MMP-13 is constitutively produced in human chondrocytes and co-endocytosed with ADAMTS-5 and TIMP-3 by the endocytic receptor LRP1

Yamamoto, Kazuhiro, Okano, Hiroshi, Miyagawa, Wakako, Visse, Robert, Shitomi, Yasuyuki, Santamaria, Salvatore, Dudhia, Jayesh, Troeberg, Linda, Strickland, Dudley K, Hirohata, Satoshi and Nagase, Hideaki (2016) MMP-13 is constitutively produced in human chondrocytes and co-endocytosed with ADAMTS-5 and TIMP-3 by the endocytic receptor LRP1. Matrix Biology, 56. pp. 57-73. ISSN 0945-053X

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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.

Item Type: Article
Additional Information: Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.
Uncontrolled Keywords: chemistry,binding, competitive,enzymology,endocytosis,hek293 cells,humans,chemistry,chemistry,protein binding,protein interaction domains and motifs,protein transport,chemistry
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
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Depositing User: LivePure Connector
Date Deposited: 09 Jan 2019 12:30
Last Modified: 18 Mar 2020 02:25
URI: https://ueaeprints.uea.ac.uk/id/eprint/69502
DOI: 10.1016/j.matbio.2016.03.007

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