title: Small molecule inhibitors of WNT/β-catenin signaling block IL-1β- and TNFα-induced cartilage degradation.
abstract: BACKGROUND
  In this study, we tested the ability of small molecule inhibitors of WNT/β-catenin signaling to block interleukin 1β (IL-1β)- and tumor necrosis factor α (TNFα)-induced cartilage degradation. Proinflammatory cytokines such as IL-1β and TNFα are potent inducers of cartilage degradation by upregulating matrix metalloproteinase (MMP) expression and activity. Because WNT/β-catenin signaling was found to be involved in IL-1β- and TNFα-induced upregulation of MMP activity, we hypothesized that inhibition of WNT/β-catenin signaling might block IL-1β- and TNFα-induced cartilage degradation. We tested the effect of small molecules that block the interaction between β-catenin and TCF/Lef transcription factors on IL-1β- and TNFα-induced cartilage degradation in mouse fetal metatarsals.
  
  
  METHODS
  We used mouse fetal metatarsals treated with IL-1β and TNFα as an ex vivo model for cytokine-induced cartilage degradation. Metatarsals were treated with IL-1β and TNFα in combination with the small molecules PKF115-584, PKF118-310 and CGP049090 at different concentrations and then harvested them for histological and gene expression analysis.
  
  
  RESULTS
  We found that IL-1β- and TNFα-induced cartilage degradation in mouse fetal metatarsals was blocked by inhibiting WNT/β-catenin signaling using small molecule PKF115-584 and partially using CGP049090 dose-dependently. In addition, we found that PKF115-584 blocked IL-1β- and TNFα-induced MMP mRNA expression, but did not reverse the inhibitory effect of IL-1β on the expression of cartilage anabolic genes.
  
  
  CONCLUSIONS
  In this study, we show that inhibition of WNT/β-catenin signaling by small molecules can effectively prevent IL-1β- and TNFα-induced cartilage degradation by blocking MMP expression and activity. Furthermore, we elucidate the involvement of WNT/β-catenin signaling in IL-1β- and TNFα-induced cartilage degradation.
authors: Ellie B M
authors: EB
authors: Landman
authors: Razvan L
authors: RL
authors: Miclea
authors: Clemens A
authors: CA
authors: van Blitterswijk
authors: Marcel
authors: M
authors: Karperien
mesh_terms: D000818:Animals; D001168:Arthritis / Q000378:metabolism* / Q000473:pathology; D002356:Cartilage / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005455:Fluorescent Antibody Technique; D057809:HEK293 Cells; D006801:Humans; D053583:Interleukin-1beta / Q000633:toxicity; D051379:Mice; D010569:Perylene / Q000031:analogs & derivatives* / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D059467:Transcriptome; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity; D060449:Wnt Signaling Pathway / Q000187:drug effects*
chemical_list: C538948:CGP049090; D053583:Interleukin-1beta; C538949:PKF115-584; D014409:Tumor Necrosis Factor-alpha; D010569:Perylene
references: Cancer Cell. 2004 Jan;5(1):91-102
references: 14749129
references: Cell Mol Life Sci. 2002 Jan;59(1):45-53
references: 11846032
references: Am J Pathol. 2003 Jul;163(1):157-63
references: 12819020
references: Biochim Biophys Acta. 1990 May 22;1052(3):366-78
references: 2162214
references: Neoplasia. 2010 Apr;12(4):326-35
references: 20360943
references: J Orofac Pain. 2000 Winter;14(1):20-30
references: 11203734
references: J Bone Miner Res. 2005 Oct;20(10):1867-77
references: 16160745
references: Ann Rheum Dis. 2002 Oct;61(10):870-6
references: 12228154
references: Stem Cells. 1994 Jan;12(1):75-86
references: 8142924
references: J Endocrinol. 2006 May;189(2):319-28
references: 16648299
references: Biochem Biophys Res Commun. 2007 Dec 28;364(4):1009-14
references: 17971297
references: Biochem Biophys Res Commun. 2006 Jul 14;345(4):1615-20
references: 16735027
references: Int J Mol Med. 2011 Apr;27(4):583-9
references: 21305249
references: Arthritis Rheum. 2012 Aug;64(8):2589-600
references: 22328140
references: Dev Cell. 2005 May;8(5):727-38
references: 15866163
references: Nat Rev Rheumatol. 2011 Jan;7(1):33-42
references: 21119608
references: Cell. 2006 Nov 3;127(3):469-80
references: 17081971
references: Inflamm Res. 2010 May;59(5):379-89
references: 19902332
references: Arthritis Rheum. 1996 Sep;39(9):1535-44
references: 8814066
references: Ann N Y Acad Sci. 2010 Mar;1192:344-50
references: 20392258
references: J Biol Chem. 2004 Jun 18;279(25):26597-604
references: 15082716
references: J Bone Miner Res. 2009 Jan;24(1):12-21
references: 18767925
references: Arthritis Rheum. 2009 Dec;60(12):3723-33
references: 19950295
references: Lab Invest. 2008 Mar;88(3):264-74
references: 18227807
references: Dev Cell. 2005 May;8(5):739-50
references: 15866164
references: J Bone Miner Res. 2004 Nov;19(11):1805-12
references: 15476580
references: Bone. 1995 Jul;17(1):63-9
references: 7577160
references: Arthritis Rheum. 2001 Jun;44(6):1237-47
references: 11407681
references: Arthritis Rheum. 2001 Mar;44(3):585-94
references: 11263773
references: Arthritis Rheum. 2007 Dec;56(12):4095-103
references: 18050203
references: J Biol Chem. 2005 May 13;280(19):19185-95
references: 15760903
references: Bone. 1999 Oct;25(4):397-404
references: 10511105
references: J Clin Invest. 1996 May 1;97(9):2011-9
references: 8621789
references: Int J Cancer. 2010 May 15;126(10):2426-36
references: 19662654
references: J Biol Chem. 2010 Jan 1;285(1):317-27
references: 19858186
references: Biorheology. 2002;39(1-2):237-46
references: 12082286
references: Osteoarthritis Cartilage. 2011 Nov;19(11):1363-72
references: 21911068
references: Ann Rheum Dis. 1997 Sep;56(9):542-9
references: 9370879
references: Am J Pathol. 2009 Nov;175(5):1993-2003
references: 19815716