Format

Send to

Choose Destination
Mol Cell Biol. 2009 Nov;29(21):5751-62. doi: 10.1128/MCB.00415-09. Epub 2009 Aug 24.

Parathyroid hormone-related peptide represses chondrocyte hypertrophy through a protein phosphatase 2A/histone deacetylase 4/MEF2 pathway.

Author information

1
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Ave., Boston, MA 02115, USA.

Abstract

The maturation of immature chondrocytes to hypertrophic chondrocytes is regulated by parathyroid hormone-related peptide (PTHrP). We demonstrate that PTHrP or forskolin administration can block induction of collagen X-luciferase by exogenous Runx2, MEF2, and Smad1 in transfected chondrocytes. We have found that PTHrP/forskolin administration represses the transcriptional activity of MEF2 and that forced expression of MEF2-VP16 can restore expression of the collagen X reporter in chondrocytes treated with these agents. PTHrP/forskolin induces dephosphorylation of histone deacetylase 4 (HDAC4) phospho-S246, which decreases interaction of HDAC4 with cytoplasmic 14-3-3 proteins and promotes nuclear translocation of HDAC4 and repression of MEF2 transcriptional activity. We have found that forskolin increases the activity of an HDAC4 phospho-S246 phosphatase and that forskolin-induced nuclear translocation of HDAC4 was reversed by the protein phosphatase 2A (PP2A) antagonist, okadaic acid. Finally, we demonstrate that knockdown of PP2A inhibits forskolin-induced nuclear translocation of HDAC4 and attenuates the ability of this signaling molecule to repress collagen X expression in chondrocytes, indicating that PP2A is critical for PTHrP-mediated regulation of chondrocyte hypertrophy.

PMID:
19704004
PMCID:
PMC2772746
DOI:
10.1128/MCB.00415-09
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center