Glycolaldehyde-modified advanced glycation end-products inhibit differentiation of human monocytes into osteoclasts via upregulation of IL-10.

Abstract

Diabetes patients are at high risk of bone fracture due to accumulation of advanced glycation end products (AGEs) and low bone turnover. Although AGEs inhibit osteoblast functions, little is known about their roles in regulation of human osteoclast differentiation. The aim of this study was to determine the roles of AGEs in regulation of human osteoclast differentiation. Human CD14+ monocytes collected from healthy individuals were stimulated in vitro with conventional cytokines to induce osteoclast differentiation. Simultaneously, glucose-modified AGEs-BSA (Glu-AGEs-BSA) and glycolaldehyde-modified AGEs-BSA (Glyco-AGEs-BSA) were added to analyze their role in regulation of osteoclast differentiation. Human CD14+ cells expressed endogenous receptor for AGE (RAGE). Stimulation with Glyco-AGEs-BSA, but not Glu-AGEs-BSA, reduced the number of tartrate-resistant acid phosphatase-positive cells in a dose-dependent manner and suppressed mRNA expression of nuclear factor of activated T-cells 1 and cathepsin K. Glyco-AGEs-BSA up-regulated pro-inflammatory cytokines and anti-inflammatory cytokine IL-10. The addition of IL-10-neutralizing antibodies abrogated the suppressive effect of Glyco-AGEs-BSA on osteoclast differentiation. Stimulation of Glyco-AGE-BSA resulted in nuclear factor (NF)-κB phosphorylation, and addition of an inhibitor of κB kinase suppressed IL-10 production. We conclude that Glyco-AGEs-BSA inhibited human osteoclast differentiation through induction of IL-10 expression via NF-κB. It can be assumed that AGE bioaccumulation in diabetic patients increases the risk of bone fracture, through inhibition of osteoclast differentiation, reduction of bone turnover, and disruption of bone remodeling.