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 language | English |
|---|---|
| Journal | Matrix Biology |
| DOIs | |
| Publication status | Accepted/In press - Mar 1 2016 |
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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 journal › Article
}
TY - JOUR
T1 - MMP-13 is constitutively produced in human chondrocytes and co-endocytosed with ADAMTS-5 and TIMP-3 by the endocytic receptor LRP1
AU - Yamamoto, Kazuhiro
AU - Okano, Hiroshi
AU - Miyagawa, Wakako
AU - Visse, Robert
AU - Shitomi, Yasuyuki
AU - Santamaria, Salvatore
AU - Dudhia, Jayesh
AU - Troeberg, Linda
AU - Strickland, Dudley K.
AU - Hirohata, Satoshi
AU - Nagase, Hideaki
PY - 2016/3/1
Y1 - 2016/3/1
N2 - 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.
AB - 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.
KW - Cartilage
KW - Collagenase
KW - Endocytosis
KW - Extracellular trafficking
KW - Matrix metalloproteinases
KW - Osteoarthritis
UR - http://www.scopus.com/inward/record.url?scp=84963983808&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84963983808&partnerID=8YFLogxK
U2 - 10.1016/j.matbio.2016.03.007
DO - 10.1016/j.matbio.2016.03.007
M3 - Article
JO - Matrix Biology
JF - Matrix Biology
SN - 0945-053X
ER -