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
N1 - Funding Information:
This work was supported by grants from Arthritis Research UK (20563 and 19466), the Arthritis Research UK Centre for Osteoarthritis Pathogenesis (20205), the Kennedy Trust for Rheumatology Research, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) (AR40994), and the National Heart, Lung and Blood Institute (HL072929, HL114379). The content is solely the responsibility of the authors and does not necessarily represent the official views of NIAMS or NIH.
Funding Information:
This work was supported by grants from Arthritis Research UK ( 20563 and 19466 ), the Arthritis Research UK Centre for Osteoarthritis Pathogenesis ( 20205 ), the Kennedy Trust for Rheumatology Research , and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) ( AR40994 ), and the National Heart, Lung and Blood Institute ( HL072929 , HL114379 ). The content is solely the responsibility of the authors and does not necessarily represent the official views of NIAMS or NIH.
Publisher Copyright:
© 2016 The Authors
PY - 2016/12/1
Y1 - 2016/12/1
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
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U2 - 10.1016/j.matbio.2016.03.007
DO - 10.1016/j.matbio.2016.03.007
M3 - Article
C2 - 27084377
AN - SCOPUS:84963983808
VL - 56
SP - 57
EP - 73
JO - Matrix Biology
JF - Matrix Biology
SN - 0945-053X
ER -
