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Osteoblast apoptosis plays an important role in age-related bone loss and osteoporosis. Our previous study revealed that advanced oxidation protein products (AOPPs) could induce nicotinamide adenine dinucleotide phosphate oxidase (NOX)-derived reactive oxygen species (ROS) production, cause mitochondrial membrane potential (ΔΨm) depolarization, trigger the mitochondria-dependent intrinsic apoptosis pathway, and lead to osteoblast apoptosis and ultimately osteopenia and bone microstructural destruction. In this study, we found that AOPPs also induced mitochondrial ROS (mtROS) generation in osteoblastic MC3T3-E1 cells, which was closely related to NOX-derived ROS, and aggravated the oxidative stress condition, thereby further promoting apoptosis. Removing excessive ROS and damaged mitochondria is the key factor in reversing AOPP-induced apoptosis. Here, by in vitro studies, we showed that rapamycin further activated PINK1/Parkin-mediated mitophagy in AOPP-stimulated MC3T3-E1 cells and significantly alleviated AOPP-induced cell apoptosis by eliminating ROS and damaged mitochondria. Our in vivo studies revealed that PINK1/Parkin-mediated mitophagy could decrease the plasma AOPP concentration and inhibit AOPP-induced osteoblast apoptosis, thus ameliorating AOPP accumulation-related bone loss, bone microstructural destruction and bone mineral density (BMD) loss. Together, our study indicated that therapeutic strategies aimed at upregulating osteoblast mitophagy and preserving mitochondrial function might have potential for treating age-related osteoporosis., (© 2023. The Author(s).)

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 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-α and IL-1β 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-α and IL-1β 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-α and IL-1β and increased collagen II and glycosaminoglycan (GAG). This study demonstrated that AOPPs increased expression of TNF-α and IL-1β 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., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Advanced oxidation protein products (AOPPs) can trigger NADPH oxidase (NOX) and lead to the production of reactive oxygen species (ROS) in the pathophysiology of rheumatoid arthritis (RA). Hydroxytyrosol (HT) is a phenolic composite in olive oil that has antioxidant and anti‑inflammatory effects and enhances autophagy. Early research has revealed that HT can activate the silent information regulator 1 (SIRT1) pathway to induce autophagy and alleviate the cartilage inflammatory response caused by H2O2. However, whether HT can attenuate AOPP‑induced NOX and inflammatory responses remains to be elucidated. The present study aimed to investigate how HT can alleviate the damage caused by AOPPs. In cell experiments, chondrocytes were pre‑stimulated with HT and then exposed to AOPPs. First, it was found that HT promoted autophagy through the SIRT1 pathway, increased the expression of autophagy‑related proteins including microtubule‑associated protein 1 light chain 3, autophagy related (ATG)5 and ATG7, and decreased the expression of P62. Furthermore, HT reduced the expression of NOX, which was affected by AOPPs in chondrocytes through the SIRT1 pathway. Finally, the expression of inflammatory cytokines caused by AOPPs was downregulated following HT treatment. In conclusion, it was found that HT reduced the expression of NOX and inhibited the inflammatory response caused by AOPPs in chondrocytes through the SIRT1 pathway.

Osteoblast apoptosis contributes to age-related bone loss. Advanced oxidation protein products (AOPPs) are recognized as the markers of oxidative stress and potent inducers of apoptosis. We have demonstrated that AOPP accumulation was correlated with age-related bone loss. However, the effect of AOPPs on the osteoblast apoptosis still remains unknown. Exposure of osteoblastic MC3T3-E1 cells to AOPPs caused the excessive generation of reactive oxygen species (ROS) by activating nicotinamide adenine dinucleotide phosphate (NADPH) oxidases. Increased ROS induced phosphorylation of mitogen-activated protein kinases (MAPKs), which subsequently triggered intrinsic apoptosis pathway by inducing mitochondrial dysfunction, endoplasmic reticulum stress, and Ca 2+ overload and eventually leads to apoptosis. Chronic AOPP loading in aged Sprague-Dawley rats induced osteoblast apoptosis and activated NADPH oxidase signaling cascade, in combination with accelerated bone loss and deteriorated bone microstructure. Our study suggests that AOPPs induce osteoblast apoptosis by the NADPH oxidase-dependent, MAPK-mediated intrinsic apoptosis pathway., (© 2018 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Pro-inflammatory cytokine-induced chondrocyte apoptosis is a primary cause of cartilage destruction in the progression of rheumatoid arthritis (RA). Advanced oxidation protein products (AOPPs), a novel pro-inflammatory mediator, have been confirmed to accumulate in patients with RA. However, the effect of AOPPs accumulation on chondrocyte apoptosis and the associated cellular mechanisms remains unclear. The present study demonstrated that the plasma formation of AOPPs was enhanced in RA rats compared with normal. Then, chondrocyte were treated with AOPPs-modified rat serum albumin (AOPPs-RSA) in vitro. Exposure of chondrocyte to AOPPs activated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and increased expression of NADPH oxidase subunits, which was mediated by receptor for advanced glycation end products (RAGE), but not scavenger receptor CD36. Moreover, AOPPs challenge triggered NADPH oxidase-dependent ROS generation which induced mitochondrial dysfunction and endoplasmic reticulum stress resulted in activation of caspase family that eventually lead to apoptosis. Lastly, blockade of RAGE, instead of CD36, largely attenuated these signals. Our study demonstrated first time that AOPPs induce chondrocyte apoptosis via RAGE-mediated and redox-dependent intrinsic apoptosis pathway in vitro. These data implicates that AOPPs may represent a novel pathogenic factor that contributes to RA progression. Targeting AOPPs-triggered cellular mechanisms might emerge as a promising therapeutic option for patients with RA.

Background: Advanced oxidation protein products (AOPPs) are acknowledged as a novel marker of oxidation-mediated protein damage. This study aimed to investigate the plasma levels of AOPPs in postmenopausal osteoporotic women, and to determine the relationship between AOPPs accumulation and lumbar bone mineral destiny (BMD) or bone turnover markers., Material and Methods: Lumbar BMD was measured by dual-energy X-ray absorptiometry. Plasma AOPPs levels as a marker of protein oxidation damage and malondialdehyde (MDA) levels as a marker of lipid peroxidation were measured by spectrophotometry. The concentrations of 2 specific markers of bone turnover, bone-specific alkaline phosphatase (BALP) and tartrate-resistant acid phosphatase5b, (TRACP 5b) were quantified using ELISA kits., Results: We recruited 60 postmenopausal women meeting osteoporosis (OP) diagnostic criteria of World Health Organization (WHO) and 60 postmenopausal women without OP. Plasma levels of AOPPs (P<0.001), BALP (P<0.001) and TRACP 5b (P<0.001) were statistically significantly increased in the postmenopausal osteoporotic women compared with controls, but there was no statistically significant difference in MDA (P=0.124) between the 2 groups. Plasma AOPPs levels were negatively correlated with lumbar BMD and positively correlated with bone turnover markers both in postmenopausal osteoporotic women and in all subjects. However, plasma MDA levels were not correlated with lumbar BMD or bone turnover markers., Conclusions: In postmenopausal osteoporotic women elevated AOPPs is associated with reduced BMD and increased bone turnover markers. Because AOPPs is stable and easy to detect it may be used as a simple plasma marker to predict the severity of postmenopausal OP.

Objective: Advanced oxidation protein products (AOPPs), a marker of oxidative stress, are prevalent in many kinds of disorders. Osteoarthritis (OA), mainly resulting from the regression of cartilage, chronic inflammation of the synovium and the subchondral bone remodeling. Although the inflammatory response of AOPPs on fibroblast-like synoviocytes (FLSs) were reported, the effect of AOPPs on cartilage and synovial in vivo remains unclear. Therefore, our study aims to investigate whether AOPPs have an effect on the articular cartilage and synovial in a rabbit model of OA., Methods: OA model were created by anterior cruciate ligament transection and medial meniscus resection (ACLT + MMx). Forty-eight male New Zealand rabbits were randomly divided into 3 groups: sham-operated group, AOPPs/ACLT + MMx group, and phosphate buffered saline (PBS)/ACLT + MMx group. In sham-operated group, the anterior cruciate ligament was just exposed without transection, and then the incision was sutured. Then intra-articular injection of AOPPs or PBS was performed in the other two groups. Through four weeks and eight weeks of treatment, rabbits in each group were sacrificed. Both hind legs were removed. India ink staining and Safranin O and fast green staining were used to evaluate the macroscopic and microscopic cartilage morphology. The protein expression of matrix metalloproteinases (MMP)-3, MMP-13 in synovium was measured by Western blot., Result: The India ink score and Mankin score of AOPPs/ACLT + MMx group were both higher than the other two groups at the two time points. Western blot have revealed that intra-articular injection of AOPPs upregulated the protein expression of MMP-3 and MMP-13 in synovium., Conclusion: AOPPs participated in the occurrence and development of OA by upregulating the protein expression of MMP-3 and MMP-13 in synovium., (© 2015 Chinese Orthopaedic Association and Wiley Publishing Asia Pty Ltd.)

Advanced oxidation protein products (AOPPs) are novel markers of oxidation-mediated protein damage, and accumulation of AOPPs is involved in many pathophysiological conditions. Our previous studies demonstrated that the serum level of AOPPs negatively correlated with the age-related change in bone mineral density (BMD) in rats and that AOPPs inhibited rat osteoblast-like cell proliferation and differentiation in vitro. However, whether AOPPs are involved in senile osteoporosis is still largely unknown. The present study aimed to test the hypothesis that accumulation of AOPPs might accelerate bone deterioration in aged rats. Seventy 18-month-old male Sprague Dawley (SD) rats were randomized to intravenous injection of vehicle, native rat serum albumin (RSA), AOPPs-modified RSA (AOPPs-RSA) with or without oral administration of apocynin (a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor), or apocynin alone. After treatment for 8 weeks or 16 weeks, seven rats in each group were sacrificed. Bone and blood samples were harvested for BMD measurement, micro-computed tomographic (micro-CT) imaging, and biochemical analysis of circulating bone biomarkers. Compared to RSA- or vehicle-treated rats, AOPPs-RSA-treated animals displayed significantly decreased total vertebral BMD and deteriorated microstructure in both the tibias and the lumbar vertebral bodies, which were associated with down-regulated plasma bone-specific alkaline phosphatase concentration and up-regulated tartrate-resistant acid phosphatase 5b concentration. These AOPPs-induced perturbations in aged rats could be prevented by the oral administration of apocynin. However, no significant differences in BMD were detected in the femurs or the biomechanical parameters tested between the different treatment groups. These data suggest that accumulation of AOPPs accelerates bone deterioration in aged rats, likely via the activation of NADPH oxidase. This study provides new information toward understanding the pathogenic basis of senile osteoporosis and may provide targets for intervention., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Advanced oxidation protein products (AOPPs), a marker of oxidative stress, are prevalent in many kinds of disorders. Rheumatoid arthritis (RA), mainly resulting from the dysfunction of fibroblast-like synoviocytes (FLSs), is related to oxidative stress. Although the increased levels of AOPPs in RA patients were reported, the effect of AOPPs on FLSs function still remains unclear. Therefore, our study aims to investigate whether AOPPs have an effect on the inflammatory response of FLSs in vitro., Methods: FLSs obtained from both knees of rats were treated with or without AOPPs-modified rat serum albumin (AOPPs-RSA) in vitro. The mRNA and protein expression of tumor necrosis factor (TNF)-α, interleukin(IL)-1β, matrix metalloproteinases(MMP)-3, MMP-13 and vascular endothelial growth factor (VEGF) were measured by real-time quantitative polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA), respectively. Reactive oxygen species (ROS) generation was detected by fluorescent microscope and fluorescence microplate reader. Immunoprecipitation, Co-Immunoprecipitation and western blot were performed to examine the activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and nuclear factor kappa B (NF-κB)., Results: Exposure of FLSs to AOPPs upregulated the mRNA and protein expression of TNF-α, IL-1β, MMP-3, MMP-13 and VEGF in a concentration dependent manner. AOPPs treatment triggered ROS production in FLSs, which was significantly abolished by ROS scavenger N-acetyl-L-cysteine (NAC), superoxide dismutase (SOD), NADPH oxidase inhibitors diphenyleneiodonium (DPI) and apocynin. Challenged AOPPs induced phosphorylation of p47(phox), triggered an interaction between p47(phox), p22(phox) and gp91(phox), and significantly upregulated expression of NADPH oxidase subunits p47(phox), p22(phox) and gp91(phox). IκB degradation and nuclear translocation of NF-κB p65 induced by AOPPs were significantly blocked by SOD, NAC, DPI and apocynin., Conclusions: These data indicate that AOPPs induce inflammatory response in FLSs is medicated through NADPH oxidase-dependent activation of NF-κB., (© 2013 S. Karger AG, Basel)

Background: Age-related bone loss is a primary factor in osteoporosis and osteoporotic fractures in the elderly. Although oxidative stress was reported to play an important role in aging and postmenopausal bone loss, data on relating oxidative stress to age-related bone loss were scanty. This study aimed to investigate whether oxidative stress is involved in age-related bone loss. Materials and Methods: Young, adult, and old male Wistar rats were used in this study. Each group consisted of 26 animals. Oxidative stress parameters, such as advanced oxidation protein products (AOPP), malondialchehyche (MDA), and superoxide dismutase (SOD), were measured in the plasma and right femur homogenates. Bone mineral density (BMD) of left femurs and histomorphometry of tibias were investigated. Results: In the plasma and femurs, the levels of AOPP and MDA were increased and the SOD activity was decreased with aging. Femur BMD decreased significantly in old rats. Bone histomorphometry indicated decreases in cancellous bone volume, trabecular thickness, percent labeled perimeter, mineral apposition rate, and bone formation rate with aging. The AOPP levels in plasma and femur, and MDA levels in the plasma were negatively correlated with the femur BMD. The SOD activity in plasma and femur was positively correlated with the femur BMD. Conclusions: Increase of oxidative stress and bone loss appear with aging. Oxidative stress is involved in age-related bone loss and might play an important role in the pathology of age-related bone loss. [Copyright &y& Elsevier]