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

36 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
JournalMatrix Biology
DOIs
Publication statusAccepted/In press - Mar 1 2016

Fingerprint

Tissue Inhibitor of Metalloproteinase-3
Low Density Lipoprotein Receptor-Related Protein-1
Matrix Metalloproteinase 13
Chondrocytes
Endocytosis
Extracellular Matrix
Hemopexin
Arthritis
Cartilage
Atherosclerosis
Fibrosis
Peptide Hydrolases
Binding Sites

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology

Cite this

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; Nagase, Hideaki.

In: Matrix Biology, 01.03.2016.

Research output: Contribution to journalArticle

Yamamoto, K, Okano, H, Miyagawa, W, Visse, R, Shitomi, Y, Santamaria, S, Dudhia, J, Troeberg, L, Strickland, DK, 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. https://doi.org/10.1016/j.matbio.2016.03.007
Yamamoto, Kazuhiro ; Okano, Hiroshi ; Miyagawa, Wakako ; Visse, Robert ; Shitomi, Yasuyuki ; Santamaria, Salvatore ; Dudhia, Jayesh ; Troeberg, Linda ; Strickland, Dudley K. ; Hirohata, Satoshi ; Nagase, Hideaki. / MMP-13 is constitutively produced in human chondrocytes and co-endocytosed with ADAMTS-5 and TIMP-3 by the endocytic receptor LRP1. In: Matrix Biology. 2016.
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AU - Visse, Robert

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AU - Santamaria, Salvatore

AU - Dudhia, Jayesh

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