Sulfated glycosaminoglycans control the extracellular trafficking and the activity of the metalloprotease inhibitor timp-3
Date
2014
Authors
Troeberg, Linda
Lazenbatt, Christopher
Anower-E-Khuda, Md. Ferdous
Freeman, Craig
Federov, Oleg
Habuchi, Hiroko
Habuchi, Osami
Kimata, Koji
Nagase, Hideaki
Journal Title
Journal ISSN
Volume Title
Publisher
Elsevier
Abstract
Summary Tissue inhibitor of metalloproteinase 3 (TIMP-3) is an important regulator of extracellular matrix (ECM) turnover. TIMP-3 binds to sulfated ECM glycosaminoglycans or is endocytosed by cells via low-density lipoprotein receptor-related protein 1 (LRP-1). Here, we report that heparan sulfate (HS) and chondroitin sulfate E (CSE) selectively regulate postsecretory trafficking of TIMP-3 by inhibiting its binding to LRP-1. HS and CSE also increased TIMP-3 affinity for glycan-binding metalloproteinases, such as adamalysin-like metalloproteinase with thrombospondin motifs 5 (ADAMTS-5), by reducing the dissociation rate constants. The sulfation pattern was crucial for these activities because monosulfated or truncated heparin had a reduced ability to bind to TIMP-3 and increase its affinity for ADAMTS-5. Therefore, sulfation of ECM glycans regulates the levels and inhibitory activity of TIMP-3 and modulates ECM turnover, and small mimicries of sulfated glycans may protect the tissue from the excess destruction seen in diseases such as osteoarthritis, cancer, and atherosclerosis.
Description
Keywords
Citation
Collections
Source
Chemistry and Biology
Type
Journal article
Book Title
Entity type
Access Statement
License Rights
Restricted until
2037-12-31
Downloads
File
Description