Document Detail

Modified expression of the ADAMTS enzymes and tissue inhibitor of metalloproteinases 3 during human intervertebral disc degeneration.
MedLine Citation:
PMID:  19180493     Owner:  NLM     Status:  MEDLINE    
OBJECTIVE: Intervertebral disc degeneration is linked to loss of extracellular matrix (ECM), particularly the early loss of aggrecan. A group of metalloproteinases called aggrecanases are important mediators of aggrecan turnover. The present study was undertaken to investigate the expression of the recognized aggrecanases and their inhibitor, tissue inhibitor of metalloproteinases 3 (TIMP-3), in human intervertebral disc tissue.
METHODS: Twenty-four nondegenerated and 30 degenerated disc samples were analyzed for absolute messenger RNA (mRNA) copy number of ADAMTS 1, 4, 5, 8, 9, and 15 and TIMP-3 by real-time reverse transcription-polymerase chain reaction. Thirty-six formalin-fixed embedded intervertebral disc samples of varying grades of degeneration were used for immunohistochemical analyses. In addition, samples from 8 subjects were analyzed for the presence of matrix metalloproteinase (MMP)- and aggrecanase-generated aggrecan products.
RESULTS: Messenger RNA for all the aggrecanases other than ADAMTS-8 was identified in intervertebral disc tissue, as was mRNA for TIMP-3. Levels of mRNA expression of ADAMTS 1, 4, 5, and 15 were significantly increased in degenerated tissue compared with nondegenerated tissue. All these aggrecanases and TIMP-3 were also detected immunohistochemically in disc tissue, and numbers of nucleus pulposus cells staining positive for ADAMTS 4, 5, 9, and 15 were significantly increased in degenerated tissue compared with nondegenerated tissue. Aggrecan breakdown products generated by MMP and aggrecanase activities were also detected in intervertebral disc tissue.
CONCLUSION: The aggrecanases ADAMTS 1, 4, 5, 9, and 15 may contribute to the changes occurring in the ECM during intervertebral disc degeneration. Targeting these enzymes may be a possible future therapeutic strategy for the prevention of intervertebral disc degeneration and its associated morbidity.
Aneta J Pockert; Stephen M Richardson; Christine L Le Maitre; Malcolm Lyon; Jonathan A Deakin; David J Buttle; Anthony J Freemont; Judith A Hoyland
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Arthritis and rheumatism     Volume:  60     ISSN:  0004-3591     ISO Abbreviation:  Arthritis Rheum.     Publication Date:  2009 Feb 
Date Detail:
Created Date:  2009-02-09     Completed Date:  2009-04-01     Revised Date:  2011-12-01    
Medline Journal Info:
Nlm Unique ID:  0370605     Medline TA:  Arthritis Rheum     Country:  United States    
Other Details:
Languages:  eng     Pagination:  482-91     Citation Subset:  AIM; IM    
University of Manchester, Manchester, UK.
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MeSH Terms
ADAM Proteins / genetics*,  metabolism
Aggrecans / metabolism
Biological Markers / metabolism
Cartilage, Articular / metabolism
Gene Dosage
Gene Expression*
Intervertebral Disc / metabolism,  pathology
Intervertebral Disc Displacement / genetics*,  metabolism,  pathology
Middle Aged
RNA, Messenger / metabolism
RNA, Ribosomal
Tissue Inhibitor of Metalloproteinase-3 / genetics*,  metabolism
Grant Support
15966//Arthritis Research UK
Reg. No./Substance:
0/Aggrecans; 0/Biological Markers; 0/RNA, Messenger; 0/RNA, Ribosomal; 0/TIMP3 protein, human; 0/Tissue Inhibitor of Metalloproteinase-3; EC 3.4.24.-/ADAM Proteins; EC 3.4.24.-/ADAMTS1 protein, human

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