaling in promoting chondrogenesis and apoptosis of ATDC5 cells.
Tricho-rhino-phalangeal syndrome (TRPS) is an autosomal dominant skeletal disorder caused by mutations of TRPS1. Based on the similar expression patterns of Trps1 and Gdf5, we hypothesized a possible functional interaction between these two molecules. Using a chondrogenic cell line (ATDC5), we investigated the association of Gdf5-mediated signaling pathways with Trps1 and the phenotypic changes of ATDC5 cells due to over-expression or suppression of Trps1. Treatment of cells with Gdf5 enhanced Trps1 protein levels and phosphorylation of p38 mitogen-activated protein kinase (MAPK) in a dose-dependent manner. Nuclear translocation of Trps1 was also induced by Gdf5. These effects were blocked by a dominant negative form of activin-linked kinase 6 (dn-Alk6) and by SB203580, an inhibitor of the p38 MAPK pathway. Conversely, Gdf5 expression was suppressed by the over-expression of Trps1. Trps1-overexpressing ATDC5 (O/E) cells differentiated into chondrocytes more quickly than mock-infected control cells, whereas cells transfected with dn-Alk6 showed slower differentiation. On the other hand, O/E cells showed an increase of apoptosis along with the up-regulation of cleaved caspase 3 and down-regulation of Bcl-2, whereas dn-Alk6 cells showed suppression of apoptosis. In conclusion, Trps1 acts downstream of the Gdf5 signaling pathway and promotes the differentiation and apoptosis of ATDC5 cells.
Itoh
Shunji
S
First Department of Pathology, Wakayama Medical University, Wakayama, Japan.
Kanno
Seiji
S
Gai
Zhibo
Z
Suemoto
Hiroki
H
Kawakatsu
Motohisa
M
Tanishima
Hiroyuki
H
Morimoto
Yoshifumi
Y
Nishioka
Katsuhiro
K
Hatamura
Ikuji
I
Yoshida
Munehito
M
Muragaki
Yasuteru
Y
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D001848:Bone Diseases, Developmental / Q000235:genetics; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002460:Cell Line; D020219:Chondrogenesis / Q000502:physiology*; D019465:Craniofacial Abnormalities / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D005246:Feedback; D050980:GATA Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D055428:Growth Differentiation Factor 5; D051379:Mice; D010641:Phenotype; D012097:Repressor Proteins; D015398:Signal Transduction; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D019485:Bone Morphogenetic Proteins; D017931:DNA Primers; D050980:GATA Transcription Factors; C525894:Gdf5 protein, mouse; D055428:Growth Differentiation Factor 5; D012097:Repressor Proteins; C525953:Trps1 protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases; C498215:Bmpr1b protein, mouse; D052005:Bone Morphogenetic Protein Receptors, Type I