Osteoarthritis (OA) is the most common joint disorder that has had an increasing prevalence due to the aging of the population. Recent studies have concluded that OA progression is related to oxidative stress and reactive oxygen species (ROS). ROS are produced at low levels in articular chondrocytes, mainly by the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and ROS production and oxidative stress have been found to be elevated in patients with OA. The cartilage of OA-affected rat exhibits a significant induction of p47phox, a cytosolic subunit of the NADPH oxidase, similarly to human osteoarthritis cartilage. Therefore, this study tested whether siRNA p47phox that is introduced with poly (D,L-lactic-co-glycolic acid) (PLGA) nanoparticles (p47phox si_NPs) can alleviate chondrocyte cell death by reducing ROS production. Here, we confirm that p47phox si_NPs significantly attenuated oxidative stress and decreased cartilage damage in mono-iodoacetate (MIA)-induced OA. In conclusion, these data suggest that p47phox si_NPs may be of therapeutic value in the treatment of osteoarthritis.

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 MIA-induced 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 nanoparticles-delivered 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 dysfunction-induced cartilage damage can be significantly decreased. Thus, p66shc siRNA PLGA nanoparticles may be a promising option for the treatment of OA.

In osteoarthritis (OA), chondrocytes in cartilage undergo phenotypic changes and senescence, restricting cartilage regeneration and favoring disease progression. Although senescence biomarker p16INK4a expression is known to induce aging by halting the cell cycle, therapeutic applications for p16INK4a targeting are limited. Here, we aimed to reduce cartilage damage and alleviate pain using p16INK4a nanoparticles in OA. The p16INK4a expression of human OA chondrocytes and synoviocytes from patients with knee OA was measured and the levels of p16INK4a, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and matrix metalloproteinase (MMP) 13 were examined. p16INK4a siRNA was encapsulated into poly (lactic-co-glycolic acid) (PLGA) nanoparticles and characterized. The partial medial meniscectomy (pMMx) model was performed for the OA model which was investigated by molecular analysis and behavioral tests. The expression of p16INK4a was increased in the synovium and articular cartilage from OA patients. p16INK4a siRNA-loaded PLGA nanoparticles (p16 si_NP) reduced the levels of TNF-α, IL-1β, and IL-6 especially in fibroblast-like synoviocytes (FLSs), and MMP13 in chondrocytes. Rhodamine-tagged NPs injected into the mouse knee joints were found mainly in the synovium. p16 si_NP injection in the pMMx model alleviated pain-associated behavior, and reduced cartilage damage and p16INK4a in the synovium, and MMP13, collagen X, and NITEGE in cartilage. The preferential reduction of p16INK4a in FLSs by the application of RNAi nanomedicine could contribute to the recovery of osteoarthritic cartilage and relieve pain, suggesting that p16INK4a may be a viable future therapeutic candidate.

Background: With a growing understanding of biomechanical disadvantages following medial meniscus posterior root tear (MMPRT), recent studies have focused on surgical repair of MMPRT. Because not all tears are repairable, surgical indications can be properly established when the outcomes of conservative treatments are revealed. This study tried to identify risk factors for osteoarthritis progression after conservative treatments for isolated MMPRT. Materials & Methods: Patients who had conservative treatments for isolated MMPRT during 2013–2016 were retrospectively reviewed. To evaluate osteoarthritis progression, those who were followed up for ≤3 years and those who already showed advanced osteoarthritis of Kellgren--Lawrence (K-L) grade 4 at the time of diagnosis were excluded. Because patients with varus malalignment were candidates for realignment osteotomy, conservative treatments for MMPRT were applied to patients with well-aligned knees. Osteoarthritis progression was determined based on the K-L grading system, and risk factors including age, sex, body mass index, lower limb alignment, preoperative K-L grade, meniscal extrusion, and the presence of subchondral bone marrow lesion (BML) were analyzed using logistic regression analyses. Results: A total of 42 patients were followed up for 57.4 ± 26.8 months. During that period, osteoarthritis progression was noted in 17 (40.5%) patients. Based on univariate analyses for each risk factor, age, meniscal extrusion, and the presence of subchondral BML were included in the multivariate logistic regression analysis. The results showed that age (p = 0.028, odds ratio = 0.87) and meniscal extrusion (p = 0.013, odds ratio = 9.65) were significant risk factors. A receiver operating characteristic curve found that the cutoff age was 63.5 years, with the area under the curve being 0.72 (sensitivity, 68.0%; specificity, 70.6%). Conclusions: About two-fifths of patients who had conservative treatments for MMPRT underwent osteoarthritis progression in the mid to long term. Age and meniscal extrusion were determining factors of osteoarthritis progression. The risk for osteoarthritis progression was decreased when the age of patients was over 63.5 years.