Skip to main content
Top
Published in: Journal of Orthopaedic Surgery and Research 1/2015

Open Access 01-12-2015 | Research article

IL-1β promotes ADAMTS enzyme-mediated aggrecan degradation through NF-κB in human intervertebral disc

Authors: Zhongyi Sun, Zhanmin Yin, Chao Liu, He Liang, Minbo Jiang, Jiwei Tian

Published in: Journal of Orthopaedic Surgery and Research | Issue 1/2015

Login to get access

Abstract

Background

The purpose of this study is to investigate IL-1β regulation of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS-4 and ADAMTS-5) expression through nuclear factor kappa B (NF-κB) in human nucleus pulposus (NP) cells.

Methods

qRT-PCR and Western blot were used to measure ADAMTS expression. Transfections and gene silencing were used to determine the role of NF-κB on cytokine-mediated ADAMTS expression and its role in aggrecan degradation.

Results

IL-1β increased ADAMTS expression in NP cells. Treatment with NF-κB inhibitors abolished the inductive effect of the cytokines on ADAMTS expression. Silencing of p65 confirmed their role in IL-1β-dependent ADAMTS-4 and ADAMTS-5 expression and aggrecan degradation.

Conclusions

By controlling the activation of NF-κB signaling, IL-1β modulates the expression of ADAMTS in NP cells. To our knowledge, this is the first study that shows the contribution of both ADAMTS-4 and ADAMTS-5 to aggrecan degradation in human NP cells.
Literature
2.
go back to reference Luoma K, Riihimäki H, Luukkonen R, Raininko R, Viikari-Juntura E, Lamminen A. Low back pain in relation to lumbar disc degeneration. Spine (Phila Pa 1976). 2000;25(4):487–92.CrossRef Luoma K, Riihimäki H, Luukkonen R, Raininko R, Viikari-Juntura E, Lamminen A. Low back pain in relation to lumbar disc degeneration. Spine (Phila Pa 1976). 2000;25(4):487–92.CrossRef
3.
go back to reference Phillips KL, Jordan-Mahy N, Nicklin MJ, Le Maitre CL. Interleukin-1 receptor antagonist deficient mice provide insights into pathogenesis of human intervertebral disc degeneration. Ann Rheum Dis. 2013;72:11.CrossRef Phillips KL, Jordan-Mahy N, Nicklin MJ, Le Maitre CL. Interleukin-1 receptor antagonist deficient mice provide insights into pathogenesis of human intervertebral disc degeneration. Ann Rheum Dis. 2013;72:11.CrossRef
4.
go back to reference Pockert AJ, Richardson SM, Le Maitre CL, Lyon M, Deakin JA, Buttle DJ, et al. Modified expression of the ADAMTS enzymes and tissue inhibitor of metalloproteinases 3 during human intervertebral disc degeneration. Arthritis Rheum. 2009;60:2. Pockert AJ, Richardson SM, Le Maitre CL, Lyon M, Deakin JA, Buttle DJ, et al. Modified expression of the ADAMTS enzymes and tissue inhibitor of metalloproteinases 3 during human intervertebral disc degeneration. Arthritis Rheum. 2009;60:2.
5.
go back to reference Furtwängler T, Chan SC, Bahrenberg G, Richards PJ, Gantenbein-Ritter B. Assessment of the matrix degenerative effects of MMP-3, ADAMTS-4, and HTRA1, injected into a bovine intervertebral disc organ culture model. Spine (Phila Pa 1976). 2013;38:22.CrossRef Furtwängler T, Chan SC, Bahrenberg G, Richards PJ, Gantenbein-Ritter B. Assessment of the matrix degenerative effects of MMP-3, ADAMTS-4, and HTRA1, injected into a bovine intervertebral disc organ culture model. Spine (Phila Pa 1976). 2013;38:22.CrossRef
6.
go back to reference Zeldich E, Koren R, Dard M, Weinberg E, Weinreb M, Nemcovsky CE. Enamel matrix derivative induces the expression of tissue inhibitor of matrix metalloproteinase-3 in human gingival fibroblasts via extracellular signal-regulated kinase. J Periodontal Res. 2010;45:2.CrossRef Zeldich E, Koren R, Dard M, Weinberg E, Weinreb M, Nemcovsky CE. Enamel matrix derivative induces the expression of tissue inhibitor of matrix metalloproteinase-3 in human gingival fibroblasts via extracellular signal-regulated kinase. J Periodontal Res. 2010;45:2.CrossRef
7.
go back to reference Verma P, Dalal K. ADAMTS-4 and ADAMTS-5: key enzymes in osteoarthritis. J Cell Biochem. 2011;112:12.CrossRef Verma P, Dalal K. ADAMTS-4 and ADAMTS-5: key enzymes in osteoarthritis. J Cell Biochem. 2011;112:12.CrossRef
8.
go back to reference Patel KP, Sandy JD, Akeda K, Miyamoto K, Chujo T, An HS, et al. Aggrecanases and aggrecanase-generated fragments in the human intervertebral disc at early and advanced stages of disc degeneration. Spine (Phila Pa 1976). 2007;32:23.CrossRef Patel KP, Sandy JD, Akeda K, Miyamoto K, Chujo T, An HS, et al. Aggrecanases and aggrecanase-generated fragments in the human intervertebral disc at early and advanced stages of disc degeneration. Spine (Phila Pa 1976). 2007;32:23.CrossRef
9.
go back to reference Zhang Q, Hui W, Litherland GJ, Barter MJ, Davidson R, Darrah C, et al. Differential Toll-like receptor-dependent collagenase expression in chondrocytes. Ann Rheum Dis. 2008;67:11.CrossRef Zhang Q, Hui W, Litherland GJ, Barter MJ, Davidson R, Darrah C, et al. Differential Toll-like receptor-dependent collagenase expression in chondrocytes. Ann Rheum Dis. 2008;67:11.CrossRef
10.
go back to reference Gruber HE, Ingram JA, Hoelscher GL, Zinchenko N, Norton HJ, Hanley Jr EN. Matrix metalloproteinase 28, a novel matrix metalloproteinase, is constitutively expressed in human intervertebral disc tissue and is present in matrix of more degenerated discs. Arthritis Res Ther. 2009;11(6):R184. doi:10.1186/ar2876. Epub 2009 Dec 9.PubMedCentralCrossRefPubMed Gruber HE, Ingram JA, Hoelscher GL, Zinchenko N, Norton HJ, Hanley Jr EN. Matrix metalloproteinase 28, a novel matrix metalloproteinase, is constitutively expressed in human intervertebral disc tissue and is present in matrix of more degenerated discs. Arthritis Res Ther. 2009;11(6):R184. doi:10.​1186/​ar2876. Epub 2009 Dec 9.PubMedCentralCrossRefPubMed
11.
go back to reference Carlos LO, Lavanya HP, Yardena S. Protective roles of matrix metalloproteinases: from mouse models to human cancer. Cell Cycle. 2009;8:3657.CrossRef Carlos LO, Lavanya HP, Yardena S. Protective roles of matrix metalloproteinases: from mouse models to human cancer. Cell Cycle. 2009;8:3657.CrossRef
12.
go back to reference Matsukawa T, Sakai T, Yonezawa T, Hiraiwa H, Hamada T, Nakashima M, et al. MicroRNA-125b regulates the expression of aggrecanase-1 (ADAMTS-4) in human osteoarthritic chondrocytes. Arthritis Res Ther. 2013;15(1):R28.PubMedCentralCrossRefPubMed Matsukawa T, Sakai T, Yonezawa T, Hiraiwa H, Hamada T, Nakashima M, et al. MicroRNA-125b regulates the expression of aggrecanase-1 (ADAMTS-4) in human osteoarthritic chondrocytes. Arthritis Res Ther. 2013;15(1):R28.PubMedCentralCrossRefPubMed
13.
go back to reference Yamamoto K, Owen K, Parker AE, Scilabra SD, Dudhia J, Strickland DK, et al. Low density lipoprotein receptor-related protein 1 (LRP1)-mediated endocytic clearance of a disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4): functional differences of non-catalytic domains of ADAMTS-4 and ADAMTS-5 in LRP1 binding. J Biol Chem. 2014;289(10):6462-74.PubMedCentralCrossRefPubMed Yamamoto K, Owen K, Parker AE, Scilabra SD, Dudhia J, Strickland DK, et al. Low density lipoprotein receptor-related protein 1 (LRP1)-mediated endocytic clearance of a disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4): functional differences of non-catalytic domains of ADAMTS-4 and ADAMTS-5 in LRP1 binding. J Biol Chem. 2014;289(10):6462-74.PubMedCentralCrossRefPubMed
14.
go back to reference Lim NH, Kashiwagi M, Visse R, Jones J, Enghild JJ, Brew K, et al. Reactive-site mutants of N-TIMP-3 that selectively inhibit ADAMTS-4 and ADAMTS-5: biological and structural implications. Biochem J. 2010;431(1):113–22.PubMedCentralCrossRefPubMed Lim NH, Kashiwagi M, Visse R, Jones J, Enghild JJ, Brew K, et al. Reactive-site mutants of N-TIMP-3 that selectively inhibit ADAMTS-4 and ADAMTS-5: biological and structural implications. Biochem J. 2010;431(1):113–22.PubMedCentralCrossRefPubMed
16.
go back to reference Hatano E, Fujita T, Ueda Y, Okuda T, Katsuda S, Okada Y et al. Expression of ADAMTS-4 (aggrecanase-1) and possible involvement in regression of lumbar disc herniation. Spine (Phila Pa 1976). 2006;31(13):1426–32.CrossRef Hatano E, Fujita T, Ueda Y, Okuda T, Katsuda S, Okada Y et al. Expression of ADAMTS-4 (aggrecanase-1) and possible involvement in regression of lumbar disc herniation. Spine (Phila Pa 1976). 2006;31(13):1426–32.CrossRef
17.
go back to reference Lee JM, Song JY, Baek M, Jung HY, Kang H, Han IB, et al. Interleukin-1β induces angiogenesis and innervation in human intervertebral disc degeneration. J Orthop Res. 2011;29(2):265–9.CrossRefPubMed Lee JM, Song JY, Baek M, Jung HY, Kang H, Han IB, et al. Interleukin-1β induces angiogenesis and innervation in human intervertebral disc degeneration. J Orthop Res. 2011;29(2):265–9.CrossRefPubMed
18.
go back to reference Mwale F, Masuda K, Pichika R, Epure LM, Yoshikawa T, Hemmad A, et al. The efficacy of Link N as a mediator of repair in a rabbit model of intervertebral disc degeneration. Arthritis Res Ther. 2011;13(4):R120.PubMedCentralCrossRefPubMed Mwale F, Masuda K, Pichika R, Epure LM, Yoshikawa T, Hemmad A, et al. The efficacy of Link N as a mediator of repair in a rabbit model of intervertebral disc degeneration. Arthritis Res Ther. 2011;13(4):R120.PubMedCentralCrossRefPubMed
19.
go back to reference Séguin CA, Bojarski M, Pilliar RM, Roughley PJ, Kandel RA. Differential regulation of matrix degrading enzymes in a TNFalpha-induced model of nucleus pulposus tissue degeneration. Matrix Biol. 2006;25(7):409–18.CrossRefPubMed Séguin CA, Bojarski M, Pilliar RM, Roughley PJ, Kandel RA. Differential regulation of matrix degrading enzymes in a TNFalpha-induced model of nucleus pulposus tissue degeneration. Matrix Biol. 2006;25(7):409–18.CrossRefPubMed
20.
go back to reference Wang J, Markova D, Anderson DG, Zheng Z, Shapiro IM, Risbud MV. TNF-α and IL-1β promote a disintegrin-like and metalloprotease with thrombospondin type I motif-5 mediatedaggrecan degradation through syndecan-4 in intervertebral disc. J Biol Chem. 2011;286(46):39738–49.PubMedCentralCrossRefPubMed Wang J, Markova D, Anderson DG, Zheng Z, Shapiro IM, Risbud MV. TNF-α and IL-1β promote a disintegrin-like and metalloprotease with thrombospondin type I motif-5 mediatedaggrecan degradation through syndecan-4 in intervertebral disc. J Biol Chem. 2011;286(46):39738–49.PubMedCentralCrossRefPubMed
21.
go back to reference Freemont AJ, Watkins A, Le Maitre C, Jeziorska M, Hoyland JA. Current understanding of cellular and molecular events in intervertebral disc degeneration: implications for therapy. J Pathol. 2002;196(4):374–9.CrossRefPubMed Freemont AJ, Watkins A, Le Maitre C, Jeziorska M, Hoyland JA. Current understanding of cellular and molecular events in intervertebral disc degeneration: implications for therapy. J Pathol. 2002;196(4):374–9.CrossRefPubMed
22.
go back to reference Pfirrmann CW, Metzdorf A, Zanetti M, Hodler J, Boos N. Magnetic resonance classification of lumbar intervertebral disc degeneration. Spine (Phila Pa 1976). 2001;26(17):1873–8.CrossRef Pfirrmann CW, Metzdorf A, Zanetti M, Hodler J, Boos N. Magnetic resonance classification of lumbar intervertebral disc degeneration. Spine (Phila Pa 1976). 2001;26(17):1873–8.CrossRef
23.
go back to reference Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25:402.CrossRefPubMed Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25:402.CrossRefPubMed
24.
go back to reference Moncada-Pazos A, Obaya AJ, Viloria CG, López-Otín C, Cal S. The nutraceutical flavonoid luteolin inhibits ADAMTS-4 and ADAMTS-5 aggrecanase activities. J Mol Med (Berl). 2011;89(6):611–9.CrossRef Moncada-Pazos A, Obaya AJ, Viloria CG, López-Otín C, Cal S. The nutraceutical flavonoid luteolin inhibits ADAMTS-4 and ADAMTS-5 aggrecanase activities. J Mol Med (Berl). 2011;89(6):611–9.CrossRef
26.
go back to reference Yatabe T, Mochizuki S, Takizawa M, Chijiiwa M, Okada A, Kimura T et al. Hyaluronan inhibits expression of ADAMTS4 (aggrecanase-1) in human osteoarthritic chondrocytes. Ann Rheum Dis. 2009;68(6):1051–8.PubMedCentralCrossRefPubMed Yatabe T, Mochizuki S, Takizawa M, Chijiiwa M, Okada A, Kimura T et al. Hyaluronan inhibits expression of ADAMTS4 (aggrecanase-1) in human osteoarthritic chondrocytes. Ann Rheum Dis. 2009;68(6):1051–8.PubMedCentralCrossRefPubMed
27.
go back to reference Tsuji T, Chiba K, Imabayashi H, Fujita Y, Hosogane N, Okada Y, et al. Age-related changes in expression of tissue inhibitor of metalloproteinases-3 associated with transition from the notochordal nucleus pulposus to the fibrocartilaginous nucleus pulposus in rabbit intervertebral disc. Spine (Phila Pa 1976). 2007;32(8):849–56.CrossRef Tsuji T, Chiba K, Imabayashi H, Fujita Y, Hosogane N, Okada Y, et al. Age-related changes in expression of tissue inhibitor of metalloproteinases-3 associated with transition from the notochordal nucleus pulposus to the fibrocartilaginous nucleus pulposus in rabbit intervertebral disc. Spine (Phila Pa 1976). 2007;32(8):849–56.CrossRef
28.
go back to reference Wuertz K, Quero L, Sekiguchi M, Klawitter M, Nerlich A, Konno Set ss. The red wine polyphenol resveratrol shows promising potential for the treatment of nucleus pulposus-mediated pain in vitro and in vivo. Spine (Phila Pa 1976). 201;36(21):E1373–84. Wuertz K, Quero L, Sekiguchi M, Klawitter M, Nerlich A, Konno Set ss. The red wine polyphenol resveratrol shows promising potential for the treatment of nucleus pulposus-mediated pain in vitro and in vivo. Spine (Phila Pa 1976). 201;36(21):E1373–84.
29.
go back to reference Tian Y, Yuan W, Fujita N, Wang J, Wang H, Shapiro IM et al. Inflammatory cytokines associated with degenerative disc disease control aggrecanase-1 (ADAMTS-4)expression in nucleus pulposus cells through MAPK and NF-κB. Am J Pathol. 2013;182(6):2310–21.PubMedCentralCrossRefPubMed Tian Y, Yuan W, Fujita N, Wang J, Wang H, Shapiro IM et al. Inflammatory cytokines associated with degenerative disc disease control aggrecanase-1 (ADAMTS-4)expression in nucleus pulposus cells through MAPK and NF-κB. Am J Pathol. 2013;182(6):2310–21.PubMedCentralCrossRefPubMed
30.
go back to reference Nasto LA, Seo HY, Robinson AR, Tilstra JS, Clauson CL, Sowa GA et al. ISSLS prize winner: inhibition of NF-κB activity ameliorates age-associated disc degeneration in a mouse model of accelerated aging. Spine (Phila Pa 1976). 2012;37(21):1819–25.CrossRef Nasto LA, Seo HY, Robinson AR, Tilstra JS, Clauson CL, Sowa GA et al. ISSLS prize winner: inhibition of NF-κB activity ameliorates age-associated disc degeneration in a mouse model of accelerated aging. Spine (Phila Pa 1976). 2012;37(21):1819–25.CrossRef
31.
32.
go back to reference Dai S, Hirayama T, Abbas S, Abu-Amer Y. The IkappaB kinase (IKK) inhibitor, NEMO-binding domain peptide, blocks osteoclastogenesis and bone erosion in inflammatory arthritis. J Biol Chem. 2004;279(36):37219-22. Epub 2004 Jul 13.CrossRefPubMed Dai S, Hirayama T, Abbas S, Abu-Amer Y. The IkappaB kinase (IKK) inhibitor, NEMO-binding domain peptide, blocks osteoclastogenesis and bone erosion in inflammatory arthritis. J Biol Chem. 2004;279(36):37219-22. Epub 2004 Jul 13.CrossRefPubMed
33.
go back to reference Kim HJ, Chang EJ, Kim HM, Lee SB, Kim HD, Su Kim G, et al. Antioxidant alpha-lipoic acid inhibits osteoclast differentiation by reducing nuclear factor-kappaB DNA bindingand prevents in vivo bone resorption induced by receptor activator of nuclear factor-kappaB ligand and tumor necrosis factor-alpha. Free Radic Biol Med. 2006;40(9):1483–93.CrossRefPubMed Kim HJ, Chang EJ, Kim HM, Lee SB, Kim HD, Su Kim G, et al. Antioxidant alpha-lipoic acid inhibits osteoclast differentiation by reducing nuclear factor-kappaB DNA bindingand prevents in vivo bone resorption induced by receptor activator of nuclear factor-kappaB ligand and tumor necrosis factor-alpha. Free Radic Biol Med. 2006;40(9):1483–93.CrossRefPubMed
34.
go back to reference Acharyya S, Villalta SA, Bakkar N, Bupha-Intr T, Janssen PM, Carathers M, et al. Interplay of IKK/NFkappaB signaling in macrophages and myofibers promotes muscle degeneration inDuchenne muscular dystrophy. J Clin Invest. 2007;117(4):889–901.PubMedCentralCrossRefPubMed Acharyya S, Villalta SA, Bakkar N, Bupha-Intr T, Janssen PM, Carathers M, et al. Interplay of IKK/NFkappaB signaling in macrophages and myofibers promotes muscle degeneration inDuchenne muscular dystrophy. J Clin Invest. 2007;117(4):889–901.PubMedCentralCrossRefPubMed
Metadata
Title
IL-1β promotes ADAMTS enzyme-mediated aggrecan degradation through NF-κB in human intervertebral disc
Authors
Zhongyi Sun
Zhanmin Yin
Chao Liu
He Liang
Minbo Jiang
Jiwei Tian
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Journal of Orthopaedic Surgery and Research / Issue 1/2015
Electronic ISSN: 1749-799X
DOI
https://doi.org/10.1186/s13018-015-0296-3

Other articles of this Issue 1/2015

Journal of Orthopaedic Surgery and Research 1/2015 Go to the issue