Matrix Metalloproteinase-9 reduces islet amyloid formation by degrading islet amyloid polypeptide

Aston-Mourney, Kathryn, Zraika, Sakeneh, Udayasankar, Jayalakshmi, Subramanian, Shoba L., Green, Pattie S., Kahn, Steve E. and Hull, Rebecca L. 2013, Matrix Metalloproteinase-9 reduces islet amyloid formation by degrading islet amyloid polypeptide, The journal of biological chemistry, vol. 288, no. 5, pp. 3553-3559, doi: 10.1074/jbc.M112.438457.

Attached Files
Name Description MIMEType Size Downloads

Title Matrix Metalloproteinase-9 reduces islet amyloid formation by degrading islet amyloid polypeptide
Author(s) Aston-Mourney, KathrynORCID iD for Aston-Mourney, Kathryn
Zraika, Sakeneh
Udayasankar, Jayalakshmi
Subramanian, Shoba L.
Green, Pattie S.
Kahn, Steve E.
Hull, Rebecca L.
Journal name The journal of biological chemistry
Volume number 288
Issue number 5
Start page 3553
End page 3559
Total pages 7
Publisher American Society for Biochemistry and Molecular Biology
Place of publication Bethesda, Maryland
Publication date 2013-02
ISSN 0021-9258
Keyword(s) alzheimer disease
amyloid deposition
amyloid deposits
amyloid formation
amyloidogenic peptides
Summary Deposition of islet amyloid polypeptide (IAPP) as amyloid is a pathological hallmark of the islet in type 2 diabetes, which is toxic to β-cells. We previously showed that the enzyme neprilysin reduces islet amyloid deposition and thereby reduces β-cell apoptosis, by inhibiting fibril formation. Two other enzymes, matrix metalloproteinase (MMP)-2 and MMP-9, are extracellular gelatinases capable of degrading another amyloidogenic peptide, Aβ, the constituent of amyloid deposits in Alzheimer disease. We therefore investigated whether MMP-2 and MMP-9 play a role in reducing islet amyloid deposition. MMP-2 and MMP-9 mRNA were present in mouse islets but only MMP-9 activity was detectable. In an islet culture model where human IAPP (hIAPP) transgenic mouse islets develop amyloid but nontransgenic islets do not, a broad spectrum MMP inhibitor (GM6001) and an MMP-2/9 inhibitor increased amyloid formation and the resultant β-cell apoptosis. In contrast, a specific MMP-2 inhibitor had no effect on either amyloid deposition or β-cell apoptosis. Mass spectrometry demonstrated that MMP-9 degraded amyloidogenic hIAPP but not nonamyloidogenic mouse IAPP. Thus, MMP-9 constitutes an endogenous islet protease that limits islet amyloid deposition and its toxic effects via degradation of hIAPP. Because islet MMP-9 mRNA levels are decreased in type 2 diabetic subjects, islet MMP-9 activity may also be decreased in human type 2 diabetes, thereby contributing to increased islet amyloid deposition and β-cell loss. Approaches to increase islet MMP-9 activity could reduce or prevent amyloid deposition and its toxic effects in type 2 diabetes.
Language eng
DOI 10.1074/jbc.M112.438457
Field of Research 110107 Metabolic Medicine
Socio Economic Objective 920104 Diabetes
HERDC Research category C1 Refereed article in a scholarly journal
Copyright notice ©2013, American Society for Biochemistry and Molecular Biology
Persistent URL

Document type: Journal Article
Collection: School of Medicine
Connect to link resolver
Unless expressly stated otherwise, the copyright for items in DRO is owned by the author, with all rights reserved.

Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 14 times in TR Web of Science
Scopus Citation Count Cited 17 times in Scopus
Google Scholar Search Google Scholar
Access Statistics: 288 Abstract Views, 7 File Downloads  -  Detailed Statistics
Created: Tue, 14 Jan 2014, 12:51:27 EST by Jane Moschetti

Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact