title: Protein kinase C isoforms zeta and iota mediate collagenase expression and cartilage destruction via STAT3- and ERK-dependent c-fos induction.
abstract: The protein kinase C (PKC) signaling pathway is a major regulator of cellular functions and is implicated in pathologies involving extracellular matrix remodeling. Inflammatory joint disease is characterized by excessive extracellular matrix catabolism, and here we assess the role of PKC in the induction of the collagenases, matrix metalloproteinase (MMP)-1 and MMP-13, in human chondrocytes by the potent cytokine stimulus interleukin-1 (IL-1) in combination with oncostatin M (OSM). IL-1 + OSM-stimulated collagenolysis and gelatinase activity were ameliorated by pharmacological PKC inhibition in bovine cartilage, as was collagenase gene induction in human chondrocytes. Small interfering RNA-mediated silencing of PKC gene expression showed that both novel (nPKC delta, nPKC eta) and atypical (aPKC zeta, aPKC iota) isoforms were involved in collagenase induction by IL-1. However, MMP1 and MMP13 induction by IL-1 + OSM was inhibited only by aPKC silencing, suggesting that only atypical isoforms play a significant role in complex inflammatory milieus. Silencing of either aPKC led to diminished IL-1 + OSM-dependent extracellular signal-regulated kinase (ERK) and signal transducer and activator of transcription (STAT) 3 phosphorylation, and c-fos expression. STAT3 gene silencing or ERK pathway inhibition also resulted in loss of IL-1 + OSM-stimulated c-fos and collagenase expression. Silencing of c-fos and c-jun expression was sufficient to abrogate IL-1 + OSM-stimulated collagenase gene induction, and overexpression of both c-fos and c-jun was sufficient to drive transcription from the MMP1 promoter in the absence of a stimulus. Our data identify atypical PKC isozymes as STAT and ERK activators that mediate c-fos and collagenase expression during IL-1 + OSM synergy in human chondrocytes. aPKCs may constitute potential therapeutic targets for inflammatory joint diseases involving increased collagenase expression.
authors.affiliation: Cell Signalling, Injury and Repair Group, Institute of Cellular Medicine, Newcastle University, Framlington Place, Newcastle-upon-Tyne NE2 4HH, United Kingdom.
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Litherland
authors.forename: Martina S
authors.initials: MS
authors.lastname: Elias
authors.forename: Wang
authors.initials: W
authors.lastname: Hui
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Macdonald
authors.forename: Jonathon B
authors.initials: JB
authors.lastname: Catterall
authors.forename: Matt J
authors.initials: MJ
authors.lastname: Barter
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Farren
authors.forename: Matthew
authors.initials: M
authors.lastname: Jefferson
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Rowan
mesh_terms: D000818:Animals; D002358:Cartilage, Articular / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D002417:Cattle; D019902:Chondrocytes / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D017364:Collagenases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D018093:Gelatinases / Q000378:metabolism; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053683:Oncostatin M / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013379:Substrate Specificity / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000378:metabolism; D000099293:Protein Kinase C-lambda; D000099221:Protein Kinase C zeta
chemical_list: D017364:Collagenases; D048049:Extracellular Signal-Regulated MAP Kinases; D018093:Gelatinases; D007375:Interleukin-1; D007527:Isoenzymes; D053683:Oncostatin M; D011493:Protein Kinase C; D016760:Proto-Oncogene Proteins c-fos; D050796:STAT3 Transcription Factor; D018808:Transcription Factor AP-1; D000099293:Protein Kinase C-lambda; D000099221:Protein Kinase C zeta; C494086:STAT3 protein, human
references.citation: J Cell Biochem. 2000 Sep 14;79(4):519-31
references.pmid: 10996843
references.citation: Ann Oncol. 2006 Jun;17 Suppl 7:vii124-7
references.pmid: 16760274
references.citation: Best Pract Res Clin Endocrinol Metab. 2007 Dec;21(4):573-86
references.pmid: 18054736
references.citation: FASEB J. 2007 Feb;21(2):535-42
references.pmid: 17158780
references.citation: J Biol Chem. 2006 Aug 25;281(34):24124-37
references.pmid: 16798739
references.citation: FEBS J. 2007 Mar;274(5):1246-55
references.pmid: 17298441
references.citation: J Neurochem. 2009 Feb;108(4):1083-96
references.pmid: 19141072
references.citation: Pharmacol Res. 2007 Jun;55(6):487-97
references.pmid: 17570678
references.citation: J Biol Chem. 2005 Sep 2;280(35):31109-15
references.pmid: 15994303
references.citation: Nat Rev Cancer. 2007 Apr;7(4):281-94
references.pmid: 17384583
references.citation: Fundam Clin Pharmacol. 2008 Jun;22(3):231-40
references.pmid: 18485142
references.citation: Int J Biochem Cell Biol. 2008;40(6-7):1362-78
references.pmid: 18258475
references.citation: J Biol Chem. 2008 May 23;283(21):14221-9
references.pmid: 18332138
references.citation: Arthritis Rheum. 2001 Jul;44(7):1620-32
references.pmid: 11465713
references.citation: J Pathol. 1980 Mar;130(3):159-67
references.pmid: 7400877
references.citation: J Clin Invest. 2008 Sep;118(9):3151-9
references.pmid: 18688284
references.citation: J Pathol. 2009 Apr;217(5):665-76
references.pmid: 19097071
references.citation: Breast Cancer Res. 2009;11(1):R13
references.pmid: 19243594
references.citation: Biochem Biophys Res Commun. 2002 May 17;293(4):1174-82
references.pmid: 12054499
references.citation: J Clin Oncol. 2007 May 1;25(13):1741-6
references.pmid: 17389337
references.citation: Anal Biochem. 1999 Nov 15;275(2):202-7
references.pmid: 10552905
references.citation: Mol Carcinog. 2005 Jan;42(1):29-39
references.pmid: 15546134
references.citation: Oncogene. 2008 Aug 14;27(35):4841-53
references.pmid: 18427549
references.citation: J Cell Physiol. 2007 Dec;213(3):626-34
references.pmid: 17786965
references.citation: Curr Cancer Drug Targets. 2004 Mar;4(2):125-46
references.pmid: 15032665
references.citation: Oncogene. 1997 Mar 6;14(9):1083-91
references.pmid: 9070657
references.citation: Carcinogenesis. 2004 Apr;25(4):585-96
references.pmid: 14656938
references.citation: J Biol Chem. 2007 Apr 13;282(15):11110-21
references.pmid: 17311929
references.citation: J Biol Chem. 1997 Jan 10;272(2):1188-96
references.pmid: 8995420
references.citation: Arthritis Rheum. 2000 Apr;43(4):801-11
references.pmid: 10765924
references.citation: J Mol Biol. 1967 Jun 14;26(2):365-9
references.pmid: 4291934
references.citation: Cell Death Differ. 2006 May;13(5):702-11
references.pmid: 16322752
references.citation: Ann Rheum Dis. 2001 Feb;60(2):150-7
references.pmid: 11156549
references.citation: Nature. 2003 Dec 4;426(6966):574-9
references.pmid: 14654844
references.citation: Ann Rheum Dis. 2003 Feb;62(2):172-4
references.pmid: 12525389
references.citation: Arthritis Rheum. 2007 Feb;56(2):409-24
references.pmid: 17265476
references.citation: Matrix. 1992 Dec;12(6):475-80
references.pmid: 1287416
references.citation: Nat Rev Mol Cell Biol. 2007 Mar;8(3):221-33
references.pmid: 17318226
references.citation: Cell Microbiol. 2007 Aug;9(8):1987-96
references.pmid: 17394560
references.citation: Am J Pathol. 2003 Jun;162(6):1975-84
references.pmid: 12759253
references.citation: J Clin Invest. 1994 Dec;94(6):2307-16
references.pmid: 7989586
references.citation: Biochem Pharmacol. 2004 Sep 15;68(6):1049-53
references.pmid: 15313400
references.citation: Ann Rheum Dis. 2006 Nov;65 Suppl 3:iii29-33
references.pmid: 17038468
references.citation: EMBO J. 2000 Apr 3;19(7):1576-86
references.pmid: 10747026
references.citation: J Cell Biochem. 2007 Oct 1;102(2):311-9
references.pmid: 17661350
references.citation: Trends Pharmacol Sci. 2007 Sep;28(9):453-8
references.pmid: 17692392
references.citation: Semin Arthritis Rheum. 1998 Jun;27(6):392-9
references.pmid: 9662758
references.citation: Arthritis Rheum. 2006 Feb;54(2):540-50
references.pmid: 16447230
references.citation: J Biol Chem. 2002 Apr 26;277(17):14408-16
references.pmid: 11839738
references.citation: J Biol Chem. 1999 Aug 20;274(34):24392-400
references.pmid: 10446219
references.citation: Ann Rheum Dis. 2002 Aug;61(8):704-13
references.pmid: 12117676
references.citation: Arthritis Rheum. 1998 Oct;41(10):1760-71
references.pmid: 9778217
references.citation: Biochem J. 2000 Oct 1;351(Pt 1):95-105
references.pmid: 10998351
references.citation: Ann N Y Acad Sci. 2007 Jun;1108:312-22
references.pmid: 17893995
references.citation: Curr Drug Targets Cardiovasc Haematol Disord. 2003 Dec;3(4):301-7
references.pmid: 14683472
references.citation: J Cell Physiol. 2007 Nov;213(2):355-64
references.pmid: 17654499
references.citation: Proc Natl Acad Sci U S A. 2005 Jul 12;102(28):9866-71
references.pmid: 15987782
references.citation: Anal Chem. 1970 Jun;42(7):702-6
references.pmid: 5431521
references.citation: Ann Rheum Dis. 2006 Feb;65(2):184-90
references.pmid: 15975972
references.citation: Protein Eng. 1998 Nov;11(11):1093-102
references.pmid: 9876932
references.citation: Mol Cell Biol. 2001 Feb;21(4):1218-27
references.pmid: 11158308
references.citation: Arthritis Rheum. 1999 Jun;42(6):1147-58
references.pmid: 10366107
references.citation: Rheumatology (Oxford). 2006 Aug;45(8):958-65
references.pmid: 16467367
references.citation: FEBS Lett. 1996 Aug 26;392(2):77-80
references.pmid: 8772178
references.citation: Nature. 1993 Jul 15;364(6434):249-52
references.pmid: 8321321
references.citation: Arthritis Rheum. 2002 Apr;46(4):961-7
references.pmid: 11953973
references.citation: Connect Tissue Res. 2004;45(3):142-50
references.pmid: 15512768
references.citation: Curr Top Med Chem. 2009;9(7):640-54
references.pmid: 19689371
references.citation: Biochem Biophys Res Commun. 1989 Mar 15;159(2):548-53
references.pmid: 2467670
references.citation: Arthritis Rheum. 2007 Dec;56(12):4074-83
references.pmid: 18050214
references.citation: J Mol Cell Cardiol. 2000 Aug;32(8):1447-57
references.pmid: 10900171
references.citation: Exp Hematol. 2003 May;31(5):398-405
references.pmid: 12763138
references.citation: Arthritis Rheum. 2001 Oct;44(10):2296-310
references.pmid: 11665970
references.citation: Front Biosci. 2006 Jan 01;11:529-43
references.pmid: 16146751
references.citation: Arthritis Res. 2002;4(3):157-64
references.pmid: 12010565
references.citation: Physiol Rev. 2008 Oct;88(4):1341-78
references.pmid: 18923184
references.citation: Biochim Biophys Acta. 2006 May-Jun;1761(5-6):542-51
references.pmid: 16574477
references.citation: J Biol Chem. 1998 Feb 27;273(9):5211-8
references.pmid: 9478976
references.citation: J Immunol. 2009 Aug 1;183(3):2104-14
references.pmid: 19596988
references.citation: Mol Cell Biol. 1996 Jan;16(1):369-75
references.pmid: 8524316
references.citation: Arthritis Rheum. 2003 Dec;48(12):3404-18
references.pmid: 14673992