De novo serine synthesis regulates chondrocyte proliferation during bone development and repair

作     者：Steve Stegen Shauni Loopmans Ingrid Stockmans Karen Moermans Peter Carmeliet Geert Carmeliet Steve Stegen;Shauni Loopmans;Ingrid Stockmans;Karen Moermans;Peter Carmeliet;Geert Carmeliet

作者机构：Laboratory of Clinical and Experimental EndocrinologyDepartment of Chronic Diseases and MetabolismKU Leuven3000 LeuvenBelgium Laboratory of Angiogenesis and Vascular MetabolismVIB Center for Cancer Biology3000 LeuvenBelgium Laboratory of Angiogenesis and Vascular MetabolismDepartment of Oncology and Leuven Cancer InstituteKU Leuven3000 LeuvenBelgium State Key Laboratory of OphthalmologyZhongshan Ophthalmic CenterSun Yat-Sen UniversityGuangzhou 510080China 

出 版 物：《Bone Research》 (骨研究（英文版）)

年 卷 期：2022年第10卷第2期

页      面：274-285页

核心收录：

学科分类：0831[工学-生物医学工程（可授工学、理学、医学学位）] 1001[医学-基础医学(可授医学、理学学位)] 10[医学] 

基　　金：supported by funding from the Research Foundation-Flanders(FWO:G.0A42.16, G.0B3418 and G0C5120N) the KU Leuven (C24/17/077) supported by long-term structural funding-Methusalem Funding by the Flemish Government and the European Research Council (ERC Advanced Research Grant EU-ERC743074) 

主　　题：synthesis starting thereby 

摘      要：The majority of the mammalian skeleton is formed through endochondral ossification starting from a cartilaginous *** cells, or chondrocytes, survive, proliferate and synthesize extracellular matrix in an avascular environment, but the metabolic requirements for these anabolic processes are not fully understood. Here, using metabolomics analysis and genetic in vivo models, we show that maintaining intracellular serine homeostasis is essential for chondrocyte function. De novo serine synthesis through phosphoglycerate dehydrogenase(PHGDH)-mediated glucose metabolism generates nucleotides that are necessary for chondrocyte proliferation and long bone growth. On the other hand, dietary serine is less crucial during endochondral bone formation, as serine-starved chondrocytes compensate by inducing PHGDH-mediated serine ***, this metabolic flexibility requires ATF4, a transcriptional regulator of amino acid metabolism and stress *** demonstrate that both serine deprivation and PHGDH inactivation enhance ATF4 signaling to stimulate de novo serine synthesis and serine uptake, respectively, and thereby prevent intracellular serine depletion and chondrocyte dysfunction. A similar metabolic adaptability between serine uptake and de novo synthesis is observed in the cartilage callus during fracture ***, the results of this study reveal a critical role for PHGDH-dependent serine synthesis in maintaining intracellular serine levels under physiological and serine-limited conditions, as adequate serine levels are necessary to support chondrocyte proliferation during endochondral ossification.