title: A matrix metalloproteinase 1-cleavable composite peptide derived from transforming growth factor β-inducible gene h3 potently inhibits collagen-induced arthritis.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Kyungpook National University School of Medicine, Daegu, South Korea.
authors.forename: Eon Jeong
authors.initials: EJ
authors.lastname: Nam
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Kang
authors.forename: Shijin
authors.initials: S
authors.lastname: Sung
authors.forename: Keum Hee
authors.initials: KH
authors.lastname: Sa
authors.forename: Kyung Hoon
authors.initials: KH
authors.lastname: Kim
authors.forename: Jae Seok
authors.initials: JS
authors.lastname: Seo
authors.forename: Jong-Ho
authors.initials: JH
authors.lastname: Kim
authors.forename: Seung Woo
authors.initials: SW
authors.lastname: Han
authors.forename: In San
authors.initials: IS
authors.lastname: Kim
authors.forename: Young Mo
authors.initials: YM
authors.lastname: Kang
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy*; D001172:Arthritis, Rheumatoid; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D016326:Extracellular Matrix Proteins / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D053509:Matrix Metalloproteinase 13; D051379:Mice; D041681:NIH 3T3 Cells / Q000187:drug effects; D009842:Oligopeptides; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use*; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D017434:Protein Structure, Tertiary; D013583:Synovial Membrane / Q000166:cytology* / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome; D000099222:betaIG-H3 Protein
chemical_list: D016326:Extracellular Matrix Proteins; D053509:Matrix Metalloproteinase 13; D009842:Oligopeptides; D010455:Peptides; D011355:Prodrugs; D016212:Transforming Growth Factor beta; D000099222:betaIG-H3 Protein; C047981:arginyl-glycyl-aspartic acid; C507081:Mmp13 protein, mouse