Skip to main content
SpringerLink
Log in

ADAMTS proteases: key roles in atherosclerosis?

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

Abstract

The ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) proteases are secreted enzymes that regulate extracellular matrix turnover by degrading specific matrix components. Roles for the proteases in inflammation and atherosclerosis have been suggested by a number of recent studies, and the role of ADAMTS-4 and -5 in the breakdown of aggrecan and subsequent degradation of cartilage during osteoarthritis has also been established. The ability of the ADAMTS proteases to degrade versican, the primary proteoglycan in the vasculature, is thought to be central to any hypothesized role for the proteases in atherosclerosis. In this review, we introduce the structure and function of the ADAMTS family of proteases and review the literature that links them with inflammation and atherosclerosis.

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

Similar content being viewed by others

References

  1. Porter S, Clark I, Keveorkian L, Edwards D (2005) The ADAMTS metalloproteinases. Biochem J 386:15–27

    Article  CAS  PubMed  Google Scholar 

  2. Jones GC, Riley GP (2005) ADAMTS proteinases: a multi-domain, multi-functional family with roles in extracellular matrix turnover and arthritis. Arthritis Res Ther 7:160–169

    Article  PubMed  Google Scholar 

  3. Wang W, Lee S, Steiglitz B, Scott I, Lebares C, Allen M, Brenner M, Takahara K, Greenspan D (2003) Transforming growth factor-beta induces secretion of activated ADAMTS-2. A procollagen III N-proteinase. J Biol Chem 278:19549–19557

    Article  CAS  PubMed  Google Scholar 

  4. Apte S (2009) A disintegrin-like and metalloprotease (reprolysin-type) with thrombospondin type 1 motif (ADAMTS) superfamily: functions and mechanisms. J Biol Chem 284:31493–31497

    Article  CAS  PubMed  Google Scholar 

  5. Shindo T, Kurihara H, Kuno K, Yokoyama H, Wada T, Kurihara Y, Imai T, Wang Y, Ogata M, Nishimatsu H, Moriyama N, Oh-hashi Y, Morita H, Ishikawa T, Nagai R, Yazaki Y, Matsushima K (2000) ADAMTS-1: a metalloproteinase-disintegrin essential for normal growth, fertility, and organ morphology and function. J Clin Invest 105:1345–1352

    Article  CAS  PubMed  Google Scholar 

  6. Kuno K, Kanada N, Nakashima E, Fujiki F, Ichimura F, Matsushima K (1997) Molecular cloning of a gene encoding a new type of metalloproteinase-disintegrin family protein with thrombospondin motifs as an inflammation associated gene. J Biol Chem 272:556–562

    Article  CAS  PubMed  Google Scholar 

  7. Vázquez F, Hastings G, Ortega M, Lane T, Oikemus S, Lombardo M, Iruela-Arispe M (1999) METH-1, a human ortholog of ADAMTS-1, and METH-2 are members of a new family of proteins with angio-inhibitory activity. J Biol Chem 274:23349–23357

    Article  PubMed  Google Scholar 

  8. Kuno K, Okada Y, Kawashima H, Nakamura H, Miyasaka M, Ohno H, Matsushima K (2000) ADAMTS-1 cleaves a cartilage proteoglycan, aggrecan. FEBS Lett 478:241–245

    Article  CAS  PubMed  Google Scholar 

  9. Naito S, Shiomi T, Okada A, Kimura T, Chijiiwa M, Fujita Y, Yatabe T, Komiya K, Enomoto H, Fujikawa K, Okada Y (2007) Expression of ADAMTS-4 (aggrecanase-1) in human osteoarthritic cartilage. Pathol Int 57:703–711

    Article  CAS  PubMed  Google Scholar 

  10. Miwa H, Gerken T, Huynh T, Duesler L, Cotter M, Hering T (2009) Conserved sequence in the aggrecan interglobular domain modulates cleavage by ADAMTS-4 and ADAMTS-5. Biochim Biophys Acta 1790:161–172

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  12. Bondeson J, Wainwright S, Hughes C, Caterson B (2008) The regulation of the ADAMTS4 and ADAMTS5 aggrecanases in osteoarthritis: a review. Clin Exp Rheumatol 26:139–145

    CAS  PubMed  Google Scholar 

  13. Wight T, Merrilees M (2004) Proteoglycans in atherosclerosis and restenosis: key roles for versican. Circ Res 94:1158–1167

    Article  CAS  PubMed  Google Scholar 

  14. Haddock G, Cross A, Allan S, Sharrack B, Callaghan J, Bunning R, Buttle D, Woodroofe M (2007) Brevican and phosphacan expression and localization following transient middle cerebral artery occlusion in the rat. Biochem Soc Trans 35:692–694

    Article  CAS  PubMed  Google Scholar 

  15. Nakamura H, Fujii Y, Inoki I, Sukimoto K, Tanzawa K, Matsuki H, Miura R, Yamaguchi Y, Okada Y (2000) Brevican is degraded by matrix metalloproteinases and aggrecanase-1 (ADAMTS4) at different sites. J Biol Chem 275:38885–38890

    Article  CAS  PubMed  Google Scholar 

  16. Viapiano M, Hockfield S, Matthews R (2008) BEHAB/brevican requires ADAMTS-mediated proteolytic cleavage to promote glioma invasion. J Neurooncol 88:261–272

    Article  CAS  PubMed  Google Scholar 

  17. Hofer T, Frankenburger M, Mages J, Lang R, Hoffmann R, Colige A, Ziegler-Heitbrock L (2008) Tissue-specific induction of ADAMTS2 in monocytes and macrophages by glucocorticoids. J Mol Med 86:323–332

    Article  CAS  PubMed  Google Scholar 

  18. Fujikawa K, Suzuki H, McMullen B, Chung D (2001) Purification of human von Willebrand factor-cleaving protease and its identification as a new member of the metalloproteinase family. Blood 98:1662–1666

    Article  CAS  PubMed  Google Scholar 

  19. Moriguchi-Goto S, Yamashita A, Tamura N, Soejima K, Takahashi M, Nakagaki T, Goto S, Asada Y (2009) ADAMTS-13 attenuates thrombus formation on type I collagen surface and disrupted plaques under flow conditions. Atherosclerosis 203:409–416

    Article  CAS  PubMed  Google Scholar 

  20. Long Zheng X (2010) ADAMTS13 testing: why bother? Blood 115:1475–1476

    Article  PubMed  Google Scholar 

  21. Kuno K, Terashima Y, Matsushima K (1999) ADAMTS-1 is an active metalloproteinase associated with the extracellular matrix. J Biol Chem 274:18821–18826

    Article  CAS  PubMed  Google Scholar 

  22. Wang P, Tortorella M, England K, Malfait A, Thomas G, Arner E, Pei D (2004) Proprotein convertase furin interacts with and cleaves pro-ADAMTS4 (Aggrecanase-1) in the trans-Golgi network. J Biol Chem 279:15434–15440

    Article  CAS  PubMed  Google Scholar 

  23. Gerhardt S, Hassall G, Hawtin P, McCall E, Flavell L, Minshull C, Hargreaves D, Ting A, Pauptit R, Parker A, Abbott W (2007) Crystal structures of human ADAMTS-1 reveal a conserved catalytic domain and a disintegrin-like domain with a fold homologous to cysteine-rich domains. J Mol Biol 373:891–902

    Article  CAS  PubMed  Google Scholar 

  24. Gao G, Westling J, Thompson V, Howell T, Gottschall P, Sandy J (2002) Activation of the proteolytic activity of ADAMTS4 (aggrecanase-1) by C-terminal truncation. J Biol Chem 277:11034–11041

    Article  CAS  PubMed  Google Scholar 

  25. Kuno K, Matsushima K (1998) ADAMTS-1 protein anchors at the extracellular matrix through the thrombospondin type 1 motifs and its spacing region. J Biol Chem 273:13912–13917

    Article  CAS  PubMed  Google Scholar 

  26. Flannery C, Zeng W, Corcoran C, Collins-Racie L, Chockalingam P, Hebert T, Mackie S, McDonagh T, Crawford T, Tomkinson K, LaVallie E, Morris E (2002) Autocatalytic cleavage of ADAMTS-4 (aggrecanase-1) reveals multiple glycosaminoglycan-binding sites. J Biol Chem 277:42775–42780

    Article  CAS  PubMed  Google Scholar 

  27. Tortorella M, Pratta M, Liu R, Abbaszade I, Ross H, Burn T, Arner E (2000) The thrombospondin motif of aggrecanase-1 (ADAMTS-4) is critical for aggrecan substrate recognition and cleavage. J Biol Chem 275:25791–25797

    Article  CAS  PubMed  Google Scholar 

  28. Hashimoto G, Shimoda M, Okada Y (2004) ADAMTS-4 (aggrecanase-1) interaction with the C-terminal domain of fibronectin inhibits proteolysis of aggrecan. J Biol Chem 279:32483–32491

    Article  CAS  PubMed  Google Scholar 

  29. Wight TN (2005) The ADAMTS proteases, extracellular matrix, and vascular disease: waking the sleeping giant(s)! Arterioscler Thromb Vasc Biol 25:12–14

    CAS  PubMed  Google Scholar 

  30. Galis Z, Khatri J (2002) Matrix metalloproteinases in vascular remodelling and atherogenesis: the good, the bad and the ugly. Circ Res 90:251–262

    CAS  PubMed  Google Scholar 

  31. Rodríguez-Manzaneque J, Westling J, Thai S, Luque A, Knauper V, Murphy G, Sandy J, Iruela-Arispe M (2002) ADAMTS1 cleaves aggrecan at multiple sites and is differentially inhibited by metalloproteinase inhibitors. Biochem Biophys Res Commun 293:501–508

    Article  PubMed  Google Scholar 

  32. Hashimoto G, Aoki H, Nakamura K, Tanzawa Y, Okada Y (2001) Inhibition of ADAMTS4 (aggrecanase-1) by tissue inhibitors of metalloproteinases (TIMP-1, 2, 3 and 4). FEBS Lett 494:192–195

    Google Scholar 

  33. Kashiwagi M, Tortorella M, Nagase H, Brew K (2001) TIMP-3 is a potent inhibitor of aggrecanase 1 (ADAM-TS4) and aggrecanase 2 (ADAM-TS5). J Biol Chem 276:12501–12504

    Article  CAS  PubMed  Google Scholar 

  34. Troeberg L, Fushimi K, Scilabra S, Nakamura H, Dive V, Thøgersen I, Enghild J, Nagase H (2009) The C-terminal domains of ADAMTS-4 and ADAMTS-5 promote association with N-TIMP-3. Matrix Biol 28:463–469

    Article  CAS  PubMed  Google Scholar 

  35. Bui Q, Prempeh M, Wilensky R (2009) Atherosclerotic plaque development. Int J Biochem Cell Biol 41:2109–2113

    Article  CAS  PubMed  Google Scholar 

  36. Lusis A, Mar R, Pajukanta P (2004) Genetics of atherosclerosis. Annu Rev Genomics Hum Genet 5:189–218

    Article  CAS  PubMed  Google Scholar 

  37. Glass C, Witztum J (2001) Atherosclerosis: the road ahead. Cell 104:503–516

    Article  CAS  PubMed  Google Scholar 

  38. Weber C, Zernecke A, Libby P (2008) The multifaceted contributions of leukocyte subsets to atherosclerosis: lessons from mouse models. Nat Rev Immunol 8:802–815

    Article  CAS  PubMed  Google Scholar 

  39. Li A, Glass C (2002) The macrophage foam cell as a target for therapeutic intervention. Nat Med 8:1235–1242

    Article  CAS  PubMed  Google Scholar 

  40. Shashkin P, Dragulev B, Ley K (2005) Macrophage differentiation to foam cells. Curr Pharm Des 11:3061–3072

    Article  CAS  PubMed  Google Scholar 

  41. Halvorsen B, Otterdal K, Dahl T, Skjelland M, Gullestad L, Øie E, Aukrust P (2008) Atherosclerotic plaque stability—what determines the fate of a plaque? Prog Cardiovasc Dis 51:183–194

    Google Scholar 

  42. Newby A (2007) Metalloproteinases and vulnerable atherosclerotic plaques. Trends Cardiovasc Med 17:253–258

    Article  CAS  PubMed  Google Scholar 

  43. Raffetto J, Khalil R (2008) Matrix metalloproteases and their inhibitors in vascular remodeling and vascular disease. Biochem Pharmacol 75:346–359

    Article  CAS  PubMed  Google Scholar 

  44. Galis Z, Sukhova G, Lark M, Libby P (1994) Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J Clin Invest 94:2493–2503

    Article  CAS  PubMed  Google Scholar 

  45. Wågsäter D, Björk H, Zhu C, Björkegren J, Valen G, Hamsten A, Eriksson P (2008) ADAMTS-4 and -8 are inflammatory regulated enzymes expressed in macrophage-rich areas of human atherosclerotic plaques. Atherosclerosis 196:514–522

    Article  PubMed  Google Scholar 

  46. Malemud C (2006) Matrix metalloproteinases (MMPs) in health and disease: an overview. Front Biosci 11:1696–1701

    Article  CAS  PubMed  Google Scholar 

  47. Worley J, Baugh M, Hughes D, Edwards D, Hogan A, Sampson M, Gavrilovic J (2003) Metalloproteinase expression in PMA-stimulated THP-1 cells. Effects of peroxisome proliferator-activated receptor-gamma (PPAR gamma) agonists and 9-cis-retinoic acid. J Biol Chem 278:51340–51346

    Article  CAS  PubMed  Google Scholar 

  48. Whatling C, Björk H, Gredmark S, Hamsten A, Eriksson P (2004) Effect of macrophage differentiation and exposure to mildly oxidised LDL on the proteolytic repertoire of THP-1 monocytes. J Lipid Res 45:1768–1776

    Article  CAS  PubMed  Google Scholar 

  49. Jönsson-Rylander A, Nilsson T, Fritsche-Danielson R, Hammarström A, Behrendt M, Andersson J, Lindgren K, Andersson A, Wallbrandt P, Rosengren B, Brodin P, Thelin A, Westin A, Hurt-Camejo E, Lee-Søgaard C (2005) Role of ADAMTS-1 in atherosclerosis: Remodeling of carotid artery, immunohistochemistry, and proteolysis of Versican. Arterioscler Thromb Vasc Biol 25:180–185

    PubMed  Google Scholar 

  50. Norata G, Björk H, Hamsten A, Catapano A, Eriksson P (2004) High-density lipoprotein subfraction 3 decreases ADAMTS-1 expression induced by lipopolysaccharide and tumor necrosis factor-alpha in human endothelial cells. Matrix Biol 22:557–560

    Article  CAS  PubMed  Google Scholar 

  51. Luque A, Carpizo D, Iruela-Arispe M (2003) ADAMTS-1/METH-1 inhibits endothelial cell proliferation by direct binding and sequestration of VEGF 165. J Biol Chem 278:23656–23665

    Article  CAS  PubMed  Google Scholar 

  52. Xu Z, Yu Y, Duh E (2006) Vascular endothelial growth factor upregulates expression of ADAMTS1 in endothelial cells through protein kinase C signaling. Invest Opthalmol Vis Sci 47:4059–4066

    Article  Google Scholar 

  53. Hatipoglu O, Hirohata S, Cilek M, Ogawa H, Miyoshi T, Obika M, Demircan K, Shinohata R, Kusachi S, Ninomiya Y (2009) ADAMTS1 is a unique hypoxic early response gene expressed by endothelial cells. J Biol Chem 284:16325–16333

    Article  CAS  PubMed  Google Scholar 

  54. Bongrazio M, Baumann C, Zakrzewicz A, Pries A, Gaehtgens P (2000) Evidence for modulation of genes involved in vascular adaptation by prolonged exposure of endothelial cells to shear stress. Cardiovasc Res 47:384–393

    Article  CAS  PubMed  Google Scholar 

  55. Lemire J, Chan C, Bressler S, Miller J, LeBaron R, Wight T (2007) Interleukin-1beta selectively decreases the synthesis of versican by arterial smooth muscle cells. J Cell Biochem 101:753–766

    Article  CAS  PubMed  Google Scholar 

  56. Kenagy R, Fischer J, Lara S, Sandy J, Clowes A, Wight T (2005) Accumulation and loss of extracellular matrix during shear stress-mediated intimal growth and regression in baboon vascular grafts. J Histochem Cytochem 53:131–140

    Article  CAS  PubMed  Google Scholar 

  57. Sandy J, Westling J, Kenagy R, Iruela-Arispe M, Verscharen C, Rodriguez-Mazaneque J, Zimmermann D, Lemire J, Fischer J, Wight T, Clowes A (2001) Versican V1 proteolysis in human aorta in vivo occurs at the Glu441–Ala442 bond, a site that is cleaved by recombinant ADAMTS-1 and ADAMTS-4. J Biol Chem 276:13372–13378

    Article  CAS  PubMed  Google Scholar 

  58. Wight T (2002) Versican: a versatile extracellular matrix proteoglycan in cell biology. Curr Opin Cell Biol 14:617–623

    Article  CAS  PubMed  Google Scholar 

  59. Rahmani M, Wong B, Ang L, Cheung C, Carthy J, Walinski H, McManus B (2006) Versican: signaling to transcriptional control pathways. Can J Physiol Pharmacol 84:77–92

    Article  CAS  PubMed  Google Scholar 

  60. Kenagy R, Plaas A, Wight T (2006) Versican degradation and vascular disease. Trends Cardiovasc Med 16:209–215

    Article  CAS  PubMed  Google Scholar 

  61. Mazzucato M, Cozzi M, Pradella P, Perissinotto D, Malmstrom A, Morgelin M, Spessotto P, Colombatti A, De Marco L, Perris R (2002) Vascular PG-M/versican variants promote platelet adhesion at low shear rates and cooperate with collagens to induce aggregation. FASEB J 16:1903–1916

    Article  CAS  PubMed  Google Scholar 

  62. Evanko S, Angello J, Wight T (1999) Formation of hyaluronan- and versican-rich pericellular matrix is required for proliferation and migration of vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 19:1004–1013

    CAS  PubMed  Google Scholar 

  63. Evanko S, Johnson P, Braun K, Underhill C, Dudhia J, Wight T (2001) Platelet-derived growth factor stimulates the formation of versican–hyaluronan aggregates and pericellular matrix expansion in arterial smooth muscle cells. Arch Biochem Biophys 394:29–38

    Article  CAS  PubMed  Google Scholar 

  64. Hirose J, Kawashima H, Yoshie O, Tashiro K, Miyasaka M (2001) Versican interacts with chemokines and modulates cellular responses. J Biol Chem 276:5228–5234

    Article  CAS  PubMed  Google Scholar 

  65. Kawashima H, Hirose M, Hirose J, Nagakubo D, Plaas A, Miyasaka M (2000) Binding of a large chondroitin sulfate/dermatan sulfate proteoglycan, v, to L-selectin, P-selectin, and CD44. J Biol Chem 275:35448–35456

    Article  CAS  PubMed  Google Scholar 

  66. Ismail N, Alavi M, Moore S (1994) Lipoprotein–proteoglycan complexes from injured rabbit aortas accelerate lipoprotein uptake by arterial smooth muscle cells. Atherosclerosis 105:79–87

    Article  CAS  PubMed  Google Scholar 

  67. Srinivasan S, Xu J, Vijayagopal P, Radhakrishnamurthy B, Berenson G (1995) Low-density lipoprotein binding affinity of arterial chondroitin sulfate proteoglycan variants modulates cholesteryl ester accumulation in macrophages. Biochim Biophys Acta 1272:61–67

    PubMed  Google Scholar 

  68. Hurt-Camejo E, Camejo G, Rosengren B, López F, Ahlström C, Fager G, Bondjers G (1992) Effect of arterial proteoglycans and glycosaminoglycans on low density lipoprotein oxidation and its uptake by human macrophages and arterial smooth muscle cells. Arterioscler Thromb Vasc Biol 12:569–583

    CAS  Google Scholar 

  69. Llorente-Cortés V, Otero-Viñas M, Hurt-Camejo E, Martínez-González J, Badimon L (2002) Human coronary smooth muscle cells internalize versican-modified LDL through LDL receptor-related protein and LDL receptors. Arterioscler Thromb Vasc Biol 22:387–393

    Article  PubMed  Google Scholar 

  70. Olin K, Potter-Perigo S, Barrett P, Wight T, Chait A (1999) Lipoprotein lipase enhances the binding of native and oxidized low density lipoproteins to versican and biglycan synthesized by cultured arterial smooth muscle cells. J Biol Chem 274:34629–34636

    Article  CAS  PubMed  Google Scholar 

  71. Wang L, Zheng J, Bai X, Liu B, Liu C, Xu Q, Zhu Y (2009) ADAMTS-7 mediates vascular smooth muscle cell migration and neointima formation in balloon-injured rat arteries. Circ Res 104:688–698

    Article  CAS  PubMed  Google Scholar 

  72. Kenagy R, Min S, Clowes A, Sandy J (2009) Cell death-associated ADAMTS4 and versican degradation in vascular tissue. J Histochem Cytochem 57:889–897

    Article  CAS  PubMed  Google Scholar 

  73. Schönherr E, Järveläinen H, Sandell L, Wight T (1991) Effects of platelet-derived growth factor and transforming growth factor-beta 1 on the synthesis of a large versican-like chondroitin sulfate proteoglycan by arterial smooth muscle cells. J Biol Chem 266:17640–17647

    PubMed  Google Scholar 

  74. Evanko S, Raines E, Ross R, Gold L, Wight T (1998) Proteoglycan distribution in lesions of atherosclerosis depends on lesion severity, structural characteristics, and the proximity of platelet-derived growth factor and transforming growth factor-beta. Am J Pathol 152:533–546

    CAS  PubMed  Google Scholar 

  75. Malfait A, Liu R, Ijiri K, Komiya S, Tortorella M (2002) Inhibition of ADAMTS-4 and ADAMTS-5 prevents aggrecan degradation in osteoarthritic cartilage. J Biol Chem 277:22201–22208

    Article  CAS  PubMed  Google Scholar 

  76. Ozbalkan Z, Efe C, Cesur M, Ertek S, Nairoglu N, Berneis K, Rizzo M (2010) An update on the relationships between rheumatoid arthritis and atherosclerosis. Atherosclerosis. doi:10.1016/j.atherosclerosis.2010.03.035

    PubMed  Google Scholar 

Download references

Acknowledgements

Rebecca C. Salter and Tim G. Ashlin were recipients of BBSRC studentships.

Disclosure of potential conflict of interests

The authors declare no conflict of interests related to this study.

Author information

Authors and Affiliations

  1. School of Biosciences, Cardiff University, Museum Avenue, Cardiff, UK, CF10 3AX

    Rebecca C. Salter, Tim G. Ashlin, Alvin P. L. Kwan & Dipak P. Ramji

Authors
  1. Rebecca C. Salter
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tim G. Ashlin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alvin P. L. Kwan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dipak P. Ramji
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dipak P. Ramji.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Salter, R.C., Ashlin, T.G., Kwan, A.P.L. et al. ADAMTS proteases: key roles in atherosclerosis?. J Mol Med 88, 1203–1211 (2010). https://doi.org/10.1007/s00109-010-0654-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-010-0654-x

Keywords

Search

Navigation