Advanced Oxidation Protein Products Aggravate Age-Related Bone Loss By Increasing Sclerostin Expression In Osteocytes Via Ros-Dependent Downregulation Of Sirt1

Advanced oxidation protein products (AOPPs) induce intracellular oxidative stress (OS) and are involved in numerous diseases. AOPPs accumulate with age, and our previous study revealed that AOPPs accelerated bone deterioration in aged rats. However, the underlying mechanism remains unknown. The present study demonstrated that AOPPs aggravated bone loss in aging male mice by increasing the resorptive activity and decreasing the formative activity of bone tissues. In addition, SOST mRNA (encoding sclerostin) and sclerostin protein levels were increased in the bone tissues of AOPP-treated mice, which was associated with enhanced OS status as well as decreased Sirtuin 1 (SIRT1) mRNA and protein expression levels. Incubation of MLO-Y4 cells with AOPPs induced the accumulation of reactive oxygen species (ROS) via the activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases. The accumulated ROS then upregulated sclerostin expression in MLO-Y4 cells by decreasing Sirt1 expression. In vivo, AOPP-challenged mice co-treated with apocynin (an inhibitor of NADPH oxidases), N-acetyl-L-cysteine (a ROS scavenger) or SRT3025 (a Sirt1 activator) displayed improved bone mass and microstructure. Moreover, sclerostin expression in the bone tissues of the co-treated groups was significantly lower compared with that in groups treated with AOPPs alone. Collectively, these data suggested that AOPPs aggravated age-related bone loss by increasing the expression of sclerostin in osteocytes via ROS-dependent downregulation of Sirt1. The present findings provide novel insights into the pathogenesis of senile osteoporosis.