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

Abstract

Osteoporosis: Targeting amino acid enzyme could strengthen bones An examination of amino acid metabolism processes in bone yields a possible therapeutic target for osteoporosis and other bone diseases. The excessive generation of osteoclasts (bone-resorbing cells) is a key trigger for conditions such as osteoporosis, where bones become fragile and prone to fracturing. Branched-chain amino acids (BCAAs) are an essential energy source for cells, particularly during differentiation and maturation. South Korean researchers led by Soo Young Lee at Ewha Womans University and Geum-Sook Hwang at the Korea Basic Science Institute, both in Seoul, examined the role of BCAAs and the enzymes that process them in bone metabolism. They found that one such enzyme, BCAT1, directly regulates BCAA levels. Both BCAT1 and intracellular BCAA rose rapidly during osteoclast differentiation. Inhibition of BCAT1 activity in mice resulted in improved bone mass. 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 kappa B 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.