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BACKGROUND The protein transduction domain (PTD) enables therapeutic proteins to directly penetrate the membranes of cells and tissues, and has been increasingly utilized. Glutaredoxin-1 (GRX-1) is an endogenous antioxidant enzyme involved in the cellular redox homeostasis system. In this study, we investigated whether PEP-1-GRX-1, a fusion protein of GRX-1 and PEP-1 peptide, a PTD, could suppress catabolic responses in primary human articular chondrocytes and a mouse carrageenan-induced paw edema model. METHODS Human articular chondrocytes were isolated enzymatically from articular cartilage and cultured in a monolayer. The transduction efficiency of PEP-1-GRX-1 into articular chondrocytes was measured by western blot and immunohistochemistry. The effects of PEP-1-GRX-1 on matrix metalloproteinases (MMPs) and catabolic factor expression in interleukin (IL)-1β- and lipopolysaccharide (LPS)-treated chondrocytes were analyzed by real-time quantitative reverse transcription-polymerase chain reaction and western blot. The effect of PEP-1-GRX1 on the mitogen-activated protein kinase (MAPK) and nuclear factor kappa-light chain-enhancer of activated B cells (NF-κB) signaling pathway were also analyzed by western blot. Finally, the inhibitory effect of PEP-1-GRX-1 on MMP-13 production was measured in vivo in a mouse carrageenan-induced paw edema model. RESULTS PEP-1-GRX-1 significantly penetrated into human chondrocytes and mouse cartilage, whereas GRX-1 did not. PEP-1-GRX-1 significantly suppressed MMP-13 expression and nitric oxide (NO) production in LPS-stimulated chondrocytes, and NO production in IL-1β-stimulated chondrocytes, compared with GRX-1. In addition, PEP-1-GRX-1 decreased IL-1β- and LPS-induced activation of MAPK and NF-κB. In the mouse model of carrageenan-induced paw edema, PEP-1-GRX-1 significantly suppressed carrageenan-induced MMP-13 production as well as paw edema. CONCLUSIONS These results demonstrate that PEP-1-GRX-1 can be transduced efficiently in vitro and in vivo into human chondrocytes and mouse cartilage tissue and downregulate catabolic responses in chondrocytes by inhibiting the MAPK and NF-κB pathway. PEP-1-GRX-1 thus has the potential to reduce catabolic responses in chondrocytes and cartilage.
Hyun Sook Hwang, and
In Young Park, and
Hyun Ah Kim, and
Soo Young Choi
November 2016,
Experimental cell research,
Hyun Sook Hwang, and
In Young Park, and
Hyun Ah Kim, and
Soo Young Choi
May 2014,
Arthritis & rheumatology (Hoboken, N.J.),
Hyun Sook Hwang, and
In Young Park, and
Hyun Ah Kim, and
Soo Young Choi
March 2007,
Biochimica et biophysica acta,
Hyun Sook Hwang, and
In Young Park, and
Hyun Ah Kim, and
Soo Young Choi
May 2002,
Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases,
Hyun Sook Hwang, and
In Young Park, and
Hyun Ah Kim, and
Soo Young Choi
January 2003,
Arthritis research & therapy,
Hyun Sook Hwang, and
In Young Park, and
Hyun Ah Kim, and
Soo Young Choi
January 2015,
American journal of translational research,
Hyun Sook Hwang, and
In Young Park, and
Hyun Ah Kim, and
Soo Young Choi
July 2006,
Osteoarthritis and cartilage,
Hyun Sook Hwang, and
In Young Park, and
Hyun Ah Kim, and
Soo Young Choi
November 2009,
Orthopedics,
Hyun Sook Hwang, and
In Young Park, and
Hyun Ah Kim, and
Soo Young Choi
July 2008,
Iranian biomedical journal,
Hyun Sook Hwang, and
In Young Park, and
Hyun Ah Kim, and
Soo Young Choi
August 2002,
Annals of the rheumatic diseases,
