Abstract
SummaryOsteoblast 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 Ca2+ 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.
Highlights
Osteoporosis is a chronic, progressive disease characterized by low bone mass, bone deterioration, and decreased bone strength, with a consequent increase in bone fragility and susceptibility to fracture (Reginster & Burlet, 2006)
We have previously found that oxidative stress and Advanced oxidation protein products (AOPPs) levels increased with age, and AOPP accumulation was correlated with age-related bone loss (Zhang, Zhong, Hou, Jiang & Chen, 2011)
AOPP-induced apoptosis was further confirmed by the in vivo study, in which TUNEL staining confirmed that chronic AOPP loading caused osteoblast apoptosis in aged rats, which was associated with decreased bone mineral density (BMD) and deteriorated bone microstructure
Summary
Osteoporosis is a chronic, progressive disease characterized by low bone mass, bone deterioration, and decreased bone strength, with a consequent increase in bone fragility and susceptibility to fracture (Reginster & Burlet, 2006). Agerelated bone loss is characterized by the reduction of bone formation, which mainly results from the decreased number and activity of osteoblasts (Kassem & Marie, 2011). Osteoblast apoptosis increases with age (Komori, 2016; Tower, 2015) and is responsible for reduction in osteoblast number and activity, which contribute to decreased bone formation (Jilka & O’Brien, 2016; Jilka, Weinstein, Parfitt & Manolagas, 2007; Weinstein & Manolagas, 2000). Increased osteoblast apoptosis results in the unbalanced coupling of bone formation and resorption and leads to bone loss and osteoporosis. In addition to being the products of oxidative stress, AOPPs are inducers of ROS generation (Witko-Sarsat et al, 1996, 1998). AOPP-induced osteoblastic cell apoptosis is mainly mediated by the nicotinamide adenine dinucleotide phosphate (NADPH) oxidases-dependent ROS generation, which activates mitogen-activated protein kinases (MAPK)-mediated intrinsic apoptosis pathway
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