title: Sulfated glycosaminoglycans control the extracellular trafficking and the activity of the metalloprotease inhibitor TIMP-3.
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.
authors.affiliation: 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.
authors.forename: Linda
authors.initials: L
authors.lastname: Troeberg
authors.affiliation: Arthritis Research UK Centre for Osteoarthritis Pathogenesis, Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford OX3 7FY, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Lazenbatt
authors.affiliation: Aichi Medical University Research Complex for Medicine Frontiers, Aichi Medical University, Nagakute, Aichi 480-1195, Japan.
authors.forename: Md Ferdous
authors.initials: MF
authors.lastname: Anower-E-Khuda
authors.affiliation: Division of Immunology and Genetics, John Curtin School of Medical Research, Australian National University, Canberra ACT 2601, Australia.
authors.forename: Craig
authors.initials: C
authors.lastname: Freeman
authors.affiliation: Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7FZ, UK.
authors.forename: Oleg
authors.initials: O
authors.lastname: Federov
authors.affiliation: Advanced Medical Research Centre, Aichi Medical University, Nagakute, Aichi 480-1195, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Habuchi
authors.affiliation: Advanced Medical Research Centre, Aichi Medical University, Nagakute, Aichi 480-1195, Japan.
authors.forename: Osami
authors.initials: O
authors.lastname: Habuchi
authors.affiliation: Aichi Medical University Research Complex for Medicine Frontiers, Aichi Medical University, Nagakute, Aichi 480-1195, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Kimata
authors.affiliation: Arthritis Research UK Centre for Osteoarthritis Pathogenesis, Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Oxford OX3 7FY, UK.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Nagase
mesh_terms: D051722:ADAM Proteins / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D002358:Cartilage, Articular / Q000378:metabolism; D002809:Chondroitin Sulfates / Q000737:chemistry / Q000378:metabolism*; D004705:Endocytosis; D005109:Extracellular Matrix / Q000378:metabolism; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D006497:Heparan Sulfate / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D011485:Protein Binding; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D051722:ADAM Proteins; D002809:Chondroitin Sulfates; D019812:Heparan Sulfate Proteoglycans; D006497:Heparan Sulfate; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D019717:Tissue Inhibitor of Metalloproteinase-3; C038142:chondroitin sulfate glycosaminoglycan; C071927:perlecan