title: Robust Therapeutic Efficacy of Matrix Metalloproteinase-2-Cleavable Fas-1-RGD Peptide Complex in Chronic Inflammatory Arthritis.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Kyungpook National University, School of Medicine, 680 Gukchaebosang-ro, Junggu, Daegu 41944, South Korea.|Cell and Matrix Research Institute, Kyungpook National University School of Medicine, 680 Gukchaebosang-ro, Junggu, Daegu 41944, South Korea.
authors.forename: Eon Jeong
authors.initials: EJ
authors.lastname: Nam
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Kyungpook National University, School of Medicine, 680 Gukchaebosang-ro, Junggu, Daegu 41944, South Korea.
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Kang
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Kyungpook National University, School of Medicine, 680 Gukchaebosang-ro, Junggu, Daegu 41944, South Korea.
authors.forename: Keum Hee
authors.initials: KH
authors.lastname: Sa
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Kyungpook National University, School of Medicine, 680 Gukchaebosang-ro, Junggu, Daegu 41944, South Korea.
authors.forename: Shijin
authors.initials: S
authors.lastname: Sung
authors.affiliation: Cell and Matrix Research Institute, Kyungpook National University School of Medicine, 680 Gukchaebosang-ro, Junggu, Daegu 41944, South Korea.|Division of Pulmonology, Department of Internal Medicine, Kyungpook National University, School of Medicine, 680 Gukchaebosang-ro, Junggu, Daegu 41944, South Korea.
authors.forename: Jae Yong
authors.initials: JY
authors.lastname: Park
authors.affiliation: School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangangu, Suwon 16419, Republic of Korea.
authors.forename: Dong-Gyu
authors.initials: DG
authors.lastname: Jo
authors.affiliation: Department of Polymer Science and Engineering, College of Engineering, Sungkyunkwan University, 2066 Seobu-ro, Jangangu, Suwon 16419, Republic of Korea.
authors.forename: Jae Hyung
authors.initials: JH
authors.lastname: Park
authors.affiliation: Biomedical Research Institute, Korea Institute of Science and Technology, 5, Hwarang-ro 14-gil, Seongukgu, Seoul 02792, Republic of Korea.
authors.forename: In San
authors.initials: IS
authors.lastname: Kim
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Kyungpook National University, School of Medicine, 680 Gukchaebosang-ro, Junggu, Daegu 41944, South Korea.|Cell and Matrix Research Institute, Kyungpook National University School of Medicine, 680 Gukchaebosang-ro, Junggu, Daegu 41944, South Korea.|Department of Biochemistry and Cellular Biology, Kyungpook National University School of Medicine, 680 Gukchaebosang-ro, Junggu, Daegu 41944, Republic of Korea.
authors.forename: Young Mo
authors.initials: YM
authors.lastname: Kang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D002908:Chronic Disease; D015536:Down-Regulation / Q000187:drug effects; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D051379:Mice; D008811:Mice, Inbred DBA; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000494:pharmacology / Q000627:therapeutic use; D012720:Severity of Illness Index; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use*; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D000099222:betaIG-H3 Protein
chemical_list: D018932:Chemokine CCL2; D016326:Extracellular Matrix Proteins; D020778:Matrix Metalloproteinase 2; D053245:RANK Ligand; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D019010:Vascular Cell Adhesion Molecule-1; D000099222:betaIG-H3 Protein; C000620179:MFK902 peptide