title: MMP-13 is constitutively produced in human chondrocytes and co-endocytosed with ADAMTS-5 and TIMP-3 by the endocytic receptor LRP1.
abstract: Matrix metalloproteinase 13 (MMP-13) degrades collagenous extracellular matrix and its aberrant activity associates with diseases such as arthritis, cancer, atherosclerosis and fibrosis. The wide range of MMP-13 proteolytic capacity suggests that it is a powerful, potentially destructive proteinase and thus it has been believed that MMP-13 is not produced in most adult human tissues in the steady state. Present study has revealed that human chondrocytes isolated from healthy adults constitutively express and secrete MMP-13, but that it is rapidly endocytosed and degraded by chondrocytes. Both pro- and activated MMP-13 bind to clusters II and III of low-density lipoprotein (LDL) receptor-related protein 1 (LRP1). Domain deletion studies indicated that the hemopexin domain is responsible for this interaction. Binding competition between MMP-13 and ADAMTS-4, -5 or TIMP-3, which also bind to cluster II, further shown that the MMP-13 binding site within cluster II is different from those of ADAMTS-4, -5 or TIMP-3. MMP-13 is therefore co-endocytosed with ADAMTS-5 and TIMP-3 by human chondrocytes. These findings indicate that MMP-13 may play a role on physiological turnover of cartilage extracellular matrix and that LRP1 is a key modulator of extracellular levels of MMP-13 and its internalization is independent of the levels of ADAMTS-4, -5 and TIMP-3.
authors.affiliation: Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford, UK. Electronic address: kazuhiro.yamamoto@kennedy.ox.ac.uk.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford, UK; Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Okano
authors.affiliation: Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford, UK; Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Wakako
authors.initials: W
authors.lastname: Miyagawa
authors.affiliation: Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Visse
authors.affiliation: Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Shitomi
authors.affiliation: Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Santamaria
authors.affiliation: Department of Clinical Sciences and Services, Royal Veterinary College, Herts, UK.
authors.forename: Jayesh
authors.initials: J
authors.lastname: Dudhia
authors.affiliation: Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
authors.forename: Linda
authors.initials: L
authors.lastname: Troeberg
authors.affiliation: Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, USA.
authors.forename: Dudley K
authors.initials: DK
authors.lastname: Strickland
authors.affiliation: Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hirohata
authors.affiliation: Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Nagase
mesh_terms: D000071116:ADAMTS5 Protein / Q000737:chemistry / Q000378:metabolism*; D001667:Binding, Competitive; D019902:Chondrocytes / Q000201:enzymology*; D004705:Endocytosis; D057809:HEK293 Cells; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000737:chemistry / Q000378:metabolism*; D053509:Matrix Metalloproteinase 13 / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D021381:Protein Transport; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000737:chemistry / Q000378:metabolism*
chemical_list: C475476:LRP1 protein, human; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3; D000071116:ADAMTS5 Protein; C121532:ADAMTS5 protein, human; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13
keywords: Cartilage; Collagenase; Endocytosis; Extracellular trafficking; Matrix metalloproteinases; Osteoarthritis