title: 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 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.
authors.affiliation: University of Melbourne Department of Paediatrics and Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, 3052 Victoria, Australia.
authors.forename: Heather
authors.initials: H
authors.lastname: Stanton
authors.forename: Fraser M
authors.initials: FM
authors.lastname: Rogerson
authors.forename: Charlotte J
authors.initials: CJ
authors.lastname: East
authors.forename: Suzanne B
authors.initials: SB
authors.lastname: Golub
authors.forename: Kate E
authors.initials: KE
authors.lastname: Lawlor
authors.forename: Clare T
authors.initials: CT
authors.lastname: Meeker
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Little
authors.forename: Karena
authors.initials: K
authors.lastname: Last
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Farmer
authors.forename: Ian K
authors.initials: IK
authors.lastname: Campbell
authors.forename: Anne M
authors.initials: AM
authors.lastname: Fourie
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Fosang
mesh_terms: D051722:ADAM Proteins; D000071121:ADAMTS4 Protein; D000071116:ADAMTS5 Protein; D053674:Aggrecans; D000818:Animals; D000941:Antigens / Q000276:immunology; D001168:Arthritis / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002356:Cartilage / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D004195:Disease Models, Animal; D010450:Endopeptidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005838:Genotype; D007375:Interleukin-1 / Q000494:pharmacology; D037181:Lectins, C-Type; D008666:Metalloendopeptidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011348:Procollagen N-Endopeptidase / Q000235:genetics / Q000378:metabolism; D011509:Proteoglycans / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D046509:Tissue Culture Techniques
chemical_list: C508320:Acan protein, mouse; D053674:Aggrecans; D000941:Antigens; D016326:Extracellular Matrix Proteins; D007375:Interleukin-1; D037181:Lectins, C-Type; D011509:Proteoglycans; D012333:RNA, Messenger; D010450:Endopeptidases; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C498489:Adamts5 protein, mouse; D008666:Metalloendopeptidases; D011348:Procollagen N-Endopeptidase; D000071121:ADAMTS4 Protein; C000603918:ADAMTS4 protein, human; C000603919:Adamts4 protein, mouse; C083641:aggrecanase