RRC ID 61244
Author Ikegami D, Akiyama H, Suzuki A, Nakamura T, Nakano T, Yoshikawa H, Tsumaki N.
Title Sox9 sustains chondrocyte survival and hypertrophy in part through Pik3ca-Akt pathways.
Journal Development
Abstract During endochondral bone formation, Sox9 expression starts in mesenchymal progenitors, continues in the round and flat chondrocyte stages at high levels, and ceases just prior to the hypertrophic chondrocyte stage. Sox9 is important in mesenchymal progenitors for their differentiation into chondrocytes, but its functions post-differentiation have not been determined. To investigate Sox9 function in chondrocytes, we deleted mouse Sox9 at two different steps after chondrocyte differentiation. Sox9 inactivation in round chondrocytes resulted in a loss of Col2a1 expression and in apoptosis. Sox9 inactivation in flat chondrocytes caused immediate terminal maturation without hypertrophy and with excessive apoptosis. Inactivation of Sox9 in the last few cell layers resulted in the absence of Col10a1 expression, suggesting that continued expression of Sox9 just prior to hypertrophy is necessary for chondrocyte hypertrophy. SOX9 knockdown also caused apoptosis of human chondrosarcoma SW1353 cells. These phenotypes were associated with reduced Akt phosphorylation. Forced phosphorylation of Akt by Pten inactivation partially restored Col10a1 expression and cell survival in Sox9(floxdel/floxdel) mouse chondrocytes, suggesting that phosphorylated Akt mediates chondrocyte survival and hypertrophy induced by Sox9. When the molecular mechanism of Sox9-induced Akt phosphorylation was examined, we found that expression of the PI3K subunit Pik3ca (p110α) was decreased in Sox9(floxdel/floxdel) mouse chondrocytes. Sox9 binds to the promoter and enhances the transcriptional activities of Pik3ca. Thus, continued expression of Sox9 in differentiated chondrocytes is essential for subsequent hypertrophy and sustains chondrocyte-specific survival mechanisms by binding to the Pik3ca promoter, inducing Akt phosphorylation.
Volume 138(8)
Pages 1507-19
Published 2011-4-1
DOI 10.1242/dev.057802
PII dev.057802
PMID 21367821
MeSH Animals Blotting, Western Cell Line Chondrocytes / cytology* Chondrocytes / metabolism* Chromatin Immunoprecipitation Class I Phosphatidylinositol 3-Kinases Embryo, Mammalian / cytology Embryo, Mammalian / metabolism Hypertrophy / genetics Hypertrophy / metabolism* Immunohistochemistry In Situ Nick-End Labeling Mice Mice, Knockout Phosphatidylinositol 3-Kinases / genetics Phosphatidylinositol 3-Kinases / metabolism* Protein Binding Proto-Oncogene Proteins c-akt / genetics Proto-Oncogene Proteins c-akt / metabolism* RNA Interference Reverse Transcriptase Polymerase Chain Reaction SOX9 Transcription Factor / genetics SOX9 Transcription Factor / metabolism* Signal Transduction / genetics Signal Transduction / physiology
IF 5.611
Human and Animal Cells HeLa(RCB0007) Saos-2(RCB0428)