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Advanced oxidation protein products increase TNF-? and IL-1? expression in chondrocytes via NADPH oxidase 4 and accelerate cartilage degeneration in osteoarthritis progression.

ABSTRACT: Interleukin (IL)-1? and tumor necrosis factor (TNF)-?, in particular, control the degeneration of articular cartilage, making them prime targets for osteoarthritis (OA) therapeutic strategies. Advanced oxidation protein products (AOPPs) are prevalent in numerous diseases. Our previous work demonstrates that intra-articular injections of AOPPs accelerate regression of cartilage in OA models. Whether AOPPs exist in the course of OA and their effects on TNF-? and IL-1? expression in chondrocytes are still unclear. This study confirmed that AOPPs levels in human synovial fluid were positively associated with severity of OA. We also found AOPPs deposition in articular cartilage in anterior cruciate ligament transection (ACLT) induced rodent OA models. AOPPs increased expression of TNF-? and IL-1? in chondrocytes in vitro, which was inhibited by pre-treatment with SB202190 (p38-MAPK inhibitor) or apocynin (NADPH oxidase inhibitor) or NOX4 knockdown by siRNAs. Subsequently, we further verified in vivo that exogenous injection of AOPPs in OA mice up-regulated expression of TNF-? and IL-1? in cartilage, which was blocked by treatment with apocynin. In parallel, apocynin attenuated articular cartilage degeneration resulting in substantially lower OARSI scores. Specifically, apocynin reduced NOX4, p-P38, TNF-? and IL-1? and increased collagen II and glycosaminoglycan (GAG). This study demonstrated that AOPPs increased expression of TNF-? and IL-1? in chondrocytes via the NADPH oxidase4-dependent and p38-MAPK mediated pathway, and accelerated cartilage degeneration in OA progression. These findings suggest an endogenous pathogenic role of AOPPs in OA progression. Targeting AOPPs-triggered cellular mechanisms might be a promising therapeutic option for patients with OA.

SUBMITTER: Liao CR

PROVIDER: S-EPMC6812020 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Advanced oxidation protein products increase TNF-α and IL-1β expression in chondrocytes via NADPH oxidase 4 and accelerate cartilage degeneration in osteoarthritis progression.

Liao Cong-Rui CR Wang Sheng-Nan SN Zhu Si-Yuan SY Wang Yi-Qing YQ Li Zong-Ze ZZ Liu Zhong-Yuan ZY Jiang Wang-Sheng WS Chen Jian-Ting JT Wu Qian Q

Redox biology 20190822

Interleukin (IL)-1β and tumor necrosis factor (TNF)-α, in particular, control the degeneration of articular cartilage, making them prime targets for osteoarthritis (OA) therapeutic strategies. Advanced oxidation protein products (AOPPs) are prevalent in numerous diseases. Our previous work demonstrates that intra-articular injections of AOPPs accelerate regression of cartilage in OA models. Whether AOPPs exist in the course of OA and their effects on TNF-α and IL-1β expression in chondrocytes ar ...[more]

PMID: 31539804

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Project description:BackgroundSarcopenia with chronic kidney disease (CKD) progression is associated with life prognosis. Oxidative stress has attracted interest as a trigger for causing CKD-related muscular atrophy. Advanced oxidation protein products (AOPPs), a uraemic toxin, are known to increase oxidative stress. However, the role of AOPPs on CKD-induced muscle atrophy remains unclear.MethodsIn a retrospective case-control clinical study, we evaluated the relationship between serum AOPPs levels and muscle strength in haemodialysis patients with sarcopenia (n = 26, mean age ± SEM: 78.5 ± 1.4 years for male patients; n = 22, mean age ± SEM: 79.1 ± 1.5 for female patients), pre-sarcopenia (n = 12, mean age ± SEM: 73.8 ± 2.0 years for male patients; n = 4, mean age ± SEM: 74.3 ± 4.1 for female patients) or without sarcopenia (n = 12, mean age ± SEM: 71.3 ± 1.6 years for male patients; n = 7, mean age ± SEM: 77.7 ± 1.6 for female ). The molecular mechanism responsible for the AOPPs-induced muscle atrophy was investigated by using 5/6-nephrectomized CKD mice, AOPPs-overloaded mice, and C2C12 mouse myoblast cells.ResultsThe haemodialysis patients with sarcopenia showed higher serum AOPPs levels as compared with the patients without sarcopenia. The serum AOPPs levels showed a negative correlation with grip strength (P < 0.01 for male patients, P < 0.01 for female patients) and skeletal muscle index (P < 0.01 for male patients). Serum AOPPs levels showed a positive correlation with cysteinylated albumin (Cys-albumin), a marker of oxidative stress (r2 = 0.398, P < 0.01). In the gastrocnemius of CKD mice, muscle AOPPs levels were also increased, and it showed a positive correlation with atrogin-1 (r2 = 0.538, P < 0.01) and myostatin expression (r2 = 0.421, P < 0.05), but a negative correlation with PGC-1α expression (r2 = 0.405, P < 0.05). Using C2C12 cells, AOPPs increased atrogin-1 and myostatin expression through the production of reactive oxygen species via CD36/NADPH oxidase pathway, and decreased myotube formation. AOPPs also induced mitochondrial dysfunction. In the AOPPs-overloaded mice showed that decreasing running time and hanging time accompanied by increasing AOPPs levels and decreasing cross-sectional area in gastrocnemius.ConclusionsAdvanced oxidation protein products contribute to CKD-induced sarcopenia, suggesting that AOPPs or its downstream signalling pathway could be a therapeutic target for the treatment of CKD-induced sarcopenia. Serum AOPPs or Cys-albumin levels could be a new diagnostic marker for sarcopenia in CKD.

Dataset Information

Advanced oxidation protein products increase TNF-? and IL-1? expression in chondrocytes via NADPH oxidase 4 and accelerate cartilage degeneration in osteoarthritis progression.

Publications

Advanced oxidation protein products increase TNF-α and IL-1β expression in chondrocytes via NADPH oxidase 4 and accelerate cartilage degeneration in osteoarthritis progression.

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