<p>p66shc siRNA Nanoparticles Ameliorate Chondrocytic Mitochondrial Dysfunction in Osteoarthritis</p>

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 p66shc-siRNA-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.

A novel dendritic mesoporous silica based sustained hydrogen sulfide donor for the alleviation of adjuvant-induced inflammation in rats

“… 2020 ; Shin et al. 2020 ). In brief, dewaxed tissue sections were stained with Weigert’s hematoxylin working solution composed of 1% hematoxylin and 30% ferric chloride (anhydrous) for 10 min.…”

Experimental Therapeutics for the Treatment of Osteoarthritis

“…161 By delivering p66shc-siRNAloaded Poly(lactide-co-glycolide) (PLGA) nanoparticles into the osteoarthritic knee joints, mitochondrial dysfunction-induced cartilage damage was significantly impaired suggesting them as an option for the treatment of OA. 122 In addition to being effective, nanoparticles should be highly cytocompatible, or capable to be easily eliminated, eg, by self-degradation to disappear, and not to accumulate and produce unwanted adverse effects.…”

“… 161 By delivering p66shc-siRNA-loaded Poly(lactide-co-glycolide) (PLGA) nanoparticles into the osteoarthritic knee joints, mitochondrial dysfunction-induced cartilage damage was significantly impaired suggesting them as an option for the treatment of OA. 122 …”

“…miRs and small interfering RNAs (siRNAs) could present future tools in OA therapy being, eg, combined with nanoparticles, microvesicles or other carriers. 122 , 193 Limitations to be addressed in future could be to maintain stability and achieve sufficient high local concentrations of therapeutical miRNAs.…”

“…121 In addition, it has been shown that PTEN-induced kinase (Pink)1 mediated chondrocytic mitophagy, initiated chondrocyte death and contributed thereby, to cartilage degeneration in OA. 122 Not only Pink1 but also Parkin proteins were increased in OA. 123 The Parkin protein might protect from ROS accumulation mediating chondrocyte survival.…”