Abstract
Bone destructive diseases such as periodontitis and rheumatoid arthritis are caused by excessive activation of osteoclasts. Osteoclastogenesis is regulated by Receptor activator of nuclear factor kappa-β ligand (RANKL) produced by osteoclastogenesis supporting cells such as osteoblast and osteocyte. Previously, we reported that NF-E2-related factor-2 (Nrf2) activation in osteoclast precursors inhibited osteoclastogenesis and bone destruction via induction of anti-oxidation and thereby attenuated intracellular ROS signaling. However, it still remains unknown whether Nrf2 activation in cells other than osteoclasts give any negative influence on supporting property for osteoclastogenesis. Here we discovered that Nrf2 activation in osteoblasts suppresses indirectly osteoclastogenesis via inhibiting the expression of interleukin-6 (IL-6) which promotes osteoclastogenesis. In this study, 5-aminolevulinic acid hydrochloride (ALA) and sodium ferrous citrate (SFC) was used as the Nrf2 activator. in vitro experiments, using osteoblast cell line, MC3T3-E1, revealed that the expression of IL-6 was increased by LPS stimulation, but decreased after ALA/SFC treatment in mRNA and protein levels. Furthermore, RANKL expression was augmented by LPS, which was blocked by ALA/SFC treatment. Neutralizing antibody against IL-6 confirmed that LPS-mediated RANKL augmentation was dependent on IL-6 induction. in vivo experiments with LPS-mediated bone destruction in mice, confirmed that augmented IL-6 expression in osteoblasts by immunochemical analysis. ALA/SFC treatment attenuated LPS-mediated IL-6 upregulation. These results suggest that Nrf2 activation in osteoblasts suppress IL-6 and inflammatory bone destruction. The Nrf2 activator acts not only on osteoclasts but also on osteoblasts, in other word, Nrf2 activation indirectly suppresses osteoclastogenesis. In conclusion, the Nrf2 activator exhibits dual inhibitory effects via direct action on osteoclast and indirect action on osteoclast supporting cells.
Highlights
Abnormal augmentation of osteoclastogenesis gives rise to bone destruction in diseases such as periodontitis (Fujikawa et al, 1996)
We firstly examined whether the aminolevulinic acid hydrochloride (ALA)/sodium ferrous citrate (SFC) activated the expression of NF-E2-related factor-2 (Nrf2)
Real-time PCR analysis revealed that the expression of Nrf2 in MC3T3-E1 cells was increased by ALA/SFC (Fig. 1A)
Summary
Abnormal augmentation of osteoclastogenesis gives rise to bone destruction in diseases such as periodontitis (Fujikawa et al, 1996). It is known that ROS is a signal molecule downstream of RANK (Bax et al, 1992; Ha et al, 2004; Kanzaki et al, 2014), and the reduction of ROS inhibits osteoclastogenesis and osteoclast activation (Li et al, 2018). Oxidative stress such as ROS exhibits cytotoxicity against cells (Wells et al, 2009), cell have protective mechanisms against these oxidative stressors (Furukawa-Hibi et al, 2005; Kensler et al, 2007). Nrf activation causes a rise in cytoprotective enzymes, which decreases intracellular ROS
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