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Impact of matrix metalloproteinases on inhibition of mineralization by fetuin.
MedLine Citation:
PMID:  23058002     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
BACKGROUND AND OBJECTIVE: Human subjects affected by inflammatory diseases, such as periodontitis, may be at increased risk for the development of cardiovascular diseases and calcification of atheromas; however, the potential mechanisms have not been defined. Alpha-2-Heremans Schmid glycoprotein (fetuin A) is an abundant serum glycoprotein of ~49 kDa that inhibits ectopic arterial calcification. We examined whether matrix metalloproteinases (MMPs), which are increased in inflammatory diseases, including periodontitis, bind and degrade fetuin and alter its ability to inhibit calcification in vitro. MATERIAL AND METHODS: Binding and cleavage of fetuin by MMPs were assessed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, in-silico analyses and mass spectrometry. The effects of intact and MMP-degraded human fetuin on mineralization were measured in a cell-free assay. RESULTS: From in-silico analyses and literature review, we found that only MMP-3 (stromelysin) and MMP-7 (matrilysin) were predicted to cleave human fetuin at levels that were physiologically relevant. In-vitro assays showed that MMP-7, and, to a lesser extent, MMP-3, degraded human fetuin in a time- and dose-dependent manner. Fetuin peptides generated by MMP-7 cleavage were identified and sequenced by mass spectrometry; novel cleavage sites were found. Hydroxyapatite mineralization in vitro was strongly inhibited by fetuin (> 1 μm), as was MMP-3-cleaved fetuin, while MMP-7-cleaved fetuin was threefold less effective in blocking mineralization. CONCLUSION: MMP-7 and, to a lesser extent, MMP-3, affect the ability of fetuin to inhibit the formation of hydroxyapatite in vitro. These data suggest that the MMPs increased in inflammatory diseases, such as periodontitis, could affect regulation of mineralization and potentially enhance the risk of calcified atheroma formation.
Authors:
R Schure; K D Costa; R Rezaei; W Lee; C Laschinger; H C Tenenbaum; C A McCulloch
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-10-12
Journal Detail:
Title:  Journal of periodontal research     Volume:  -     ISSN:  1600-0765     ISO Abbreviation:  J. Periodont. Res.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-12     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0055107     Medline TA:  J Periodontal Res     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
© 2012 John Wiley & Sons A/S.
Affiliation:
Discipline of Periodontology, Faculty of Dentistry, University of Toronto, Toronto, ON, Canada.
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