Abstract
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.
Original language | English |
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Pages (from-to) | 1300-1309 |
Number of pages | 10 |
Journal | Chemistry & Biology |
Volume | 21 |
Issue number | 10 |
Early online date | 28 Aug 2014 |
DOIs | |
Publication status | Published - 23 Oct 2014 |
Externally published | Yes |
Keywords
- ADAM Proteins/chemistry
- Animals
- Cartilage, Articular/metabolism
- Chondroitin Sulfates/chemistry
- Endocytosis
- Extracellular Matrix/metabolism
- Heparan Sulfate Proteoglycans/metabolism
- Heparitin Sulfate/chemistry
- Humans
- Kinetics
- Low Density Lipoprotein Receptor-Related Protein-1/chemistry
- Mice
- Protein Binding
- Tissue Inhibitor of Metalloproteinase-3/antagonists & inhibitors
Profiles
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Linda Troeberg
- Norwich Medical School - Associate Professor
- Metabolic Health - Member
- Musculoskeletal Medicine - Member
Person: Research Group Member, Research Centre Member, Academic, Teaching & Research