BCAT1 promotes osteoclast maturation by regulating branched-chain amino acid metabolism

Miyeon Go, Eunji Shin, Seo Young Jang, Miso Nam, Geum Sook Hwang, Soo Young Lee

Research output: Contribution to journalArticlepeer-review

Abstract

Branched-chain aminotransferase 1 (BCAT1) transfers the amine group on branched-chain amino acids (BCAAs) to alpha-ketoglutarate. This generates glutamate along with alpha-keto acids that are eventually oxidized to provide the cell with energy. BCAT1 thus plays a critical role in sustaining BCAA concentrations and availability as an energy source. Osteoclasts have high metabolic needs during differentiation. When we assessed the levels of amino acids in bone marrow macrophages (BMMs) that were undergoing receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclast differentiation, we found that the BCAA levels steadily increase during this process. In vitro analyses then showed that all three BCAAs but especially valine were needed for osteoclast maturation. Moreover, selective inhibition of BCAT1 with gabapentin significantly reduced osteoclast maturation. Expression of enzymatically dead BCAT1 also abrogated osteoclast maturation. Importantly, gabapentin inhibited lipopolysaccharide (LPS)-induced bone loss of calvaria in mice. These findings suggest that BCAT1 could serve as a therapeutic target that dampens osteoclast formation.

Original languageEnglish
Pages (from-to)825-833
Number of pages9
JournalExperimental and Molecular Medicine
Volume54
Issue number6
DOIs
StatePublished - Jun 2022

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