Glutamate-centered metabolic and signaling networks in skeletal homeostasis and diseases

Glutamate (Glu) occupies an unusual position in skeletal biology, functioning as both a local signaling molecule and a central intermediate of cellular metabolism. Although these roles are often discussed separately, they converge on processes that determine bone and cartilage homeostasis. This review integrates glutamatergic signaling with the intracellular glutamine (Gln)-Glu-α-ketoglutarate (α-KG)-glutathione (GSH) pathway and examines how Glu availability is translated into cell-specific responses. Across osteoblasts (OBs), osteoclasts (OCLs), bone marrow mesenchymal stem cells (BMSCs), and chondrocytes, Glu receptors and transporters modulate Ca 2 ⁺, cyclic adenosine monophosphate (cAMP), and kinase signaling, whereas Gln-derived Glu supports tricarboxylic acid (TCA)-cycle metabolism, biosynthesis, epigenetic regulation, and antioxidant defense. The balance between these signaling and metabolic functions varies with cell type, differentiation stage, nutrient supply, mechanical loading, and inflammation. This context dependence may explain why Glu-associated pathways can support bone formation in one setting but favor resorption or cartilage damage in another. Evidence from osteoporosis, osteoarthritis, intervertebral disc degeneration, and multiple myeloma-associated bone disease highlights how disturbed nutrient availability and local Glu handling can impair tissue homeostasis. However, most mechanistic evidence remains preclinical, and Glu-related concentrations, spatial gradients, and metabolic fluxes in human skeletal tissues are poorly defined. Stable-isotope tracing, spatial metabolomics, cell-specific genetic models, and targeted delivery strategies will be essential for translating this Glu-centered network into skeletal therapies.