Chemical Bach1 Inhibition Attenuates Osteoclastogenesis

Objectives: It was reported that reactive oxygen species (ROS) play a role in osteoclast differentiation as intra-cellular signaling molecule. Previously we reported that transcriptional factor nuclear factor E2-related factor 2 (Nrf2) negatively regulate osteoclastogenesis via anti-oxidative enzyme expression and thereby ROS scavenging. However, it is still remain unknown Bach1, the competitor for Nrf2 in transcriptional regulation of anti-oxidative enzymes can be therapeutic target for bone destructive disease. We hypothesized that chemical Bach1 inhibition activates Nrf2-dependent anti-oxidative enzyme expression, diminish intracellular ROS signaling, and thereby attenuates osteoclastogenesis.
Methods: Mouse monocyte cell-line RAW264.7 were stimulated with sRANKL with or without Bach1 inhibition by sodium ferrous citrate (SFC) and 5-Aminolevulinic acid (ALA). sRANKL-dependent osteoclastogenesis were observed, and marker genes for osteoclast differentiation were examined by realtime PCR. Expressions of Nrf2, Keap1, and cytoprotective genes such as heme oxygenase 1, were examined by realtime PCR.
Results: sRANKL-dependent osteoclastogenesis was inhibited by SFC, ALA, and combination of them. Osteoclast marker gene expression was dose-dependently inhibited. Bach1 inhibition increased anti-oxidative stress enzyme expression.
Conclusions: Chemical Bach1 inhibition activates Nrf2-dependent anti-oxidative enzyme expression, and thereby attenuates osteoclastogenesis. Bach1 inhibition could be therapeutic target for bone destructive disease.