High glutamate levels in the bone marrow of multiple myeloma patients promote osteoclast formation: a novel target for osteolytic bone disease

Abstract

Multiple Myeloma (MM) is a glutamine (Gln)-addicted cancer. Consequently, the MM bone microenvironment (BM) is characterized by lower Gln and higher glutamate (Glu) levels than those in pre-malignant monoclonal gammopathies. Such MM-dependent metabolic perturbation impairs osteoblast differentiation in the bone microenvironment, but its effect on osteoclast (OCL) bone resorption is still unknown. We first show that bone marrow mononuclear cells from MM patients release higher levels of Glu compared to those from patients with monoclonal gammopathy of undetermined significance (MGUS) or smoldering multiple myeloma (SMM). This increased Glu production correlates with elevated bone resorption activity. We then demonstrate that Glu stimulates OCL differentiation via the activation of NF-κB-NFATc1 pathway in low-Glu BM samples from pre-malignant patients but not in high-Glu samples of MM patients. Secondly, the early phase of OCL formation was associated with high Glu intracellular content and induction of the Glu transporter EAAT1. Consistently, the pharmacological inhibition of EAAT1 hinders OCL differentiation by blocking the RANKL-dependent signaling pathway and actin cytoskeleton reorganization. Overall, our data indicate that high Glu levels in MM bone marrow are involved in OCL formation, suggesting that targeting Glu transport may represent a novel approach for the prevention of osteolytic lesions in MM patients.