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Molecular and Cellular Biology, November 2009, p. 5751-5762, Vol. 29, No. 21
0270-7306/09/$08.00+0     doi:10.1128/MCB.00415-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Parathyroid Hormone-Related Peptide Represses Chondrocyte Hypertrophy through a Protein Phosphatase 2A/Histone Deacetylase 4/MEF2 Pathway{triangledown}

Elena Kozhemyakina,1 Todd Cohen,2 Tso-Pang Yao,2 and Andrew B. Lassar1*

Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Ave., Boston, Massachusetts 02115,1 Department of Pharmacology & Cancer Biology, Duke University, Durham, North Carolina 277102

Received 31 March 2009/ Returned for modification 8 June 2009/ Accepted 14 August 2009

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.

* Corresponding author. Mailing address: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Ave., Boston, MA 02115. Phone: (617) 432-3831. Fax: (617) 738-0516. E-mail: andrew_lassar{at}hms.harvard.edu

{triangledown} Published ahead of print on 24 August 2009.

Molecular and Cellular Biology, November 2009, p. 5751-5762, Vol. 29, No. 21
0270-7306/09/$08.00+0     doi:10.1128/MCB.00415-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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