Toscani Denise, Lungu Oxana, Chiu Martina, Maccari Chiara, Raimondi Vincenzo, Taurino Giuseppe, Bianchi Massimiliano G, Scita Matteo, Dalla Palma Benedetta, Iannozzi Nicolas Thomas, Vescovini Rosanna, Dessena Mattia, Sitzia Camilla, Storti Paola, Andreoli Roberta, Bussolati Ovidio, Giuliani Nicola
Laboratory of Hematology, Department of Medicine and Surgery, University of Parma, Parma, Italy.
Hematology and BMT Unit, "Azienda Ospedaliero-Universitaria di Parma", Parma, Italy.
Leukemia. 2025 Jul 28. doi: 10.1038/s41375-025-02715-2.
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.
多发性骨髓瘤（MM）是一种对谷氨酰胺（Gln）成瘾的癌症。因此，与恶性前单克隆丙种球蛋白病相比，MM骨微环境（BM）的特征是谷氨酰胺水平较低，谷氨酸（Glu）水平较高。这种依赖MM的代谢紊乱会损害骨微环境中的成骨细胞分化，但其对破骨细胞（OCL）骨吸收的影响仍不清楚。我们首先表明，与意义未明的单克隆丙种球蛋白病（MGUS）或冒烟型多发性骨髓瘤（SMM）患者相比，MM患者的骨髓单个核细胞释放的Glu水平更高。这种增加的Glu产生与骨吸收活性升高相关。然后我们证明，Glu通过激活恶性前患者低Glu BM样本中的NF-κB-NFATc1途径刺激OCL分化，但在MM患者的高Glu样本中则不然。其次，OCL形成的早期阶段与高Glu细胞内含量和Glu转运体EAAT1的诱导有关。一致地，EAAT1的药理学抑制通过阻断RANKL依赖的信号通路和肌动蛋白细胞骨架重组来阻碍OCL分化。总体而言，我们的数据表明MM骨髓中的高Glu水平参与了OCL的形成，这表明靶向Glu转运可能是预防MM患者溶骨性病变的一种新方法。
