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

Research output: Contribution to journalArticle

57 Citations (Scopus)

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
DOIs
Publication statusPublished - Dec 1 2016

Keywords

  • Cartilage
  • Collagenase
  • Endocytosis
  • Extracellular trafficking
  • Matrix metalloproteinases
  • Osteoarthritis

ASJC Scopus subject areas

  • Molecular Biology

Fingerprint Dive into the research topics of 'MMP-13 is constitutively produced in human chondrocytes and co-endocytosed with ADAMTS-5 and TIMP-3 by the endocytic receptor LRP1'. Together they form a unique fingerprint.

  • Cite this

    Yamamoto, K., Okano, H., Miyagawa, W., Visse, R., Shitomi, Y., Santamaria, S., Dudhia, J., Troeberg, L., Strickland, D. K., Hirohata, S., & Nagase, H. (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, 57-73. https://doi.org/10.1016/j.matbio.2016.03.007