Open AccessA Matrix Metalloproteinase 1–Cleavable Composite Peptide Derived From Transforming Growth Factor β–Inducible Gene h3 Potently Inhibits Collagen‐Induced Arthritis
Author(s) -
Nam Eon Jeong,
Kang Jin Hee,
Sung Shijin,
Sa Keum Hee,
Kim Kyung Hoon,
Seo Jae Seok,
Kim JongHo,
Han Seung Woo,
Kim In San,
Kang Young Mo
Publication year - 2013
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.37932
Subject(s) - matrix metalloproteinase , proteases , arthritis , peptide , rheumatoid arthritis , transforming growth factor , matrix metalloproteinase 3 , microbiology and biotechnology , metalloproteinase , protease , chemistry , medicine , immunology , cancer research , biology , biochemistry , enzyme
Objective Transforming growth factor β–inducible gene h3 (βIG‐H3), which is abundantly expressed in rheumatoid synovium, and matrix metalloproteinases (MMP) play important roles in the pathogenesis of rheumatoid arthritis (RA). The aim of this study was to determine the therapeutic efficacy of βIG‐H3–derived peptides using MMP‐1–dependent target tissue delivery in chronic inflammatory arthritis. Methods Peptides developed from βIG‐H3 derivatives, including the second and fourth YH peptides, the fourth fas‐1 domain, the fourth fas‐1 domain truncated for H1 and H2 sequences (dhfas‐1), and an MMP‐1– cleavable composite peptide (MFK24), were cloned. We confirmed the specificity of MFK24 cleavage by immunoblot analysis after treatment with different proteases. Results The YH18 peptide in the fourth fas‐1 domain of βIG‐H3 was weakly effective in suppressing arthritis severity in mice with collagen‐induced arthritis (CIA). Treatment with higher‐dose dhfas‐1 (30 mg/kg) showed remarkable efficacy, whereas treatment with a lower dose (10 mg/kg) resulted in only partial improvement. MFK24, a composite peptide consisting of dhfas‐1 and RGD peptide linked by MMP‐1 substrate, was cleaved specifically by MMP‐1. The adhesion and migration of NIH3T3 cells mediated by βIG‐H3 were inhibited by MFK24 at a low concentration. MFK24 suppressed the adhesion of NIH3T3 cells more efficiently compared with murine dhfas‐1 (MFK00) or RGD, either alone or in combination. The therapeutic efficacy of MFK24 in mice with CIA was remarkably enhanced, with consistently reduced expression of inflammatory mediators within joint tissue. Conclusion This proof‐of‐concept study showed that an MMP‐cleavable composite peptide, based on βIG‐H3 derivatives, had markedly improved therapeutic efficacy in chronic inflammatory arthritis, implicating a new expandable strategy for enhancement of the efficacy of 2 different active molecules in RA.