A matrix metalloproteinase 1-cleavable composite peptide derived from transforming growth factor β-inducible gene h3 potently inhibits collagen-induced arthritis

Eon Jeong Nam, Jin Hee Kang, Shijin Sung, Keum Hee Sa, Kyung Hoon Kim, Jae Seok Seo, Jong Ho Kim, Seung Woo Han, In-San Kim, Young Mo Kang

Research output: Contribution to journalArticle

19 Citations (Scopus)

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. 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.

Original languageEnglish
Pages (from-to)1753-1763
Number of pages11
JournalArthritis and Rheumatism
Volume65
Issue number7
DOIs
Publication statusPublished - 2013 Jul 1
Externally publishedYes

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Matrix Metalloproteinase 1
Experimental Arthritis
Transforming Growth Factors
Peptides
Genes
Arthritis
Matrix Metalloproteinases
Rheumatoid Arthritis
Synovial Membrane
Cell Adhesion
Cell Movement
Peptide Hydrolases
Therapeutics
Joints

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Pharmacology (medical)

Cite this

A matrix metalloproteinase 1-cleavable composite peptide derived from transforming growth factor β-inducible gene h3 potently inhibits collagen-induced arthritis. / Nam, Eon Jeong; Kang, Jin Hee; Sung, Shijin; Sa, Keum Hee; Kim, Kyung Hoon; Seo, Jae Seok; Kim, Jong Ho; Han, Seung Woo; Kim, In-San; Kang, Young Mo.

In: Arthritis and Rheumatism, Vol. 65, No. 7, 01.07.2013, p. 1753-1763.

Research output: Contribution to journalArticle

Nam, Eon Jeong ; Kang, Jin Hee ; Sung, Shijin ; Sa, Keum Hee ; Kim, Kyung Hoon ; Seo, Jae Seok ; Kim, Jong Ho ; Han, Seung Woo ; Kim, In-San ; Kang, Young Mo. / A matrix metalloproteinase 1-cleavable composite peptide derived from transforming growth factor β-inducible gene h3 potently inhibits collagen-induced arthritis. In: Arthritis and Rheumatism. 2013 ; Vol. 65, No. 7. pp. 1753-1763.
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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. 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.",
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T1 - A matrix metalloproteinase 1-cleavable composite peptide derived from transforming growth factor β-inducible gene h3 potently inhibits collagen-induced arthritis

AU - Nam, Eon Jeong

AU - Kang, Jin Hee

AU - Sung, Shijin

AU - Sa, Keum Hee

AU - Kim, Kyung Hoon

AU - Seo, Jae Seok

AU - Kim, Jong Ho

AU - Han, Seung Woo

AU - Kim, In-San

AU - Kang, Young Mo

PY - 2013/7/1

Y1 - 2013/7/1

N2 - 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.

AB - 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.

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