Background: It is well known that advanced glycation end products (AGEs) trigger an inflammation response, induce both diabetic vascular complications and impaired bone metabolism, and increase a fracture risk in patients with diabetes. However, the role of AGEs in bone resorption remains unclear and we investigated the role of AGEs in human osteoclast differentiation.
Methods: Differentiation of osteoclast was evaluated by tartrate-resistant acid phosphatase (TRAP) staining and quantitative PCR. The supernatant of osteoclastogenesis was investigated by the cytometric bead array.
Results: When human peripheral monocytes purified from healthy volunteers were cultured with AGE-1, AGE-3 or control BSA in the presence of M-CSF and RANKL for 12 days, AGE-3, but not AGE-1, markedly decreased the number of TRAP-positive osteoclasts induced by the culture. AGE-3, but not AGE-1, significantly decreased the mRNA expression levels of RANK and cathepsin K in human monocytes. The mRNA expression of IL-10, TNF-α, IL-6 and IL-1β was increased by AGE-3 in human monocytes. However, the enhanced expression of IL-10 mRNA was suppressed by IKK inhibitors which inhibit NF-κB-mediated signaling, while IL-10 expression was not suppressed by JNK or ERK inhibitors. On the other hand, when IL-10 alone was added to the culture condition, the protein levels of TNF-α, IL-6 and IL-1β were suppressed. The suppressive effect on osteoclastogenesis by AGE-3 was cancelled in addition of the neutralizing antibody against IL-10.
Conclusion: Our results revealed that AGEs regulated the cytokine production through NF-κB during the osteoclastogenesis from human peripheral monocytes. In contrast to AGE-1, AGE-3, which contributes to the development of diabetic vascular compli cations, inhibited human osteoclast differentiation. These inhibitory effects of AGE-3 depended on the production of IL-10. The present study indicates that accumulation of AGE-3 induces low bone turnover through IL-10, thereby contributing to an increased risk fracture in patients with diabetes.