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AB0096 PEP-1-FK506BP12 Inhibits Matrix Metalloproteinase Expression in Human Articular Chondrocytes and in a Mouse Carrageenan-Induced Arthritis Model
  1. I.Y. Park1,
  2. K.M. Son2,
  3. H.A. Kim1
  1. 1Hallym University sacred Heart Hospital, Pyongchon.Anyang, Kyunggi
  2. 2Hallym University chuncheon sacred Heart Hospital, Gangwon-do, Korea, Republic Of

Abstract

Background Osteoarthritis (OA) is a degenerative disease characterized by the death of chondrocytes and the gradual loss of articular cartilage. Recently, transfer of a therapeutic protein into cells by the use of protein transduction domain (PTD) that targets the lipid bilayer directly has been tested in terms of therapeutic applications. The FK506-binding protein 12 kDa (FK506BP12) binds immunosuppressive drugs such as FK506 and modulates T cell activation via calcineurin inhibition. The anti-inflammatory properties of and immunomodulatory role played by FK506BP12, independent of FK506, have been demonstrated in several disease models

Objectives In this study, we investigated the ability of PEP-1-FK506BP12, consisting of FK506BP12 fused to the PTD PEP-1 peptide, to suppress catabolic responses in primary human chondrocytes and in a mouse carrageenan-induced paw arthritis model.

Methods Western blotting and immunofluorescence analysis showed that PEP-1-FK506BP12 efficiently penetrated chondrocytes and cartilage explants.

Results In interleukin-1β (IL-1β)-treated chondrocytes, PEP-1-FK506BP12 significantly suppressed the expression of catabolic enzymes, including matrix metalloproteinases (MMPs)-1, -3, and -13; and cyclooxygenase-2, at both the mRNA and protein levels, whereas FK506BP12 alone did not. In addition, PEP-1-FK506BP12 decreased IL-1β-induced phosphorylation of the mitogen-activated protein kinase (MAPK) complex (p38, JNK, and ERK) and the inhibitor kappa B alpha. In the mouse model of carrageenan-induced paw arthritis, PEP-1-FK506BP12 suppressed both carrageenan-induced MMP-13 production and paw inflammation.

Conclusions Thus, PEP-1-FK506BP12 may have therapeutic potential in the alleviation of OA progression.

References

  1. S.R. Goldring, M.B. Goldring, The role of cytokines in cartilage matrix degeneration in osteoarthritis, Clin. Orthop. Relat. Res. (2004) S27-36.

  2. D.W. Kim, S.H. Lee, S.K. Ku, et al., Transduced PEP-1-FK506BP ameliorates corneal injury in Botulinum toxin A-induced dry eye mouse model, BMB Rep. 46 (2013) 124-129.

  3. S.Y. Kim, E.J. Sohn, D.W. Kim, et al., Transduced PEP-1-FK506BP ameliorates atopic dermatitis in NC/Nga mice, J. Invest. Dermatol. 131 (2013) 1477-1485.

Acknowledgements This research was supported by a grant (A120960) from the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea, by National Research Foundation of Korea; Mid-career Research program grant (NRF-2009-0084569), and by Hallym University Research Fund.

Disclosure of Interest None declared

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