ArticleBone research2022
De novo serine synthesis regulates chondrocyte proliferation during bone development and repair.
Article in Bone research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 31 citations in OpenAlex.
- Engineered Cyanobacteria-Hydrogel Microecological System for Oxygen Reprogramming Synergizes Immunomodulation With Anabolism in Osteoarthritis Therapy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Metabolomic analysis of gingival crevicular fluid for dental age and skeletal maturity assessment in growing individuals.European journal of orthodontics · 2026Article
- SERINC3 promotes osteogenic differentiation of BMSCs via IL-32/AMPK-mediated autophagy and mitochondrial energy metabolism.Stem cell research & therapy · 2026Article
- Changes in bone characteristics precede serum mineral deterioration in a mouse model of early stage chronic kidney disease.JBMR plus · 2026Article
- PHGDH-mediated serine synthesis reduces oligodendrocyte death by sustaining GSH and NADPH levels after brain ischemia.Frontiers in pharmacology · 2026Article
- PHGDH-mediated serine synthesis in astrocytes supports neuroinflammation by sustaining NADH level to promote histone acetylation.Cell death & disease · 2025Article
- Serine metabolism in aging and age-related diseases.GeroScience · 2025Review
- The pentose phosphate pathway controls oxidative protein folding and prevents ferroptosis in chondrocytes.Nature metabolism · 2025Article
- Metabolic reprogramming in skeletal cell differentiation.Bone research · 2024Review
- Metabolic regulation of skeletal cell fate and function.Nature reviews. Endocrinology · 2024Review
- Serine Metabolism Regulates the Replicative Senescence of Human Dental Pulp Cells through Histone Methylation.Current issues in molecular biology · 2024Article
- Knockdown of Kmt2d leads to growth impairment by activating the Akt/β-catenin signaling pathway.G3 (Bethesda, Md.) · 2024Article
- Articular cartilage repair biomaterials: strategies and applications.Materials today. Bio · 2024Review
- Combined Transcriptomics and Metabolomics Identify Regulatory Mechanisms of Porcine Vertebral Chondrocyte Development In Vitro.International journal of molecular sciences · 2024Article
- Functions and Metabolism of Amino Acids in Bones and Joints of Cats and Dogs.Advances in experimental medicine and biology · 2024Article
- The serine synthesis pathway drives osteoclast differentiation through epigenetic regulation of NFATc1 expression.Nature metabolism · 2024Article
- Lineage-specific multifunctional double-layer scaffold accelerates the integrated regeneration of cartilage and subchondral bone.Materials today. Bio · 2023Article
- Beyond energy and growth: the role of metabolism in developmental signaling, cell behavior and diapause.Development (Cambridge, England) · 2023Article
- Nutrient metabolism of the nucleus pulposus: A literature review.North American Spine Society journal · 2023Article
- Glucose metabolism in skeletal cells.Bone reports · 2022Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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Registered trials
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