A novel cryptic binding motif, LRSKSRSFQVSDEQY, in the C-terminal fragment of MMP-3/7-cleaved osteopontin as a novel ligand for α9β1 integrin is involved in the anti-type II collagen antibody-induced arthritis

Shigeyuki Kon; Yosuke Nakayama; Naoki Matsumoto; Koyu Ito; Masashi Kanayama; Chiemi Kimura; Hitomi Kouro; Dai Ashitomi; Tadashi Matsuda; Toshimitsu Uede

doi:10.1371/journal.pone.0116210

A novel cryptic binding motif, LRSKSRSFQVSDEQY, in the C-terminal fragment of MMP-3/7-cleaved osteopontin as a novel ligand for α9β1 integrin is involved in the anti-type II collagen antibody-induced arthritis

PLoS One. 2014 Dec 29;9(12):e116210. doi: 10.1371/journal.pone.0116210. eCollection 2014.

Authors

Affiliations

¹ Division of Molecular Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan; Department of Immunology, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido, Japan.
² Division of Molecular Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan.
³ Department of Immunology, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido, Japan.

Abstract

Osteopontin (OPN) is a multifunctional protein that has been linked to various intractable inflammatory diseases. One way by which OPN induces inflammation is the production of various functional fragments by enzyme cleavage. It has been well appreciated that OPN is cleaved by thrombin, and/or matrix metalloproteinase-3 and -7 (MMP-3/7). Although the function of thrombin-cleaved OPN is well characterized, little is known about the function of MMP-3/7-cleaved OPN. In this study, we found a novel motif, LRSKSRSFQVSDEQY, in the C-terminal fragment of MMP-3/7-cleaved mouse OPN binds to α9β1 integrin. Importantly, this novel motif is involved in the development of anti-type II collagen antibody-induced arthritis (CAIA). This study provides the first in vitro and in vivo evidence that OPN cleavage by MMP-3/7 is an important regulatory mechanism for CAIA.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Motifs
Amino Acid Sequence
Animals
Antibodies / pharmacology
Arthritis, Experimental / metabolism*
Arthritis, Experimental / pathology
Arthritis, Experimental / prevention & control
CHO Cells
Cell Movement / drug effects
Collagen Type II / immunology*
Cricetinae
Cricetulus
Integrins / metabolism*
Ligands
Matrix Metalloproteinase 3 / metabolism*
Matrix Metalloproteinase 7 / metabolism*
Melanoma, Experimental
Mice
Molecular Sequence Data
NIH 3T3 Cells
Osteopontin / chemistry*
Osteopontin / metabolism*
Peptides / metabolism
Protein Binding / drug effects
Wound Healing / drug effects

Substances

Antibodies
Collagen Type II
Integrins
Ligands
Peptides
integrin alpha 9 beta 1
Osteopontin
Matrix Metalloproteinase 3
Matrix Metalloproteinase 7

Grants and funding

This work was supported in part by research grant from JSPS KAKENHI, Grant Number 24590072, the Akiyama Life Science Foundation, and Suzuken Memorial Foundation to SK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.