Myeloma Cells Deplete Bone Marrow Glutamine and Inhibit Osteoblast Differentiation Limiting Asparagine Availability.
Myeloma Cells Deplete Bone Marrow Glutamine and Inhibit Osteoblast Differentiation Limiting Asparagine Availability.
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骨髓瘤细胞耗尽骨髓谷氨酰胺并抑制成骨细胞分化，限制天冬酰胺的可用性。
DOI：
10.3390/cancers12113267
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发表时间：
2020-11-05
期刊：
影响因子：
5.2
通讯作者：
Giuliani N
中科院分区：
文献类型：
--
作者：
Chiu M;Toscani D;Marchica V;Taurino G;Costa F;Bianchi MG;Andreoli R;Franceschi V;Storti P;Burroughs-Garcia J;Eufemiese RA;Dalla Palma B;Campanini N;Martella E;Mancini C;Shan J;Kilberg MS;D'Amico G;Dander E;Agnelli L;Pruneri G;Donofrio G;Bussolati O;Giuliani N
溶骨性骨病变是多发性骨髓瘤（MM）的重要临床特征。MM细胞代谢非常高量的谷氨酰胺（Gln），并在骨髓中显著降低Gln。在这篇文章中，我们证明MM依赖性Gln缺失会损害骨髓间充质基质细胞分化为成骨细胞（形成新骨组织的细胞）。我们还发现，成骨细胞分化与谷氨酰胺酶（代谢Gln的主要酶）、SNAT 2（能够将Gln积累到细胞中的转运蛋白）和天冬酰胺合成酶（使用Gln获得天冬酰胺（Asn）的酶）的表达增加有关。天冬酰胺拯救了谷氨酰胺饥饿间充质基质细胞的成骨分化。这些结果表明，MM细胞损害成骨细胞分化，通过Gln耗竭阻碍间充质Asn合成。除了提供一个代谢机制的潜在溶骨性病变的MM，这些结果表明，天冬酰胺补充剂可以预防骨质疏松症患者。多发性骨髓瘤（MM）细胞消耗大量谷氨酰胺，因此，MM患者骨髓（BM）中的氨基酸浓度低于正常值。在这里，我们表明，MM依赖性谷氨酰胺耗竭诱导基质细胞中的谷氨酰胺合成酶，如MM患者的BM活检所示，并通过与MM细胞共培养人间充质基质细胞（MSC）在体外复制。此外，谷氨酰胺耗竭阻碍了MSC的成骨细胞分化，这也被MM细胞的耗尽的低谷氨酰胺培养基严重钝化，并被谷氨酰胺恢复所拯救。谷氨酰胺酶和浓缩谷氨酰胺转运蛋白SNAT 2在体内和体外成骨细胞形成过程中被诱导，并且两者都是MSC分化所需的，这表明对氨基酸的需求增加。成骨细胞生成还触发谷氨酰胺依赖性天冬酰胺合成酶（ASNS）的诱导，并且在非必需氨基酸中，天冬酰胺通过恢复由谷氨酰胺饥饿改变的分化MSC的转录谱来拯救谷氨酰胺饥饿MSC的分化。因此，天冬酰胺可用性降低提供了BM中MM依赖性Gln耗竭与成骨细胞分化受损之间的机制联系。因此，抑制MM细胞中的Gln代谢和向基质细胞补充天冬酰胺可能构成预防MM溶骨性病变的新方法。
Osteolytic bone lesions represent an important clinical feature of multiple myeloma (MM). MM cells metabolize very high amounts of glutamine (Gln) and significantly lower Gln in the bone marrow. In this contribution we demonstrate that MM-dependent Gln depletion impairs the differentiation of bone marrow mesenchymal stromal cells into osteoblasts, the cells that form new bone tissue. We also found that osteoblast differentiation is associated with increased expression of glutaminase, the main enzyme that metabolizes Gln, SNAT2, a transporter able to accumulate Gln into the cells, and asparagine synthetase, the enzyme that uses Gln to obtain asparagine (Asn). Asn rescued osteoblast differentiation of Gln-starved mesenchymal stromal cells. These results demonstrate that MM cells impair osteoblast differentiation, hindering mesenchymal Asn synthesis through Gln depletion. Besides providing a metabolic mechanism underlying osteolytic lesions in MM, these results suggest that Asn supplementation may prevent bone disease in MM patients. Multiple myeloma (MM) cells consume huge amounts of glutamine and, as a consequence, the amino acid concentration is lower-than-normal in the bone marrow (BM) of MM patients. Here we show that MM-dependent glutamine depletion induces glutamine synthetase in stromal cells, as demonstrated in BM biopsies of MM patients, and reproduced in vitro by co-culturing human mesenchymal stromal cells (MSCs) with MM cells. Moreover, glutamine depletion hinders osteoblast differentiation of MSCs, which is also severely blunted by the spent, low-glutamine medium of MM cells, and rescued by glutamine restitution. Glutaminase and the concentrative glutamine transporter SNAT2 are induced during osteoblastogenesis in vivo and in vitro, and both needed for MSCs differentiation, pointing to enhanced the requirement for the amino acid. Osteoblastogenesis also triggers the induction of glutamine-dependent asparagine synthetase (ASNS), and, among non-essential amino acids, asparagine rescues differentiation of glutamine-starved MSCs, by restoring the transcriptional profiles of differentiating MSCs altered by glutamine starvation. Thus, reduced asparagine availability provides a mechanistic link between MM-dependent Gln depletion in BM and impairment of osteoblast differentiation. Inhibition of Gln metabolism in MM cells and supplementation of asparagine to stromal cells may, therefore, constitute novel approaches to prevent osteolytic lesions in MM.
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