Document Detail


Evidence of a novel aggrecan-degrading activity in cartilage: Studies of mice deficient in both ADAMTS-4 and ADAMTS-5.
MedLine Citation:
PMID:  18512787     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVE: To characterize aggrecan catabolism and the overall phenotype in mice deficient in both ADAMTS-4 and ADAMTS-5 (TS-4/TS-5 Delta-cat) activity. METHODS: Femoral head cartilage from the joints of TS-4/TS-5 Delta-cat mice and wild-type mice were cultured in vitro, and aggrecan catabolism was stimulated with either interleukin-1alpha (IL-1alpha) or retinoic acid. Total aggrecan release was measured, and aggrecanase activity was examined by Western blotting using neoepitope antibodies for detecting cleavage at EGE 373-374 ALG, SELE 1279-1280 GRG, FREEE 1467-1468 GLG, and AQE 1572-1573 AGEG. Aggrecan catabolism in vivo was examined by Western blotting of cartilage that had been extracted immediately ex vivo. RESULTS: TS-4/TS-5 Delta-cat mice were viable, fertile, and phenotypically normal. TS-4/TS-5 Delta-cat cartilage explants did not release aggrecan in response to IL-1alpha, and there was no detectable increase in aggrecanase neoepitopes. TS-4/TS-5 Delta-cat cartilage explants released aggrecan in response to retinoic acid. There was no retinoic acid-stimulated cleavage at either EGE 373-374 ALG or AQE 1572-1573 AGEG. There was a low level of cleavage at SELE 1279-1280 GRG and major cleavage at FREEE 1467-1468 GLG. Ex vivo, cleavage at FREEE 1467-1468 GLG was substantially reduced, but still present, in TS-4/TS-5 Delta-cat mouse cartilage compared with wild-type mouse cartilage. CONCLUSION: An aggrecanase other than ADAMTS-4 and ADAMTS-5 is expressed in mouse cartilage and is up-regulated by retinoic acid but not IL-1alpha. The novel aggrecanase appears to have different substrate specificity from either ADAMTS-4 or ADAMTS-5, cleaving E-G bonds but not E-A bonds. Neither ADAMTS-4 nor ADAMTS-5 is required for normal skeletal development or aggrecan turnover in cartilage.
Authors:
Fraser M Rogerson; Heather Stanton; Charlotte J East; Suzanne B Golub; Leonie Tutolo; Pamela J Farmer; Amanda J Fosang
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Arthritis and rheumatism     Volume:  58     ISSN:  0004-3591     ISO Abbreviation:  Arthritis Rheum.     Publication Date:  2008 Jun 
Date Detail:
Created Date:  2008-06-19     Completed Date:  2008-07-24     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0370605     Medline TA:  Arthritis Rheum     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1664-73     Citation Subset:  AIM; IM    
Affiliation:
University of Melbourne Department of Paediatrics, and Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia. fraser.rogerson@mcri.edu.au
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MeSH Terms
Descriptor/Qualifier:
ADAM Proteins / deficiency*
Aggrecans / metabolism*
Animals
Blotting, Western
Cartilage / metabolism
Endopeptidases / metabolism*
Femur Head / metabolism
Mice
Mice, Knockout
Procollagen N-Endopeptidase / deficiency*
Chemical
Reg. No./Substance:
0/Aggrecans; EC 3.4.-/Endopeptidases; EC 3.4.24.-/ADAM Proteins; EC 3.4.24.-/Adamts5 protein, mouse; EC 3.4.24.-/aggrecanase-1; EC 3.4.24.14/Procollagen N-Endopeptidase; EC 3.4.99.-/aggrecanase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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