title: Sulforaphane represses matrix-degrading proteases and protects cartilage from destruction in vitro and in vivo.
abstract: OBJECTIVE
  Sulforaphane (SFN) has been reported to regulate signaling pathways relevant to chronic diseases. The aim of this study was to investigate the impact of SFN treatment on signaling pathways in chondrocytes and to determine whether sulforaphane could block cartilage destruction in osteoarthritis.
  
  
  METHODS
  Gene expression, histone acetylation, and signaling of the transcription factors NF-E2-related factor 2 (Nrf2) and NF-κB were examined in vitro. The bovine nasal cartilage explant model and the destabilization of the medial meniscus (DMM) model of osteoarthritis in the mouse were used to assess chondroprotection at the tissue and whole-animal levels.
  
  
  RESULTS
  SFN inhibited cytokine-induced metalloproteinase expression in primary human articular chondrocytes and in fibroblast-like synovial cells. SFN acted independently of Nrf2 and histone deacetylase activity to regulate metalloproteinase expression in human articular chondrocytes but did mediate prolonged activation of JNK and p38 MAPK. SFN attenuated NF-κB signaling at least through inhibition of DNA binding in human articular chondrocytes, with decreased expression of several NF-κB-dependent genes. Compared with cytokines alone, SFN (10 μM) abrogated cytokine-induced destruction of bovine nasal cartilage at both the proteoglycan and collagen breakdown levels. An SFN-rich diet (3 μmoles/day SFN versus control chow) decreased the arthritis score in the DMM model of osteoarthritis in the mouse, with a concurrent block of early DMM-induced gene expression changes.
  
  
  CONCLUSIONS
  SFN inhibits the expression of key metalloproteinases implicated in osteoarthritis, independently of Nrf2, and blocks inflammation at the level of NF-κB to protect against cartilage destruction in vitro and in vivo.
authors: University of East Anglia, Norwich, UK.
authors: Rose K
authors: RK
authors: Davidson
authors: Orla
authors: O
authors: Jupp
authors: Rachel
authors: R
authors: de Ferrars
authors: Colin D
authors: CD
authors: Kay
authors: Kirsty L
authors: KL
authors: Culley
authors: Rosemary
authors: R
authors: Norton
authors: Clare
authors: C
authors: Driscoll
authors: Tonia L
authors: TL
authors: Vincent
authors: Simon T
authors: ST
authors: Donell
authors: Yongping
authors: Y
authors: Bao
authors: Ian M
authors: IM
authors: Clark
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism*; D002358:Cartilage, Articular / Q000187:drug effects* / Q000378:metabolism; D002417:Cattle; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology*; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010003:Osteoarthritis / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013454:Sulfoxides
chemical_list: D017879:Isothiocyanates; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; D013454:Sulfoxides; D020782:Matrix Metalloproteinases; C016766:sulforaphane
references: Osteoarthritis Cartilage. 2001;9 Suppl A:S69-75
references: 11680692
references: Arthritis Res Ther. 2005;7(3):R503-12
references: 15899037
references: J Cell Biochem. 2000 Sep 14;79(4):519-31
references: 10996843
references: J Cell Physiol. 2011 Jul;226(7):1771-9
references: 21506109
references: Arthritis Rheum. 2013 Jul;65(7):1822-30
references: 23575963
references: Rheumatology (Oxford). 2012 Jun;51(6):1006-16
references: 22332123
references: Environ Mol Mutagen. 2009 Apr;50(3):213-21
references: 19197985
references: Am J Clin Nutr. 2005 Dec;82(6):1283-91
references: 16332662
references: Proc Natl Acad Sci U S A. 2009 Sep 29;106(39):16663-8
references: 19805354
references: J Pathol. 2008 Mar;214(4):515-22
references: 18200630
references: BMC Musculoskelet Disord. 2010 Dec 08;11:280
references: 21143861
references: Arthritis Rheum. 2010 Jan;62(1):159-70
references: 20039434
references: Biochem Pharmacol. 2009 Jun 15;77(12):1806-13
references: 19428335
references: Physiol Genomics. 2007 Dec 19;32(1):74-81
references: 17895394
references: Methods Mol Biol. 2001;151:451-6
references: 11217320
references: Oncogene. 2005 Jun 30;24(28):4486-95
references: 15856023
references: J Biol Chem. 2001 Aug 24;276(34):32008-15
references: 11410599
references: J Cell Biol. 1998 Jun 15;141(6):1291-300
references: 9628886
references: Mol Cells. 2005 Dec 31;20(3):364-70
references: 16404151
references: Semin Cancer Biol. 2007 Oct;17(5):363-9
references: 17555985
references: EMBO J. 2003 Aug 1;22(15):3898-909
references: 12881424
references: Nat Med. 2010 Jun;16(6):678-86
references: 20495570
references: Carcinogenesis. 2001 Mar;22(3):425-31
references: 11238182
references: Antioxid Redox Signal. 2005 Nov-Dec;7(11-12):1601-11
references: 16356123
references: Matrix Biol. 2000 Aug;19(4):333-44
references: 10963994
references: Arthritis Rheum. 1996 Apr;39(4):648-56
references: 8630116
references: Arthritis Res Ther. 2007;9(4):R66
references: 17617909
references: Biochim Biophys Acta. 2012 Jan;1824(1):133-45
references: 21777704
references: Cancer Res. 2006 Sep 1;66(17):8804-13
references: 16951197
references: Carcinogenesis. 2006 Oct;27(10):2038-46
references: 16675473
references: Arthritis Rheum. 2009 Jul;60(7):2019-27
references: 19565481
references: Mol Biol Rep. 2010 Dec;37(8):3967-72
references: 20237852
references: Carcinogenesis. 2000 Jun;21(6):1175-82
references: 10837007
references: Trends Mol Med. 2012 Jun;18(6):337-47
references: 22578879
references: Clin Cancer Res. 2004 Apr 1;10(7):2429-40
references: 15073121
references: Osteoarthritis Cartilage. 2008 Apr;16(4):515-21
references: 18203633
references: Mol Cell Proteomics. 2009 Jan;8(1):172-89
references: 18784066
references: Inflamm Res. 2010 Jun;59(6):443-50
references: 19924513
references: PLoS One. 2012;7(3):e33467
references: 22428055
references: Osteoarthritis Cartilage. 2005 Aug;13(8):643-54
references: 15936958
references: Vascul Pharmacol. 2012 Mar-Apr;56(3-4):131-41
references: 22155163
references: Mol Cancer Res. 2003 Mar;1(5):333-45
references: 12651907
references: EMBO J. 1998 Oct 1;17(19):5718-33
references: 9755172
references: Cell Mol Life Sci. 2007 May;64(9):1105-27
references: 17396224
references: Hum Pathol. 2013 Sep;44(9):1780-8
references: 23618358
references: PLoS One. 2012;7(5):e37728
references: 22629448
references: Arterioscler Thromb Vasc Biol. 2009 Nov;29(11):1851-7
references: 19729611
references: Cancer Lett. 2009 Feb 8;274(1):132-42
references: 18952368
references: Nature. 2005 Mar 31;434(7033):644-8
references: 15800624
references: Arthritis Rheum. 2012 Jun;64(6):1697-707
references: 22392533
references: Rheumatology (Oxford). 2009 Aug;48(8):932-8
references: 19491303