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

Heather Stanton; Fraser M Rogerson; Charlotte J East; Suzanne B Golub; Kate E Lawlor; Clare T Meeker; Christopher B Little; Karena Last; Pamela J Farmer; Ian K Campbell; Anne M Fourie; Amanda J Fosang

doi:10.1038/nature03417

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

Nature. 2005 Mar 31;434(7033):648-52. doi: 10.1038/nature03417.

Authors

Heather Stanton¹, Fraser M Rogerson, Charlotte J East, Suzanne B Golub, Kate E Lawlor, Clare T Meeker, Christopher B Little, Karena Last, Pamela J Farmer, Ian K Campbell, Anne M Fourie, Amanda J Fosang

Affiliation

¹ University of Melbourne Department of Paediatrics and Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, 3052 Victoria, Australia.

PMID: 15800625
DOI: 10.1038/nature03417

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 motifs) family of proteinases. ADAMTS1, 8 and 9 have weak aggrecan-degrading activity. However, they are not thought to be the primary aggrecanases because ADAMTS1 null mice are not protected from experimental arthritis, and cleavage by ADAMTS8 and 9 is highly inefficient. Although ADAMTS4 and 5 are expressed in joint tissues, 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ADAM Proteins
ADAMTS4 Protein
ADAMTS5 Protein
Aggrecans
Animals
Antigens / immunology
Arthritis / enzymology
Arthritis / genetics
Arthritis / immunology
Arthritis / metabolism
Cartilage / drug effects
Cartilage / enzymology*
Cartilage / metabolism
Disease Models, Animal
Endopeptidases / deficiency
Endopeptidases / genetics
Endopeptidases / metabolism*
Extracellular Matrix Proteins / metabolism
Genotype
Interleukin-1 / pharmacology
Lectins, C-Type
Metalloendopeptidases / deficiency
Metalloendopeptidases / genetics
Metalloendopeptidases / metabolism*
Mice
Mice, Knockout
Procollagen N-Endopeptidase / genetics
Procollagen N-Endopeptidase / metabolism
Proteoglycans / metabolism
RNA, Messenger / genetics
RNA, Messenger / metabolism
Reverse Transcriptase Polymerase Chain Reaction
Tissue Culture Techniques

Substances

Acan protein, mouse
Aggrecans
Antigens
Extracellular Matrix Proteins
Interleukin-1
Lectins, C-Type
Proteoglycans
RNA, Messenger
Endopeptidases
ADAM Proteins
ADAMTS5 Protein
Adamts5 protein, mouse
Metalloendopeptidases
Procollagen N-Endopeptidase
ADAMTS4 Protein
ADAMTS4 protein, human
Adamts4 protein, mouse
aggrecanase