Skip to main content
SpringerLink
Log in

The IL-1β/AP-1/miR-30a/ADAMTS-5 axis regulates cartilage matrix degradation in human osteoarthritis

  • Original Article
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

The proinflammatory cytokine interleukin-1β (IL-1β) is involved in the initiation and progression of osteoarthritis (OA) by stimulating the expression of matrix-degrading proteinases, such as a disintegrin metalloproteinase with thrombospondin motifs-5 (ADAMTS-5), a key player in OA pathogenesis. However, how IL-1β induces ADAMTS-5 overexpression is poorly understood. We demonstrate that IL-1β regulates ADAMTS-5 expression by suppressing microRNA-30a (miR-30a). Bioinformatics was performed to predict miRNAs targeting ADAMTS-5. miR-30a inhibited ADAMTS-5 expression by directly targeting its 3′-untranslated region. miR-30a expression was downregulated in OA patients and was negatively correlated with ADAMTS-5 expression and positively correlated with Hospital for Special Surgery (HSS) scores. IL-1β suppressed miR-30a expression by recruiting the activator protein (AP-1) transcription factor c-jun/c-fos to the miR-30a promoter. IL-1β-induced c-jun/c-fos expression regulated ADAMTS-5 expression and cartilage matrix degradation via miR-30a in human chondrocytes. These data indicate that the IL-1β/AP-1/miR-30a/ADAMTS-5 pathway contributes to IL-1β-induced cartilage matrix degradation in human OA chondrocytes. miR-30a may act as a pivotal regulator of cartilage homeostasis and a potential diagnostic and therapeutic target for OA.

Key messages

  • ADAMTS-5 was identified as a novel direct target of miR-30a.

  • IL-1β suppresses miR-30a expression through activation of AP-1 (c-jun/c-fos).

  • AP-1/miR-30a is essential for IL-1β-induced ADAMTS-5 upregulation in OA.

  • Downregulation of miR-30a in OA is negatively correlated with ADAMTS-5 expression.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Glasson SS, Askew R, Sheppard B, Carito B, Blanchet T, Ma HL, Flannery CR, Peluso D, Kanki K, Yang Z et al (2005) Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis. Nature 434:644–648

    Article  CAS  PubMed  Google Scholar 

  2. Aicher WK, Rolauffs B (2014) The spatial organisation of joint surface chondrocytes: review of its potential roles in tissue functioning, disease and early, preclinical diagnosis of osteoarthritis. Ann Rheum Dis 73:645–653

    Article  PubMed  Google Scholar 

  3. de Lange-Brokaar BJ, Ioan-Facsinay A, Yusuf E, Visser AW, Kroon HM, van Osch GJ, Zuurmond AM, Stojanovic-Susulic V, Bloem JL, Nelissen RG et al (2015) Association of pain in knee osteoarthritis with distinct patterns of synovitis. Arthritis Rheumatol 67:733–740

    Article  PubMed  Google Scholar 

  4. Glyn-Jones S, Palmer AJ, Agricola R, Price AJ, Vincent TL, Weinans H, Carr AJ (2015) Osteoarthritis. Lancet 386:376–387

    Article  CAS  PubMed  Google Scholar 

  5. Blalock D, Miller A, Tilley M, Wang J (2015) Joint instability and osteoarthritis. Clin Med Insights Arthritis Musculoskelet Disord 8:15–23

    PubMed  PubMed Central  Google Scholar 

  6. Kapoor M, Martel-Pelletier J, Lajeunesse D, Pelletier JP, Fahmi H (2011) Role of proinflammatory cytokines in the pathophysiology of osteoarthritis. Nat Rev Rheumatol 7:33–42

    Article  CAS  PubMed  Google Scholar 

  7. Mabey T, Honsawek S (2015) Cytokines as biochemical markers for knee osteoarthritis. World J Orthop 6:95–105

    Article  PubMed  PubMed Central  Google Scholar 

  8. Wojdasiewicz P, Poniatowski LA, Szukiewicz D (2014) The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of osteoarthritis. Mediators Inflamm 2014:561459

    Article  PubMed  PubMed Central  Google Scholar 

  9. Kerkhof HJ, Doherty M, Arden NK, Abramson SB, Attur M, Bos SD, Cooper C, Dennison EM, Doherty SA, Evangelou E et al (2011) Large-scale meta-analysis of interleukin-1 beta and interleukin-1 receptor antagonist polymorphisms on risk of radiographic hip and knee osteoarthritis and severity of knee osteoarthritis. Osteoarthritis Cartilage 19:265–271

    Article  CAS  PubMed  Google Scholar 

  10. Bian Q, Wang YJ, Liu SF, Li YP (2012) Osteoarthritis: genetic factors, animal models, mechanisms, and therapies. Front Biosci (Elite Ed) 4:74–100

    Article  Google Scholar 

  11. Calich AL, Domiciano DS, Fuller R (2010) Osteoarthritis: can anti-cytokine therapy play a role in treatment? Clin Rheumatol 29:451–455

    Article  PubMed  Google Scholar 

  12. Daheshia M, Yao JQ (2008) The interleukin 1beta pathway in the pathogenesis of osteoarthritis. J Rheumatol 35:2306–2312

    Article  CAS  PubMed  Google Scholar 

  13. Lim NH, Meinjohanns E, Meldal M, Bou-Gharios G, Nagase H (2014) In vivo imaging of MMP-13 activity in the murine destabilised medial meniscus surgical model of osteoarthritis. Osteoarthritis Cartilage 22:862–868

    Article  CAS  PubMed  Google Scholar 

  14. Verma P, Dalal K (2011) ADAMTS-4 and ADAMTS-5: key enzymes in osteoarthritis. J Cell Biochem 112:3507–3514

    Article  CAS  PubMed  Google Scholar 

  15. van den Berg WB (2011) Osteoarthritis year 2010 in review: pathomechanisms. Osteoarthritis Cartilage 19:338–341

    Article  PubMed  Google Scholar 

  16. Troeberg L, Nagase H (2012) Proteases involved in cartilage matrix degradation in osteoarthritis. Biochim Biophys Acta 1824:133–145

    Article  CAS  PubMed  Google Scholar 

  17. Fosang AJ, Rogerson FM (2010) Identifying the human aggrecanase. Osteoarthritis Cartilage 18:1109–1116

    Article  CAS  PubMed  Google Scholar 

  18. Huang K, Wu LD (2008) Aggrecanase and aggrecan degradation in osteoarthritis: a review. J Int Med Res 36:1149–1160

    Article  CAS  PubMed  Google Scholar 

  19. Fosang AJ, Little CB (2008) Drug insight: aggrecanases as therapeutic targets for osteoarthritis. Nat Clin Pract Rheumatol 4:420–427

    Article  CAS  PubMed  Google Scholar 

  20. Nagase H, Kashiwagi M (2003) Aggrecanases and cartilage matrix degradation. Arthritis Res Ther 5:94–103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Deng H, O’Keefe H, Davie CP, Lind KE, Acharya RA, Franklin GJ, Larkin J, Matico R, Neeb M, Thompson MM et al (2012) Discovery of highly potent and selective small molecule ADAMTS-5 inhibitors that inhibit human cartilage degradation via encoded library technology (ELT). J Med Chem 55:7061–7079

    Article  CAS  PubMed  Google Scholar 

  22. Matsushita T, Sasaki H, Takayama K, Ishida K, Matsumoto T, Kubo S, Matsuzaki T, Nishida K, Kurosaka M, Kuroda R (2013) The overexpression of SIRT1 inhibited osteoarthritic gene expression changes induced by interleukin-1beta in human chondrocytes. J Orthop Res 31:531–537

    Article  CAS  PubMed  Google Scholar 

  23. Wang J, Markova D, Anderson DG, Zheng Z, Shapiro IM, Risbud MV (2011) TNF-alpha and IL-1beta promote a disintegrin-like and metalloprotease with thrombospondin type I motif-5-mediated aggrecan degradation through syndecan-4 in intervertebral disc. J Biol Chem 286:39738–39749

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Tahiri K, Korwin-Zmijowska C, Richette P, Heraud F, Chevalier X, Savouret JF, Corvol MT (2008) Natural chondroitin sulphates increase aggregation of proteoglycan complexes and decrease ADAMTS-5 expression in interleukin 1 beta-treated chondrocytes. Ann Rheum Dis 67:696–702

    Article  CAS  PubMed  Google Scholar 

  25. Zhu H, Leung PC, MacCalman CD (2007) Expression of ADAMTS-5/implantin in human decidual stromal cells: regulatory effects of cytokines. Hum Reprod 22:63–74

    Article  CAS  PubMed  Google Scholar 

  26. Pattoli MA, MacMaster JF, Gregor KR, Burke JR (2005) Collagen and aggrecan degradation is blocked in interleukin-1-treated cartilage explants by an inhibitor of IkappaB kinase through suppression of metalloproteinase expression. J Pharmacol Exp Ther 315:382–388

    Article  CAS  PubMed  Google Scholar 

  27. Turner SL, Mangnall D, Bird NC, Bunning RA, Blair-Zajdel ME (2012) Expression of ADAMTS-1, ADAMTS-4, ADAMTS-5 and TIMP3 by hepatocellular carcinoma cell lines. Int J Oncol 41:1043–1049

    CAS  PubMed  Google Scholar 

  28. Bau B, Gebhard PM, Haag J, Knorr T, Bartnik E, Aigner T (2002) Relative messenger RNA expression profiling of collagenases and aggrecanases in human articular chondrocytes in vivo and in vitro. Arthritis Rheum 46:2648–2657

    Article  CAS  PubMed  Google Scholar 

  29. Bondeson J, Wainwright SD, Lauder S, Amos N, Hughes CE (2006) The role of synovial macrophages and macrophage-produced cytokines in driving aggrecanases, matrix metalloproteinases, and other destructive and inflammatory responses in osteoarthritis. Arthritis Res Ther 8:R187

    Article  PubMed  PubMed Central  Google Scholar 

  30. Legendre F, Bogdanowicz P, Martin G, Domagala F, Leclercq S, Pujol JP, Ficheux H (2007) Rhein, a diacerhein-derived metabolite, modulates the expression of matrix degrading enzymes and the cell proliferation of articular chondrocytes by inhibiting ERK and JNK-AP-1 dependent pathways. Clin Exp Rheumatol 25:546–555

    CAS  PubMed  Google Scholar 

  31. Miyaki S, Asahara H (2012) Macro view of microRNA function in osteoarthritis. Nat Rev Rheumatol 8:543–552

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Tsezou A (2014) Osteoarthritis year in review 2014: genetics and genomics. Osteoarthr Cartil 22:2017–2024

    Article  CAS  PubMed  Google Scholar 

  33. Beyer C, Zampetaki A, Lin NY, Kleyer A, Perricone C, Iagnocco A, Distler A, Langley SR, Gelse K, Sesselmann S et al (2015) Signature of circulating microRNAs in osteoarthritis. Ann Rheum Dis 74, e18

    Article  PubMed  Google Scholar 

  34. Le LT, Swingler TE, Clark IM (2013) Review: the role of microRNAs in osteoarthritis and chondrogenesis. Arthritis Rheum 65:1963–1974

    Article  CAS  PubMed  Google Scholar 

  35. Nakasa T, Nagata Y, Yamasaki K, Ochi M (2011) A mini-review: microRNA in arthritis. Physiol Genomics 43:566–570

    Article  CAS  PubMed  Google Scholar 

  36. Li X, Gibson G, Kim JS, Kroin J, Xu S, van Wijnen AJ, Im HJ (2011) MicroRNA-146a is linked to pain-related pathophysiology of osteoarthritis. Gene 480:34–41

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Vonk LA, Kragten AH, Dhert WJ, Saris DB, Creemers LB (2014) Overexpression of hsa-miR-148a promotes cartilage production and inhibits cartilage degradation by osteoarthritic chondrocytes. Osteoarthr Cartil 22:145–153

    Article  CAS  PubMed  Google Scholar 

  38. Miyaki S, Sato T, Inoue A, Otsuki S, Ito Y, Yokoyama S, Kato Y, Takemoto F, Nakasa T, Yamashita S et al (2010) MicroRNA-140 plays dual roles in both cartilage development and homeostasis. Genes Dev 24:1173–1185

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Luan Y, Kong L, Howell DR, Ilalov K, Fajardo M, Bai XH, Di Cesare PE, Goldring MB, Abramson SB, Liu CJ (2008) Inhibition of ADAMTS-7 and ADAMTS-12 degradation of cartilage oligomeric matrix protein by alpha-2-macroglobulin. Osteoarthr Cartil 16:1413–1420

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Xu X, Fan Z, Kang L, Han J, Jiang C, Zheng X, Zhu Z, Jiao H, Lin J, Jiang K et al (2013) Hepatitis B virus X protein represses miRNA-148a to enhance tumorigenesis. The J Clin Invest 123:630–645

    CAS  PubMed  Google Scholar 

  41. Frank S, Peters MA, Wehmeyer C, Strietholt S, Koers-Wunrau C, Bertrand J, Heitzmann M, Hillmann A, Sherwood J, Seyfert C et al (2013) Regulation of matrixmetalloproteinase-3 and matrixmetalloproteinase-13 by SUMO-2/3 through the transcription factor NF-kappaB. Ann Rheum Dis 72:1874–1881

    Article  CAS  PubMed  Google Scholar 

  42. Swingler TE, Wheeler G, Carmont V, Elliott HR, Barter MJ, Abu-Elmagd M, Donell ST, Boot-Handford RP, Hajihosseini MK, Munsterberg A et al (2012) The expression and function of microRNAs in chondrogenesis and osteoarthritis. Arthritis Rheum 64:1909–1919

    Article  CAS  PubMed  Google Scholar 

  43. Zhang Q, Tang Q, Qin D, Yu L, Huang R, Lv G, Zou Z, Jiang XC, Zou C, Liu W et al (2015) Role of microRNA 30a targeting insulin receptor substrate 2 in colorectal tumorigenesis. Mol Cell Biol 35:988–1000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Fu J, Xu X, Kang L, Zhou L, Wang S, Lu J, Cheng L, Fan Z, Yuan B, Tian P et al (2014) miR-30a suppresses breast cancer cell proliferation and migration by targeting Eya2. Biochem Biophys Res Commun 445:314–319

    Article  CAS  PubMed  Google Scholar 

  45. Xu K, Xu P, Yao JF, Zhang YG, Hou WK, Lu SM (2013) Reduced apoptosis correlates with enhanced autophagy in synovial tissues of rheumatoid arthritis. Inflamm Res 62:229–237

    Article  CAS  PubMed  Google Scholar 

  46. Qiu Z, Dai Y (2014) Roadmap of miR-122-related clinical application from bench to bedside. Expert Opin Investig Drugs 23:347–355

    Article  CAS  PubMed  Google Scholar 

  47. Shiozawa S, Tsumiyama K (2009) Pathogenesis of rheumatoid arthritis and c-Fos/AP-1. Cell Cycle 8:1539–1543

    Article  CAS  PubMed  Google Scholar 

  48. Schonthaler HB, Guinea-Viniegra J, Wagner EF (2011) Targeting inflammation by modulating the Jun/AP-1 pathway. Ann Rheum Dis 70(Suppl 1):i109–i112

    Article  CAS  PubMed  Google Scholar 

  49. Grabiec AM, Korchynskyi O, Tak PP, Reedquist KA (2012) Histone deacetylase inhibitors suppress rheumatoid arthritis fibroblast-like synoviocyte and macrophage IL-6 production by accelerating mRNA decay. Ann Rheum Dis 71:424–431

    Article  CAS  PubMed  Google Scholar 

  50. Liacini A, Sylvester J, Li WQ, Huang W, Dehnade F, Ahmad M, Zafarullah M (2003) Induction of matrix metalloproteinase-13 gene expression by TNF-alpha is mediated by MAP kinases, AP-1, and NF-kappaB transcription factors in articular chondrocytes. Exp Cell Res 288:208–217

    Article  CAS  PubMed  Google Scholar 

  51. Lim H, Kim HP (2011) Matrix metalloproteinase-13 expression in IL-1beta-treated chondrocytes by activation of the p38 MAPK/c-Fos/AP-1 and JAK/STAT pathways. Arch Pharm Res 34:109–117

    Article  CAS  PubMed  Google Scholar 

  52. Yang YM, Lee WH, Lee CG, An J, Kim ES, Kim SH, Lee SK, Lee CH, Dhanasekaran DN, Moon A et al (2015) Galpha12 gep oncogene deregulation of p53-responsive microRNAs promotes epithelial-mesenchymal transition of hepatocellular carcinoma. Oncogene 34:2910–2921

    Article  CAS  PubMed  Google Scholar 

  53. Chen YJ, Chang LS (2013) Hydroquinone-induced miR-122 down-regulation elicits ADAM17 up-regulation, leading to increased soluble TNF-alpha production in human leukemia cells with expressed Bcr/Abl. Biochem Pharmacol 86:620–631

    Article  CAS  PubMed  Google Scholar 

  54. Pellegrino L, Stebbing J, Braga VM, Frampton AE, Jacob J, Buluwela L, Jiao LR, Periyasamy M, Madsen CD, Caley MP et al (2013) miR-23b regulates cytoskeletal remodeling, motility and metastasis by directly targeting multiple transcripts. Nucleic Acids Res 41:5400–5412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank Dr. Jiying Chen for collection of the data, for providing valuable comments and for providing some of the samples. This work was supported by the China Major State Basic Research Development Program (2012CB945100), the National Natural Science Foundation (81330053, 81472589, 81101387, 81371976, 31100604 and 81372161), and the Beijing Nova Program (Z141102001814055). The General Hospital of the Chinese People’s Liberation Army and Beijing Institute of Biotechnology contributed equally to this work.

Author information

Author notes

    Authors and Affiliations

    1. Department of Orthopaedics, General Hospital of Chinese People’s Liberation Army, Beijing, 100853, China

      Quanbo Ji, Qiang Zhang & Yan Wang

    2. Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing, 100850, China

      Xiaojie Xu, Ling Li, Yingchun Liang, Tian Hong & Qinong Ye

    3. Department of Orthopaedic Surgery, Royal Liverpool University Hospital, Prescot Street, Liverpool, UK

      Qiang Zhang

    4. Department of Nuclear Medicine, Peking University First Hospital, Beijing, 100034, China

      Lei Kang

    5. Department of Traditional Chinese Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

      Yameng Xu

    6. Department of Science and Technology, Academy of Military Medical Sciences, Beijing, 100850, China

      Ke Zhang

    Authors
    1. Quanbo Ji
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Xiaojie Xu
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Qiang Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Lei Kang
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Yameng Xu
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Ke Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Ling Li
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Yingchun Liang
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Tian Hong
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. Qinong Ye
      View author publications

      You can also search for this author in PubMed Google Scholar

    11. Yan Wang
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Xiaojie Xu.

    Ethics declarations

    All human studies were conducted with the informed consent of the patients and followed the protocols approved by the Institutional Ethics Review Board (no. 20090611-3) of the General Hospital of the People’s Liberation Army (Beijing, China).

    Competing financial interests

    The authors declare no competing financial interests.

    Additional information

    Quanbo Ji, Xiaojie Xu, Qiang Zhang and Lei Kang contributed equally to this work.

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    ESM 1

    (PDF 3703 kb)

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Ji, Q., Xu, X., Zhang, Q. et al. The IL-1β/AP-1/miR-30a/ADAMTS-5 axis regulates cartilage matrix degradation in human osteoarthritis. J Mol Med 94, 771–785 (2016). https://doi.org/10.1007/s00109-016-1418-z

    Download citation

    • Received:

    • Revised:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s00109-016-1418-z

    Keywords

    Search

    Navigation