Journal Article

Robust Therapeutic Efficacy of Matrix Metalloproteinase-2-Cleavable Fas-1-RGD Peptide Complex in Chronic Inflammatory Arthritis

Kang, Jin Hee, Park, Jae Yong, Kim, In San, Sung, Shijin, Park, Jae Hyung, Jo, Dong-Gyu, Nam, Eon Jeong, Kang, Young Mo, Sa, Keum Hee

2016

Overview

Therapeutic agents that are transformable via introducing cleavable linkage by locally enriched MMP-2 within inflamed synovium would enhance therapeutic efficacy on chronic inflammatory arthritis. Transforming growth factor-β-inducible gene-h3 (βig-h3), which consists of four fas-1 domains and an Arg-Gly-Asp (RGD) motif, intensifies inflammatory processes by facilitating adhesion and migration of fibroblast-like synoviocyte in the pathogenesis of rheumatoid arthritis (RA). The aim of this study was to investigate whether a MMP-2-cleavable peptide complex consisting of a fas-1 domain and an RGD peptide blocks the interaction between βig-h3 and resident cells and leads to the amelioration of inflammatory arthritis. We designed βig-h3-derivatives, including the fourth fas-1 domain truncated for H1 and H2 sequences of mouse (MFK00) and MMP-2-cleavable peptide complex (MFK902). MMP-2 selectivity was examined by treatment with a series of proteases. MFK902 efficacy was determined by the adhesion and migration assay with NIH3T3 cells in vitro and collagen-induced arthritis (CIA) model using male DBA/1J mice in vivo. The mice were treated intraperitoneally with MFK902 at different dosages. MFK902 was specifically cleaved by active MMP-2 in a concentration-dependent manner, and βig-h3-mediated adhesion and migration were more effectively inhibited by MFK902, compared with RGD or MFK00 peptides. The arthritis activity of murine CIA, measured by clinical arthritis index and incidence of arthritic paws, was significantly ameliorated after treatment with all dosages of MFK902 (1, 10, and 30 mg/kg). MFK902 ameliorated histopathologic deterioration and reduced the expression of inflammatory mediators simultaneously with improvement of clinical features. In addition, a favorable safety profile of MFK902 was demonstrated in vivo. The present study revealed that MMP-2-cleavable peptide complex based on βig-h3 structure is a potent and safe therapeutic agent for chronic inflammatory arthritis, thus providing reliable evidence for a MMP-2-cleavable mechanism as a tissue-targeted strategy for treatment of RA.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adhesion / Amino Acid Sequence / Analysis / Angiogenesis / Animals / Arthritis / Arthritis, Experimental - drug therapy / Arthritis, Experimental - metabolism / Arthritis, Experimental - pathology / Biology and Life Sciences / Bone morphogenetic proteins / Cell adhesion & migration / Cell Adhesion - drug effects / Cell migration / Cell Movement - drug effects / Chemical compounds / Chemokine CCL2 - genetics / Chemokine CCL2 - metabolism / Chronic Disease / Cloning / Collagen / Down-Regulation - drug effects / Effectiveness / Enzymes / Extracellular Matrix Proteins - genetics / Extracellular Matrix Proteins - pharmacology / Extracellular Matrix Proteins - therapeutic use / Gelatinase A / Glycine / Growth factors / Health aspects / Immunoglobulins / In vivo methods and tests / Inflammation / Internal medicine / Localization / Male / Matrix metalloproteinase / Matrix Metalloproteinase 2 - metabolism / Matrix metalloproteinases / Medicine / Medicine and Health Sciences / Metalloproteinase / Mice / Mice, Inbred DBA / Microscopy, Fluorescence / Molecular Sequence Data / NIH 3T3 Cells / Pathogenesis / Peptides / Pharmacology / Proteases / Proteins / RANK Ligand - genetics / RANK Ligand - metabolism / Recombinant Fusion Proteins - genetics / Recombinant Fusion Proteins - pharmacology / Recombinant Fusion Proteins - therapeutic use / Recombinant Proteins - biosynthesis / Recombinant Proteins - pharmacology / Recombinant Proteins - therapeutic use / Research and Analysis Methods / Rheumatoid arthritis / Rheumatoid factor / Rheumatology / RNA, Messenger - metabolism / Sequences / Severity of Illness Index / Synovium / Transforming growth factor / Transforming Growth Factor beta - genetics / Transforming Growth Factor beta - pharmacology / Transforming Growth Factor beta - therapeutic use / Transforming growth factor-b / Vascular Cell Adhesion Molecule-1 - genetics / Vascular Cell Adhesion Molecule-1 - metabolism