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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 publication

DOI

10.1016/j.chembiol.2014.07.014

Type

Journal article

Journal

Chemistry & biology

Publication Date

10/2014

Volume

21

Pages

1300 - 1309

Addresses

Arthritis Research UK Centre for Osteoarthritis Pathogenesis, Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford OX3 7FY, UK. Electronic address: linda.troeberg@kennedy.ox.ac.uk.

Keywords

Cartilage, Articular, Extracellular Matrix, Animals, Humans, Mice, Chondroitin Sulfates, Heparitin Sulfate, Tissue Inhibitor of Metalloproteinase-3, Endocytosis, Protein Binding, Kinetics, ADAM Proteins, Heparan Sulfate Proteoglycans, Low Density Lipoprotein Receptor-Related Protein-1