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.
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
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)
Kuno, K. et al. ADAMTS-1 cleaves a cartilage proteoglycan, aggrecan. FEBS Lett. 478, 241–245 (2000)
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)
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)
Collins-Racie, L. A. et al. ADAMTS-8 exhibits aggrecanase activity and is expressed in human articular cartilage. Matrix Biol. 23, 219–230 (2004)
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)
Abbaszade, I. et al. Cloning and characterization of ADAMTS11, an aggrecanase from the ADAMTS family. J. Biol. Chem. 274, 23443–23450 (1999)
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)
Vankemmelbeke, M. N. et al. Expression and activity of ADAMTS-5 in synovium. Eur. J. Biochem. 268, 1259–1268 (2001)
Yamanishi, Y. et al. Expression and regulation of aggrecanase in arthritis: the role of TGF-β. J. Immunol. 168, 1405–1412 (2002)
Ilic, M. Z. et al. Bovine joint capsule and fibroblasts derived from joint capsule express aggrecanase activity. Matrix Biol. 19, 257–265 (2000)
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)
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)
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)
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)
Glasson, S. S. et al. Characterization of and osteoarthritis susceptibility in ADAMTS-4-knockout mice. Arthritis Rheum. 50, 2547–2558 (2004)
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)
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)
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)
Kevorkian, L. et al. Expression profiling of metalloproteinases and their inhibitors in cartilage. Arthritis Rheum. 50, 131–141 (2004)
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)
Pfaffl, M. W. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 29, e45 (2001)
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)
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)
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.
The authors declare that they have no competing financial interests.
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
International Journal of Experimental Pathology (2020)
The gene expression and protein profiles of ADAMTS and TIMP in human chondrosarcoma cell lines induced by insulin: The potential mechanisms for skeletal and articular abnormalities in diabetes
Electronic Journal of General Medicine (2020)
Expression Levels of A Disintegrin-like Metalloproteinase with Thrombospondin Motifs-4 and -5 (ADAMTS-4 and ADAMTS-5) in Inflamed and Healthy Gingival Tissues
Combinatorial Chemistry & High Throughput Screening (2020)
Scientific Reports (2020)
Are serum levels of ADAMTS5, TAS and TOS at 24–28 gestational weeks associated with adverse perinatal outcomes in gestational diabetic women?
Journal of Obstetrics and Gynaecology (2020)