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TAK1 regulates SOX9 expression in chondrocytes and is essential for postnatal development of the growth plate and articular cartilages.

Publication ,  Journal Article
Gao, L; Sheu, T-J; Dong, Y; Hoak, DM; Zuscik, MJ; Schwarz, EM; Hilton, MJ; O'Keefe, RJ; Jonason, JH
Published in: J Cell Sci
December 15, 2013

TAK1 is a MAP3K that mediates non-canonical TGF-β and BMP signaling. During the embryonic period, TAK1 is essential for cartilage and joint development as deletion of Tak1 in chondro-osteo progenitor cells leads to severe chondrodysplasia with defects in both chondrocyte proliferation and maturation. We have investigated the role of TAK1 in committed chondrocytes during early postnatal development. Using the Col2a1-CreER(T2); Tak1(f/f) mouse model, we induced deletion of Tak1 at postnatal day 7 and characterized the skeletal phenotypes of these mice at 1 and 3 months of age. Mice with chondrocyte-specific Tak1 deletion exhibited severe growth retardation and reduced proteoglycan and type II collagen content in the extracellular matrix of the articular cartilage. We found reduced Col2a1 and Acan expression, but increased Mmp13 and Adamts5 expression, in Tak1-deficient chondrocytes along with reduced expression of the SOX trio of transcription factors, SOX9, SOX5 and SOX6. In vitro, BMP2 stimulated Sox9 gene expression and Sox9 promoter activity. These effects were reduced; however, following Tak1 deletion or treatment with a TAK1 kinase inhibitor. TAK1 affects both canonical and non-canonical BMP signal transduction and we found that both of these pathways contribute to BMP2-mediated Sox9 promoter activation. Additionally, we found that ATF2 directly binds the Sox9 promoter in response to BMP signaling and that this effect is dependent upon TAK1 kinase activity. These novel findings establish that TAK1 contributes to BMP2-mediated Sox9 gene expression and is essential for the postnatal development of normal growth plate and articular cartilages.

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Published In

J Cell Sci

DOI

EISSN

1477-9137

Publication Date

December 15, 2013

Volume

126

Issue

Pt 24

Start / End Page

5704 / 5713

Location

England

Related Subject Headings

  • SOX9 Transcription Factor
  • Proteoglycans
  • Protein Binding
  • Promoter Regions, Genetic
  • Mice, Transgenic
  • Mice
  • MAP Kinase Kinase Kinases
  • Growth Plate
  • Gene Expression Regulation
  • Gene Deletion
 

Citation

APA
Chicago
ICMJE
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Gao, L., Sheu, T.-J., Dong, Y., Hoak, D. M., Zuscik, M. J., Schwarz, E. M., … Jonason, J. H. (2013). TAK1 regulates SOX9 expression in chondrocytes and is essential for postnatal development of the growth plate and articular cartilages. J Cell Sci, 126(Pt 24), 5704–5713. https://doi.org/10.1242/jcs.135483
Gao, Lin, Tzong-jen Sheu, Yufeng Dong, Donna M. Hoak, Michael J. Zuscik, Edward M. Schwarz, Matthew J. Hilton, Regis J. O’Keefe, and Jennifer H. Jonason. “TAK1 regulates SOX9 expression in chondrocytes and is essential for postnatal development of the growth plate and articular cartilages.J Cell Sci 126, no. Pt 24 (December 15, 2013): 5704–13. https://doi.org/10.1242/jcs.135483.
Gao L, Sheu T-J, Dong Y, Hoak DM, Zuscik MJ, Schwarz EM, et al. TAK1 regulates SOX9 expression in chondrocytes and is essential for postnatal development of the growth plate and articular cartilages. J Cell Sci. 2013 Dec 15;126(Pt 24):5704–13.
Gao, Lin, et al. “TAK1 regulates SOX9 expression in chondrocytes and is essential for postnatal development of the growth plate and articular cartilages.J Cell Sci, vol. 126, no. Pt 24, Dec. 2013, pp. 5704–13. Pubmed, doi:10.1242/jcs.135483.
Gao L, Sheu T-J, Dong Y, Hoak DM, Zuscik MJ, Schwarz EM, Hilton MJ, O’Keefe RJ, Jonason JH. TAK1 regulates SOX9 expression in chondrocytes and is essential for postnatal development of the growth plate and articular cartilages. J Cell Sci. 2013 Dec 15;126(Pt 24):5704–5713.
Journal cover image

Published In

J Cell Sci

DOI

EISSN

1477-9137

Publication Date

December 15, 2013

Volume

126

Issue

Pt 24

Start / End Page

5704 / 5713

Location

England

Related Subject Headings

  • SOX9 Transcription Factor
  • Proteoglycans
  • Protein Binding
  • Promoter Regions, Genetic
  • Mice, Transgenic
  • Mice
  • MAP Kinase Kinase Kinases
  • Growth Plate
  • Gene Expression Regulation
  • Gene Deletion