Glutamine Metabolism Regulates Proliferation and Lineage Allocation in Skeletal Stem Cells

Abstract

Skeletal stem cells (SSC) are postulated to provide a continuous supply of osteoblasts throughout life. However, under certain conditions, the SSC population can become incorrectly specified or is not maintained, resulting in reduced osteoblast formation, decreased bone mass, and in severe cases osteoporosis. Glutamine metabolism has emerged as a critical regulator of many cellular processes in diverse pathologies. The enzyme glutaminase (GLS) deaminates glutamine to form glutamate, the rate-limiting first step in glutamine metabolism. Using genetic and metabolic approaches, we demonstrate GLS and glutamine metabolism is required in SSC to regulate osteoblast and adipocyte specification and bone formation. Mechanistically, transaminase dependent α-ketoglutarate production is critical for the proliferation, specification and differentiation of SSC. Collectively, these data suggest stimulating GLS activity may provide a therapeutic approach to expand SSCs in aged individuals and enhance osteoblast differentiation and activity to increase bone mass.