Metabolic Control During Macrophage Polarization by a Citrate-Functionalized Scaffold for Maintaining Bone Homeostasis.

Metabolites, as markers of phenotype at the molecular level, can regulate the function of DNA, RNA, and proteins through chemical modifications or interactions with large molecules. Citrate is an important metabolite that affects macrophage polarization and osteoporotic bone function. Therefore, a better understanding of the precise effect of citrate on macrophage polarization may provide an effective alternative strategy to reverse osteoporotic bone metabolism. In this study, we fabricated a citrate functional scaffold to control the metabolic pathway during macrophage polarization based on the metabolic differences between pro-inflammatory and anti-inflammatory phenotypes for maintaining bone homeostasis. Mechanistically, only outside M1 macrophages were accumulated high concentrations of citrate, in contrast, M2 macrophages consumed massive citrate. Therefore, citrate-functionalized scaffolds exerted more sensitive inhibitory effects on metabolic enzyme activity during M1 macrophage polarization than M2 macrophage polarization. Citrate could block glycolysis related enzymes by occupying the binding-site and ensure sufficient metabolic flux in the TCA cycle, so as to turn the metabolism of macrophages to oxidative phosphorylation of M2 macrophage, largely maintaining bone homeostasis. Our studies indicate that exogenous citrate can realize metabolic control of macrophage polarization for maintaining bone homeostasis in osteoporosis. This article is protected by copyright. All rights reserved.