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.
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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