Age-related accumulation of advanced oxidation protein products promotes osteoclastogenesis through disruption of redox homeostasis

Enhanced osteoclastogenesis is one of the major causes of age-related bone loss. Aging is accompanied by accumulation of advanced oxidation protein products (AOPPs). However, whether AOPPs accumulation contributing to the osteoclastogenesis with aging remains unclear. Here, we showed that AOPPs accumulation was associated with the enhanced osteoclastogenesis and deterioration of bone microstructure in aged mice. In vitro, AOPPs directly induced osteoclastogenesis by interaction with receptor activator of nuclear factor κ B (RANK) and the receptor for advanced glycation end products (RAGE) in the primary bone marrow monocytes. Bindings of AOPPs to RANK and RAGE were able to activate nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, trigger generation of reactive oxygen species, then induce phosphorylation of mitogen-activated protein kinases and c-fos, upregulation of the nuclear factor of activated T cell c1, eventually induce bone marrow monocytes to differentiate into mature osteoclasts. Chronic exposure to AOPPs enhanced osteoclastogenesis and bone loss in mice, which could be alleviated by NADPH oxidase inhibitor apocynin. Local injection of AOPPs into subperiosteal area induced bone resorption at the site of administration, which was similar to the effect of RANK ligand. Together, these results suggested that AOPPs could serve as a novel regulator of osteoclastogenesis and AOPPs accumulation might play an important role in the development of age-related bone loss.