Correct functioning of chondrocytes is crucial for long bone growth and fracture repair. These cells are highly anabolic but survive and function in an avascular environment, implying specific metabolic requirements that are, however, poorly characterized. Here, we show that chondrocyte identity and function are closely linked with glutamine metabolism in a feedforward process. The master chondrogenic transcription factor SOX9 stimulates glutamine metabolism by increasing glutamine consumption and levels of glutaminase 1 (GLS1), a rate-controlling enzyme in this pathway. Consecutively, GLS1 action is critical for chondrocyte properties and function via a tripartite mechanism. First, glutamine controls chondrogenic gene expression epigenetically through glutamate dehydrogenase-dependent acetyl-CoA synthesis, necessary for histone acetylation. Second, transaminase-mediated aspartate synthesis supports chondrocyte proliferation and matrix synthesis. Third, glutamine-derived glutathione synthesis avoids harmful reactive oxygen species accumulation and allows chondrocyte survival in the avascular growth plate. Collectively, our study identifies glutamine as a metabolic regulator of cartilage fitness during bone development.

软骨细胞的正确功能对于长骨生长和骨折修复至关重要。这些细胞具有很高的合成代谢能力，但可以在无血管的环境中存活并发挥功能，这意味着对新陈代谢的要求却很差。在这里，我们表明软骨细胞的身份和功能与前馈过程中的谷氨酰胺代谢密切相关。主软骨形成转录因子SOX9通过增加谷氨酰胺的消耗和谷氨酰胺酶1（GLS1）（该途径中的一种速率控制酶）的水平来刺激谷氨酰胺代谢。连续地，GLS1的作用对于软骨细胞的特性和通过三方机制起作用至关重要。首先，谷氨酰胺通过组氨酸乙酰化所必需的谷氨酸脱氢酶依赖性乙酰辅酶A合成来表观遗传地控制软骨基因的表达。第二，转氨酶介导的天冬氨酸合成支持软骨细胞增殖和基质合成。第三，谷氨酰胺衍生的谷胱甘肽合成避免了有害的活性氧的积累，并使软骨细胞在无血管生长板上存活。总的来说，我们的研究确定谷氨酰胺是骨骼发育过程中软骨适应性的代谢调节剂。