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ADAMTS-5: the story so far.
A J Fosang1, F M Rogerson, C J East
1University of Melbourne Department of Paediatrics and Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia. amanda.fosang@mcri.edu.au
European Cells & Materials
|February 6, 2008
Summary
ADAMTS-5 is the primary aggrecanase in mouse cartilage, unlike ADAMTS-4. While research is ongoing for humans, ADAMTS-5 shows higher activity and distinct gene regulation compared to ADAMTS-4.
Area of Science:
- Biochemistry
- Molecular Biology
- Rheumatology
Background:
- ADAMTS-5 was recently identified as the main aggrecanase in mouse cartilage, shifting focus from ADAMTS-4.
- The roles of ADAMTS-4 and ADAMTS-5 in human cartilage aggrecanolysis remain debated.
- Limited information was available on ADAMTS-5 regulation, expression, and activity prior to this research.
Purpose of the Study:
- To review and synthesize current data on ADAMTS-5 in cartilage aggrecanolysis.
- To compare the activity, regulation, and expression of ADAMTS-5 and ADAMTS-4.
- To clarify the relative importance of ADAMTS-4 and ADAMTS-5 in human cartilage.
Main Methods:
- In vitro studies utilizing siRNA, neutralizing antibodies, and immunoprecipitation.
- Analysis of ADAMTS-5 and ADAMTS-4 deficient mouse models in experimental arthritis.
- Comparison of recombinant human ADAMTS-5 and ADAMTS-4 activity.
- Investigation of C-terminal processing's effect on enzyme activity.
- Examination of gene regulation and expression patterns in human chondrocytes and synovial fibroblasts.
Main Results:
- ADAMTS-5-deficient mice are protected from cartilage erosion in arthritis models, unlike ADAMTS-4 deficient mice.
- Recombinant human ADAMTS-5 exhibits significantly higher catalytic activity than ADAMTS-4.
- ADAMTS-5 is typically constitutively expressed in human chondrocytes and synovial fibroblasts.
- ADAMTS-4 expression is induced by pro-inflammatory cytokines, contrasting with ADAMTS-5's constitutive expression.
- Enzyme activity for both ADAMTS-4 and ADAMTS-5 is modulated by C-terminal processing.
Conclusions:
- ADAMTS-5 plays a significant role in cartilage aggrecanolysis, potentially more so than ADAMTS-4, especially in pathological conditions.
- The opposing gene regulation patterns of ADAMTS-5 and ADAMTS-4 suggest distinct biological functions.
- Further research is needed to definitively establish ADAMTS-5 as the major aggrecanase in human cartilage, but current evidence strongly supports its critical role.
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