Suppression of NF-κB activity via nanoparticle-based siRNA delivery alters early cartilage responses to injury.
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.
Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110.
Huimin
H
Yan
Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, MO 63110.
Xin
X
Duan
Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110.
Hua
H
Pan
Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, MO 63110.
Nilsson
N
Holguin
Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, MO 63110.
Muhammad Farooq
MF
Rai
Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110.
Antonina
A
Akk
Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110.
Luke E
LE
Springer
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.
Samuel A
SA
Wickline
Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, MO 63110; wicklines@aol.com sandelll@wudosis.wustl.edu cpham@wustl.edu.
Linda J
LJ
Sandell
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.
Christine T N
CT
Pham
NF-κB; autophagy; nanomedicine; posttraumatic osteoarthritis; siRNA
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