ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro

Abstract

Aggrecan is the major proteoglycan in cartilage, endowing this tissue with the unique capacity to bear load and resist compression. In arthritic cartilage, aggrecan is degraded by one or more ‘aggrecanases’ from the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs1) family of proteinases. ADAMTS1, 8 and 9 have weak aggrecan-degrading activity2,3,4,5. However, they are not thought to be the primary aggrecanases because ADAMTS1 null mice are not protected from experimental arthritis6, and cleavage by ADAMTS8 and 9 is highly inefficient. Although ADAMTS4 and 5 are expressed in joint tissues7,8,9,10,11,12,13, and are known to be efficient aggrecanases in vitro, the exact contribution of these two enzymes to cartilage pathology is unknown. Here we show that ADAMTS5 is the major aggrecanase in mouse cartilage, both in vitro and in a mouse model of inflammatory arthritis. Our data suggest that ADAMTS5 may be a suitable target for the development of new drugs designed to inhibit cartilage destruction in arthritis, although further work will be required to determine whether ADAMTS5 is also the major aggrecanase in human arthritis.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Generation of the ADAMTS4 and ADAMTS5 Δ-cat mice.
Figure 2: IL-1α stimulation of aggrecan release in cartilage explant cultures.
Figure 3: Antigen-induced arthritis in control and ADAMTS5-deficient mice.

References

  1. 1

    Kuno, K. et al. 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 (1997)

    CAS  Article  Google Scholar 

  2. 2

    Kuno, K. et al. ADAMTS-1 cleaves a cartilage proteoglycan, aggrecan. FEBS Lett. 478, 241–245 (2000)

    CAS  Article  Google Scholar 

  3. 3

    Rodriguez-Manzaneque, J. C. et al. ADAMTS1 cleaves aggrecan at multiple sites and is differentially inhibited by metalloproteinase inhibitors. Biochem. Biophys. Res. Commun 293, 501–508 (2002)

    CAS  Article  Google Scholar 

  4. 4

    Somerville, R. P. et al. Characterization of ADAMTS-9 and ADAMTS-20 as a distinct ADAMTS subfamily related to Caenorhabditis elegans GON-1. J. Biol. Chem. 278, 9503–9513 (2003)

    CAS  Article  Google Scholar 

  5. 5

    Collins-Racie, L. A. et al. ADAMTS-8 exhibits aggrecanase activity and is expressed in human articular cartilage. Matrix Biol. 23, 219–230 (2004)

    CAS  Article  Google Scholar 

  6. 6

    Little, C. B. et al. ADAMTS-1 knockout mice do not exhibit abnormalities in aggrecan turnover in vitro or in vivo . Arthritis Rheum. (in the press)

  7. 7

    Abbaszade, I. et al. Cloning and characterization of ADAMTS11, an aggrecanase from the ADAMTS family. J. Biol. Chem. 274, 23443–23450 (1999)

    CAS  Article  Google Scholar 

  8. 8

    Tortorella, M. D., Malfait, A. M., Deccico, C. & Arner, E. The role of ADAM-TS4 (aggrecanase-1) and ADAM-TS5 (aggrecanase-2) in a model of cartilage degradation. Osteoarthritis Cartilage 9, 539–552 (2001)

    CAS  Article  Google Scholar 

  9. 9

    Vankemmelbeke, M. N. et al. Expression and activity of ADAMTS-5 in synovium. Eur. J. Biochem. 268, 1259–1268 (2001)

    CAS  Article  Google Scholar 

  10. 10

    Yamanishi, Y. et al. Expression and regulation of aggrecanase in arthritis: the role of TGF-β. J. Immunol. 168, 1405–1412 (2002)

    CAS  Article  Google Scholar 

  11. 11

    Ilic, M. Z. et al. Bovine joint capsule and fibroblasts derived from joint capsule express aggrecanase activity. Matrix Biol. 19, 257–265 (2000)

    CAS  Article  Google Scholar 

  12. 12

    Bau, B. et al. Relative messenger RNA expression profiling of collagenases and aggrecanases in human articular chondrocytes in vivo and in vitro . Arthritis Rheum. 46, 2648–2657 (2002)

    CAS  Article  Google Scholar 

  13. 13

    Koshy, P. J. et al. The modulation of matrix metalloproteinase and ADAM gene expression in human chondrocytes by interleukin-1 and oncostatin M: A time-course study using real-time quantitative reverse transcription-polymerase chain reaction. Arthritis Rheum. 46, 961–967 (2002)

    CAS  Article  Google Scholar 

  14. 14

    Schwenk, F., Baron, U. & Rajewsky, K. A cre-transgenic mouse strain for the ubiquitous deletion of loxP-flanked gene segments including deletion in germ cells. Nucleic Acids Res. 23, 5080–5081 (1995)

    CAS  Article  Google Scholar 

  15. 15

    Mendell, J. T., Sharifi, N. A., Meyers, J. L., Martinez-Murillo, F. & Dietz, H. C. Nonsense surveillance regulates expression of diverse classes of mammalian transcripts and mutes genomic noise. Nature Genet. 36, 1073–1078 (2004)

    CAS  Article  Google Scholar 

  16. 16

    Glasson, S. S. et al. Characterization of and osteoarthritis susceptibility in ADAMTS-4-knockout mice. Arthritis Rheum. 50, 2547–2558 (2004)

    CAS  Article  Google Scholar 

  17. 17

    van Meurs, J. B. et al. Increased vulnerability of postarthritic cartilage to a second arthritic insult: accelerated MMP activity in a flare up of arthritis. Ann. Rheum. Dis. 58, 350–356 (1999)

    CAS  Article  Google Scholar 

  18. 18

    van Meurs, J. B. et al. Kinetics of aggrecanase- and metalloproteinase-induced neoepitopes in various stages of cartilage destruction in murine arthritis. Arthritis Rheum. 42, 1128–1139 (1999)

    CAS  Article  Google Scholar 

  19. 19

    van Meurs, J. B. et al. Interleukin-1 receptor antagonist prevents expression of the metalloproteinase-generated neoepitope VDIPEN in antigen-induced arthritis. Arthritis Rheum. 41, 647–656 (1998)

    CAS  Article  Google Scholar 

  20. 20

    Kevorkian, L. et al. Expression profiling of metalloproteinases and their inhibitors in cartilage. Arthritis Rheum. 50, 131–141 (2004)

    CAS  Article  Google Scholar 

  21. 21

    Farndale, R. W., Sayers, C. A. & Barrett, A. J. A direct spectrophotometric microassay for sulfated glycosaminoglycans in cartilage cultures. Connect. Tissue Res. 9, 247–248 (1982)

    CAS  Article  Google Scholar 

  22. 22

    Pfaffl, M. W. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 29, e45 (2001)

    CAS  Article  Google Scholar 

  23. 23

    Mould, A. W. et al. Vegfb gene knockout mice display reduced pathology and synovial angiogenesis in both antigen-induced and collagen-induced models of arthritis. Arthritis Rheum. 48, 2660–2669 (2003)

    CAS  Article  Google Scholar 

  24. 24

    Glant, T. T. et al. Cartilage-specific constitutive expression of TSG-6 protein (product of tumor necrosis factor α-stimulated gene 6) provides a chondroprotective, but not antiinflammatory, effect in antigen-induced arthritis. Arthritis Rheum. 46, 2207–2218 (2002)

    CAS  Article  Google Scholar 

Download references

Acknowledgements

The authors are grateful to Johnson & Johnson Pharmaceutical Research and Development (San Diego) for donating the floxed mice. We thank E. Arner and M. Tortorella for providing the anti-AGEG antibody. We also gratefully acknowledge the mouse husbandry support provided by the Disease Models Unit of the Murdoch Childrens Research Institute. The work was funded by the National Health and Medical Research Council (Australia), and the Murdoch Childrens Research Institute.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Amanda J. Fosang.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Stanton, H., Rogerson, F., East, C. et al. ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro. Nature 434, 648–652 (2005). https://doi.org/10.1038/nature03417

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.