典型文献
De novo serine synthesis regulates chondrocyte proliferation during bone development and repair
文献摘要：
The majority of the mammalian skeleton is formed through endochondral ossification starting from a cartilaginous template.Cartilage 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 synthesis.Mechanistically,this metabolic flexibility requires ATF4,a transcriptional regulator of amino acid metabolism and stress responses.We 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 repair.Together,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.
文献关键词：
中图分类号：
作者姓名：
Steve Stegen;Shauni Loopmans;Ingrid Stockmans;Karen Moermans;Peter Carmeliet;Geert Carmeliet
作者机构：
Laboratory of Clinical and Experimental Endocrinology,Department of Chronic Diseases and Metabolism,KU Leuven,3000 Leuven,Belgium;Laboratory of Angiogenesis and Vascular Metabolism,VIB Center for Cancer Biology,3000 Leuven,Belgium;Laboratory of Angiogenesis and Vascular Metabolism,Department of Oncology and Leuven Cancer Institute,KU Leuven,3000 Leuven,Belgium;State Key Laboratory of Ophthalmology,Zhongshan Ophthalmic Center,Sun Yat-Sen University,Guangzhou 510080,China
文献出处：
引用格式：
[1]Steve Stegen;Shauni Loopmans;Ingrid Stockmans;Karen Moermans;Peter Carmeliet;Geert Carmeliet-.De novo serine synthesis regulates chondrocyte proliferation during bone development and repair)[J].骨研究（英文版）,2022(02):274-285
A类：
endochondral,cartilaginous
B类：
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AB值：
0.553747
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