Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 102, Issue 7, Pages 2414-2419Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0407510102
Keywords
cartilage; mesenchymal stem cell; peroxisome proliferator-activated receptor-gamma; coactivator 1 alpha; limb development
Categories
Funding
- NCRR NIH HHS [M01 RR00833, M01 RR000833] Funding Source: Medline
- NIAMS NIH HHS [R01 AR050631, AR050631] Funding Source: Medline
- NICHD NIH HHS [R01 HD042167, R01 HD042167-02] Funding Source: Medline
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Chondrogenesis is a multistep pathway in which multipotential mesenchymal stem cells (MSC) differentiate into chondrocytes. The transcription factor Sox9 (SRY-related high mobility group-Box gene 9) regulates chondrocyte differentiation and cartilage-specific expression of genes, such as Col2a1 (collagen type II alpha1). However, Sox9 expression is detected not only in chondrogenic tissue but also in nonchondrogenic tissues, suggesting the existence of a molecular partner(s) required for Sox9 to control chondrogenesis and chondrogenic gene expression. Here, we report identification of peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) as a coactivator for Sox9 during chondrogenesis. Expression of PGC-1alpha is induced at chondrogenesis sites during mouse embryonic limb development and during chondrogenesis in human MSC cultures. PGC-1alpha directly interacts with Sox9 and promotes Sox9-dependent transcriptional activity, suggesting that PGC-1alpha acts as a transcriptional coactivator for Sox9. Consistent with this finding, PGC-1a disruption in MSC by small interfering RNA inhibits Col2a1 expression during chondrogenesis. Furthermore, overexpression of both PGC-1alpha and Sox9 induced expression of chondrogenic genes, including Col2a1, followed by chondrogenesis in the MSC and developing chick limb. Together, our results suggest a transcriptional mechanism for chondrogenesis that is coordinated by PGC-1alpha.
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