Molecular regulatory mechanisms of osteoclastogenesis through cytoprotective enzymes

Abstract

It has been reported that reactive oxygen species (ROS), such as hydrogen peroxide and superoxide, take part in osteoclast differentiation as intra-cellular signaling molecules. The current assumed signaling cascade from RANK to ROS production is RANK, TRAF6, Rac1, and then Nox. The target molecules of ROS in RANKL signaling remain unclear; however, several reports support the theory that NF-κB signaling could be the crucial downstream signaling molecule of RANKL-mediated ROS signaling. Furthermore, ROS exert cytotoxic effects such as peroxidation of lipids and phospholipids and oxidative damage to proteins and DNA. Therefore, cells have several protective mechanisms against oxidative stressors that mainly induce cytoprotective enzymes and ROS scavenging. Three well-known mechanisms regulate cytoprotective enzymes including Nrf2-, FOXO-, and sirtuin-dependent mechanisms. Several reports have indicated a crosslink between FOXO- and sirtuin-dependent regulatory mechanisms. The agonists against the regulatory mechanisms are reported to induce these cytoprotective enzymes successfully. Some of them inhibit osteoclast differentiation and bone destruction via attenuation of intracellular ROS signaling. In this review article, we discuss the above topics and summarize the current information available on the relationship between cytoprotective enzymes and osteoclastogenesis.

Keywords: FOXO; Heme-oxygenase 1 (HO-1); Nrf2; Osteoclast; Oxidative stress; Sirtuin.

Graphical abstract

Fig. 1

Summary of the current information about the intracellular signaling cascade of RANKL. Intracellular signaling molecules after RANK were identified. The current assumed signaling cascade from RANK to ROS production is also described. Some reports suggest that NF-κB is the crucial downstream molecule of RANKL-mediated ROS signaling.

Fig. 2

Nrf2-mediated cytoprotective enzymes scavenge ROS. Nrf2 transcriptionally regulates the expressions of HO1, GCS, NQO1, and G6PD. HO1 convert heme into carbon oxide (CO) and bilirubin, and they scavenge ROS. GCS increases intracellular glutathione, which results in ROS scavenging. NQO1 reduces oxyradicals. G6PD increases intracellular NADPH, which augments ROS scavenging.

Fig. 3

FOXO-mediated cytoprotective enzymes scavenge ROS. FOXO regulates the expressions of MnSOD (SOD2) and catalase (CAT). MnSOD convert superoxide into H2O2, followed by the conversion into H2O and O2 by CAT.

Fig. 4

SIRT-mediated cytoprotective enzymes scavenge ROS. SIRT regulates the expressions of MnSOD (SOD2) and catalase (CAT). MnSOD convert superoxide into H2O2, followed by the conversion into H2O and O2 by CAT.

Fig. 5

Nrf2, FOXO, and sirtuin negatively regulate osteoclastogenesis via attenuation of intracellular ROS signaling. Nrf2 regulates the transcription of cytoprotective enzymes and ROS scavenging. However, Keap1 attenuates cytoprotective enzymes via degradation of Nrf2. Other mechanisms regulating cytoprotective enzymes have roles in ROS regulation: FOXO directly, and sirtuin directly and indirectly (via FOXO).