Metabolic regulation of osteoclast differentiation and bone resorption

Project Summary: Glutamine is a conditionally essential amino acid that has myriad uses in the cell. Aside from direct incorporation into protein, glutamine can be metabolized to generate nucleotides, other amino acids, the Krebs cycle intermediate -ketoglutarate (KG) which is important for energy production and anabolic reactions, and glutathione (GSH) to protect against oxidative stress. We recently determined that mature osteoclasts are characterized by increased abundance of amino acids and nucleotides. Importantly, inhibiting glutamine metabolism reduced nucleotide abundance and inhibited osteoclast differentiation. Unfortunately, the necessity of glutamine metabolism to regulate osteoclast differentiation and bone resorption in vivo has not been investigated. Moreover, how glutamine derived purine nucleotides mechanistically regulate osteoclasts remains enigmatic. In this proposal, we will 1) establish the necessity and sufficiency of glutaminase (GLS) dependent glutamine metabolism to regulate osteoclast differentiation and bone resorption, 2) evaluate the efficacy of the GLS inhibitor Telaglenastat to inhibit bone bone resorption in the ovariectomy mouse model of human osteoporosis, and 3) define the mechanisms by which glutamate oxaloacetate transaminase 2 (GOT2) dependent purine biosynthesis functions downstream of GLS to regulate osteoclast metabolism and differentiation. Our findings will have broad implications in understanding the roel and regulation of metabolism during osteoclast differentiation and activity, bone homeostasis and pathological bone loss.