Protein kinase C isoforms zeta and iota mediate collagenase expression and cartilage destruction via STAT3- and ERK-dependent c-fos induction.
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.
Litherland
Gary J
GJ
Cell Signalling, Injury and Repair Group, Institute of Cellular Medicine, Newcastle University, Framlington Place, Newcastle-upon-Tyne NE2 4HH, United Kingdom.
Elias
Martina S
MS
Hui
Wang
W
Macdonald
Christopher D
CD
Catterall
Jonathon B
JB
Barter
Matt J
MJ
Farren
Matthew J
MJ
Jefferson
Matthew
M
Rowan
Andrew D
AD
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
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
J Cell Biochem. 2000 Sep 14;79(4):519-31
10996843
Ann Oncol. 2006 Jun;17 Suppl 7:vii124-7
16760274
Best Pract Res Clin Endocrinol Metab. 2007 Dec;21(4):573-86
18054736
FASEB J. 2007 Feb;21(2):535-42
17158780
J Biol Chem. 2006 Aug 25;281(34):24124-37
16798739
FEBS J. 2007 Mar;274(5):1246-55
17298441
J Neurochem. 2009 Feb;108(4):1083-96
19141072
Pharmacol Res. 2007 Jun;55(6):487-97
17570678
J Biol Chem. 2005 Sep 2;280(35):31109-15
15994303
Nat Rev Cancer. 2007 Apr;7(4):281-94
17384583
Fundam Clin Pharmacol. 2008 Jun;22(3):231-40
18485142
Int J Biochem Cell Biol. 2008;40(6-7):1362-78
18258475
J Biol Chem. 2008 May 23;283(21):14221-9
18332138
Arthritis Rheum. 2001 Jul;44(7):1620-32
11465713
J Pathol. 1980 Mar;130(3):159-67
7400877
J Clin Invest. 2008 Sep;118(9):3151-9
18688284
J Pathol. 2009 Apr;217(5):665-76
19097071
Breast Cancer Res. 2009;11(1):R13
19243594
Biochem Biophys Res Commun. 2002 May 17;293(4):1174-82
12054499
J Clin Oncol. 2007 May 1;25(13):1741-6
17389337
Anal Biochem. 1999 Nov 15;275(2):202-7
10552905
Mol Carcinog. 2005 Jan;42(1):29-39
15546134
Oncogene. 2008 Aug 14;27(35):4841-53
18427549
J Cell Physiol. 2007 Dec;213(3):626-34
17786965
Curr Cancer Drug Targets. 2004 Mar;4(2):125-46
15032665
Oncogene. 1997 Mar 6;14(9):1083-91
9070657
Carcinogenesis. 2004 Apr;25(4):585-96
14656938
J Biol Chem. 2007 Apr 13;282(15):11110-21
17311929
J Biol Chem. 1997 Jan 10;272(2):1188-96
8995420
Arthritis Rheum. 2000 Apr;43(4):801-11
10765924
J Mol Biol. 1967 Jun 14;26(2):365-9
4291934
Cell Death Differ. 2006 May;13(5):702-11
16322752
Ann Rheum Dis. 2001 Feb;60(2):150-7
11156549
Nature. 2003 Dec 4;426(6966):574-9
14654844
Ann Rheum Dis. 2003 Feb;62(2):172-4
12525389
Arthritis Rheum. 2007 Feb;56(2):409-24
17265476
Matrix. 1992 Dec;12(6):475-80
1287416
Nat Rev Mol Cell Biol. 2007 Mar;8(3):221-33
17318226
Cell Microbiol. 2007 Aug;9(8):1987-96
17394560
Am J Pathol. 2003 Jun;162(6):1975-84
12759253
J Clin Invest. 1994 Dec;94(6):2307-16
7989586
Biochem Pharmacol. 2004 Sep 15;68(6):1049-53
15313400
Ann Rheum Dis. 2006 Nov;65 Suppl 3:iii29-33
17038468
EMBO J. 2000 Apr 3;19(7):1576-86
10747026
J Cell Biochem. 2007 Oct 1;102(2):311-9
17661350
Trends Pharmacol Sci. 2007 Sep;28(9):453-8
17692392
Semin Arthritis Rheum. 1998 Jun;27(6):392-9
9662758
Arthritis Rheum. 2006 Feb;54(2):540-50
16447230
J Biol Chem. 2002 Apr 26;277(17):14408-16
11839738
J Biol Chem. 1999 Aug 20;274(34):24392-400
10446219
Ann Rheum Dis. 2002 Aug;61(8):704-13
12117676
Arthritis Rheum. 1998 Oct;41(10):1760-71
9778217
Biochem J. 2000 Oct 1;351(Pt 1):95-105
10998351
Ann N Y Acad Sci. 2007 Jun;1108:312-22
17893995
Curr Drug Targets Cardiovasc Haematol Disord. 2003 Dec;3(4):301-7
14683472
J Cell Physiol. 2007 Nov;213(2):355-64
17654499
Proc Natl Acad Sci U S A. 2005 Jul 12;102(28):9866-71
15987782
Anal Chem. 1970 Jun;42(7):702-6
5431521
Ann Rheum Dis. 2006 Feb;65(2):184-90
15975972
Protein Eng. 1998 Nov;11(11):1093-102
9876932
Mol Cell Biol. 2001 Feb;21(4):1218-27
11158308
Arthritis Rheum. 1999 Jun;42(6):1147-58
10366107
Rheumatology (Oxford). 2006 Aug;45(8):958-65
16467367
FEBS Lett. 1996 Aug 26;392(2):77-80
8772178
Nature. 1993 Jul 15;364(6434):249-52
8321321
Arthritis Rheum. 2002 Apr;46(4):961-7
11953973
Connect Tissue Res. 2004;45(3):142-50
15512768
Curr Top Med Chem. 2009;9(7):640-54
19689371
Biochem Biophys Res Commun. 1989 Mar 15;159(2):548-53
2467670
Arthritis Rheum. 2007 Dec;56(12):4074-83
18050214
J Mol Cell Cardiol. 2000 Aug;32(8):1447-57
10900171
Exp Hematol. 2003 May;31(5):398-405
12763138
Arthritis Rheum. 2001 Oct;44(10):2296-310
11665970
Front Biosci. 2006 Jan 01;11:529-43
16146751
Arthritis Res. 2002;4(3):157-64
12010565
Physiol Rev. 2008 Oct;88(4):1341-78
18923184
Biochim Biophys Acta. 2006 May-Jun;1761(5-6):542-51
16574477
J Biol Chem. 1998 Feb 27;273(9):5211-8
9478976
J Immunol. 2009 Aug 1;183(3):2104-14
19596988
Mol Cell Biol. 1996 Jan;16(1):369-75
8524316
Arthritis Rheum. 2003 Dec;48(12):3404-18
14673992