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

• Published in: PloS one 2014-12, Vol.9 (12), p.e116210-e116210
• Main Authors: Kon, Shigeyuki, Nakayama, Yosuke, Matsumoto, Naoki, Ito, Koyu, Kanayama, Masashi, Kimura, Chiemi, Kouro, Hitomi, Ashitomi, Dai, Matsuda, Tadashi, Uede, Toshimitsu
• Format: Article
• Language: English
• Subjects: Adhesives; Amino Acid Motifs; Amino Acid Sequence; Animals; Antibodies - pharmacology; Arthritis; Arthritis, Experimental - metabolism; Arthritis, Experimental - pathology; Arthritis, Experimental - prevention & control; Biocompatibility; Biology and Life Sciences; Biomedical materials; Cell adhesion & migration; Cell Movement - drug effects; CHO Cells; Cleavage; Collagen (type II); Collagen Type II - immunology; Cricetinae; Cricetulus; Fragmentation; Immunoglobulins; Immunology; In vivo methods and tests; Inflammatory diseases; Integrins - metabolism; Ligands; Matrix metalloproteinase; Matrix Metalloproteinase 3 - metabolism; Matrix Metalloproteinase 7 - metabolism; Medicine; Melanoma, Experimental; Metalloproteinase; Mice; Molecular Sequence Data; Neutrophils; NIH 3T3 Cells; Osteopontin; Osteopontin - chemistry; Osteopontin - metabolism; Peptides; Peptides - metabolism; Pharmaceutical sciences; Protein Binding - drug effects; Regulatory mechanisms (biology); Stromelysin 1; Thrombin; Wound Healing - drug effects
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0116210

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.