title: Parathyroid hormone-related peptide represses chondrocyte hypertrophy through a protein phosphatase 2A/histone deacetylase 4/MEF2 pathway.
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.
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Ave., Boston, MA 02115, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Kozhemyakina
authors.forename: Todd
authors.initials: T
authors.lastname: Cohen
authors.forename: Tso-Pang
authors.initials: TP
authors.lastname: Yao
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Lassar
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002645:Chickens; D019902:Chondrocytes / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D005576:Colforsin / Q000494:pharmacology; D024121:Collagen Type X / Q000235:genetics / Q000378:metabolism; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D017930:Genes, Reporter; D006655:Histone Deacetylases / Q000378:metabolism*; D006984:Hypertrophy; D008156:Luciferases / Q000378:metabolism; D064326:MEF2 Transcription Factors; D051379:Mice; D018006:Myogenic Regulatory Factors / Q000378:metabolism*; D019319:Okadaic Acid / Q000494:pharmacology; D044162:Parathyroid Hormone-Related Protein / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051898:Smad1 Protein / Q000235:genetics; D051901:Smad4 Protein / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D048948:14-3-3 Proteins; D024121:Collagen Type X; D050659:Core Binding Factor Alpha 1 Subunit; D064326:MEF2 Transcription Factors; C578041:Mef2c protein, mouse; D018006:Myogenic Regulatory Factors; D044162:Parathyroid Hormone-Related Protein; D011993:Recombinant Fusion Proteins; D051898:Smad1 Protein; D051901:Smad4 Protein; D005576:Colforsin; D019319:Okadaic Acid; D008156:Luciferases; D054648:Protein Phosphatase 2; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases
references.citation: Dev Biol. 1999 Apr 15;208(2):375-91
references.pmid: 10191052
references.citation: J Cell Physiol. 2004 Mar;198(3):428-40
references.pmid: 14755548
references.citation: Proc Natl Acad Sci U S A. 1996 Sep 17;93(19):10240-5
references.pmid: 8816783
references.citation: Mol Cell Biol. 1995 Apr;15(4):1858-69
references.pmid: 7891679
references.citation: J Biol Chem. 2007 Nov 16;282(46):33752-33759
references.pmid: 17873280
references.citation: J Biol Chem. 2006 Sep 22;281(38):27724-32
references.pmid: 16870618
references.citation: Proc Natl Acad Sci U S A. 2000 Jul 5;97(14):7835-40
references.pmid: 10869435
references.citation: Dev Biol. 2006 Apr 1;292(1):116-28
references.pmid: 16476422
references.citation: Proc Natl Acad Sci U S A. 2000 Dec 19;97(26):14400-5
references.pmid: 11114197
references.citation: Mol Cell Biol. 1996 Jun;16(6):2627-36
references.pmid: 8649370
references.citation: J Bone Miner Res. 1998 Oct;13(10):1521-9
references.pmid: 9783540
references.citation: Mol Cell Biol. 2001 Sep;21(18):6312-21
references.pmid: 11509672
references.citation: Nature. 2000 Nov 2;408(6808):106-11
references.pmid: 11081517
references.citation: Genes Dev. 2002 Aug 1;16(15):1990-2005
references.pmid: 12154128
references.citation: Cell. 2004 Nov 12;119(4):555-66
references.pmid: 15537544
references.citation: Proc Natl Acad Sci U S A. 2000 Apr 11;97(8):4070-5
references.pmid: 10737771
references.citation: Genes Dev. 2007 Mar 15;21(6):638-43
references.pmid: 17369396
references.citation: Nat Med. 2007 May;13(5):597-603
references.pmid: 17468767
references.citation: J Bone Miner Res. 1994 Nov;9(11):1759-68
references.pmid: 7532346
references.citation: Genes Dev. 1997 Sep 1;11(17):2191-203
references.pmid: 9303535
references.citation: Development. 1999 May;126(10):2045-52
references.pmid: 10207130
references.citation: Mol Cell Biol. 2008 May;28(9):2952-70
references.pmid: 18299387
references.citation: Biochem J. 2001 Feb 1;353(Pt 3):417-39
references.pmid: 11171037
references.citation: Development. 2006 Feb;133(4):651-62
references.pmid: 16421188
references.citation: Genes Dev. 1994 Feb 1;8(3):277-89
references.pmid: 8314082
references.citation: Proc Natl Acad Sci U S A. 1997 Dec 9;94(25):13689-94
references.pmid: 9391087
references.citation: Mol Biol Cell. 2008 Feb;19(2):655-67
references.pmid: 18045992
references.citation: J Clin Invest. 2006 Jul;116(7):1853-64
references.pmid: 16767219
references.citation: Exp Cell Res. 2004 Sep 10;299(1):128-36
references.pmid: 15302580
references.citation: Dev Cell. 2002 Aug;3(2):183-94
references.pmid: 12194850
references.citation: Mol Cell Biol. 2000 Sep;20(18):6904-12
references.pmid: 10958686
references.citation: Dev Cell. 2007 Mar;12(3):377-89
references.pmid: 17336904
references.citation: Proc Natl Acad Sci U S A. 2007 Feb 20;104(8):2979-84
references.pmid: 17301223
references.citation: Proc Natl Acad Sci U S A. 2008 Mar 25;105(12):4727-32
references.pmid: 18339811
references.citation: Science. 1996 Aug 2;273(5275):663-6
references.pmid: 8662561
references.citation: Genes Dev. 2004 Apr 15;18(8):952-63
references.pmid: 15107406