p66shc siRNA nanoparticles ameliorate chondrocytic mitochondrial dysfunction in osteoarthritis

Hyo Jung Shin, Hyewon Park, Nara Shin, Juhee Shin, Do Hyeong Gwon, Hyeok Hee Kwon, Yuhua Yin, Jeong Ah Hwang, Jinpyo Hong, Jun Young Heo, Cuk Seong Kim, Yongbum Joo, Youngmo Kim, Jinhyun Kim, Jaewon Beom, Dong Woon Kim

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Background: Osteoarthritis (OA) is the most common type of joint disease associated with cartilage breakdown. However, the role played by mitochondrial dysfunction in OA remains inadequately understood. Therefore, we investigated the role played by p66shc during oxidative damage and mitochondrial dysfunction in OA and the effects of p66shc downregulation on OA progression. Methods: Monosodium iodoacetate (MIA), which is commonly used to generate OA animal models, inhibits glycolysis and biosynthetic processes in chondrocytes, eventually causing cell death. To observe the effects of MIA and poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles, histological analysis, immunohistochemistry, micro-CT, mechanical paw withdrawal thresholds, quantitative PCR, and measurement of oxygen consumption rate and extracellular acidification rate were conducted. Results: p-p66shc was highly expressed in cartilage from OA patients and rats with MIAinduced OA. MIA caused mitochondrial dysfunction and reactive oxygen species (ROS) production, and the inhibition of p66shc phosphorylation attenuated MIA-induced ROS production in human chondrocytes. Inhibition of p66shc by PLGA-based nanoparticlesdelivered siRNA ameliorated pain behavior, cartilage damage, and inflammatory cytokine production in the knee joints of MIA-induced OA rats. Conclusion: p66shc is involved in cartilage degeneration in OA. By delivering p66shcsiRNA- loaded nanoparticles into the knee joints with OA, mitochondrial dysfunctioninduced cartilage damage can be significantly decreased. Thus, p66shc siRNA PLGA nanoparticles may be a promising option for the treatment of OA.

Original languageEnglish
Pages (from-to)2379-2390
Number of pages12
JournalInternational Journal of Nanomedicine
Volume15
DOIs
StatePublished - 2020

Keywords

  • Mitochondrial dysfunction
  • Monosodium iodoacetate
  • Osteoarthritis
  • PLGA-based nanoparticles
  • ROS
  • p66shc

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