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

Kazuhiro Yamamoto, Hiroshi Okano, Wakako Miyagawa, Robert Visse, Yasuyuki Shitomi, Salvatore Santamaria, Jayesh Dudhia, Linda Troeberg, Dudley K Strickland, Satoshi Hirohata, Hideaki Nagase

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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.

Original languageEnglish
Pages (from-to)57-73
Number of pages17
JournalMatrix Biology
Volume56
Early online date12 Apr 2016
DOIs
Publication statusPublished - Dec 2016

Keywords

  • ADAMTS5 Protein/chemistry
  • Binding, Competitive
  • Chondrocytes/enzymology
  • Endocytosis
  • HEK293 Cells
  • Humans
  • Low Density Lipoprotein Receptor-Related Protein-1/chemistry
  • Matrix Metalloproteinase 13/chemistry
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein Transport
  • Tissue Inhibitor of Metalloproteinase-3/chemistry

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