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Proc Natl Acad Sci U S A. 2016 Oct 11;113(41):E6199-E6208. Epub 2016 Sep 28.

Suppression of NF-κB activity via nanoparticle-based siRNA delivery alters early cartilage responses to injury.

Author information

1
Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110.
2
Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, MO 63110.
3
Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110.
4
Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110 wicklines@aol.com sandelll@wudosis.wustl.edu cpham@wustl.edu.
5
Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, MO 63110; wicklines@aol.com sandelll@wudosis.wustl.edu cpham@wustl.edu.
6
Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110; wicklines@aol.com sandelll@wudosis.wustl.edu cpham@wustl.edu.

Abstract

Osteoarthritis (OA) is a major cause of disability and morbidity in the aging population. Joint injury leads to cartilage damage, a known determinant for subsequent development of posttraumatic OA, which accounts for 12% of all OA. Understanding the early molecular and cellular responses postinjury may provide targets for therapeutic interventions that limit articular degeneration. Using a murine model of controlled knee joint impact injury that allows the examination of cartilage responses to injury at specific time points, we show that intraarticular delivery of a peptidic nanoparticle complexed to NF-κB siRNA significantly reduces early chondrocyte apoptosis and reactive synovitis. Our data suggest that NF-κB siRNA nanotherapy maintains cartilage homeostasis by enhancing AMPK signaling while suppressing mTORC1 and Wnt/β-catenin activity. These findings delineate an extensive crosstalk between NF-κB and signaling pathways that govern cartilage responses postinjury and suggest that delivery of NF-κB siRNA nanotherapy to attenuate early inflammation may limit the chronic consequences of joint injury. Therapeutic benefits of siRNA nanotherapy may also apply to primary OA in which NF-κB activation mediates chondrocyte catabolic responses. Additionally, a critical barrier to the successful development of OA treatment includes ineffective delivery of therapeutic agents to the resident chondrocytes in the avascular cartilage. Here, we show that the peptide-siRNA nanocomplexes are nonimmunogenic, are freely and deeply penetrant to human OA cartilage, and persist in chondrocyte lacunae for at least 2 wk. The peptide-siRNA platform thus provides a clinically relevant and promising approach to overcoming the obstacles of drug delivery to the highly inaccessible chondrocytes.

KEYWORDS:

NF-κB; autophagy; nanomedicine; posttraumatic osteoarthritis; siRNA

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