Glutamine metabolite α -ketoglutarate acts as an epigenetic co-factor to interfere with osteoclast differentiation

Osteoclasts (OCs) have been well-known involved in the exacerbation of bone-related diseases. However, the role of metabolites on osteoclastogenesis has not been well characterized. Herein, we found osteoclastogenesis was negatively regulated by alpha-ketoglutarate (alpha KG) in vitro and in vivo (C57BL/6 mouse). Kinetic transcriptome analysis revealed the upregulation of solute carrier family 7 member 11 (Slc7a11), a subunit of the cysteine/ glutamate antiporter, as well as the downregulation of typical OC maker genes through alpha KG treatment. Given that Slc7a11 could control ROS level through glutathione import, we measured intracellular ROS, then RANKLinduced ROS production was inhibited by alpha KG. Notably, we highlight that alpha KG plays an epigenetic co-factor at the Slc7a11 promoter by demethylating repressive histone H3K9 methylation and simultaneously increasing the nuclear factor erythroid 2-related factor (Nrf2) binding, a critical transcription factor through chromatin immunoprecipitation (ChIP) analysis. Together, we suggested that alpha KG could be a therapeutic strategy for OC activated diseases.

Automated summary

The study showed that alpha-ketoglutarate negatively regulates osteoclastogenesis by controlling ROS levels and epigenetic mechanisms, with Slc7a11 playing a key role in the process.