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.

Highlights

  • During endochondral bone formation, multipotent mesenchymal progenitors condense and differentiate into chondrocytes

  • Compared to multipotent skeletal progenitor cells,[19] growth plate chondrocytes showed higher phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase 1 (PSAT1) mRNA and protein levels and higher gene expression levels of enzymes involved in one-carbon metabolism, such as SHMT1/2 and methylenetetrahydrofolate dehydrogenase 1/2 (MTHFD1/2) (Fig. 1a, b)

  • The increased expression of SSPrelated genes was linked to the chondrogenic phenotype, since genetic modulation of the expression of SOX9, the master chondrogenic transcription factor,[20] altered the expression of synthesis pathway (SSP) enzymes: SOX9 overexpression in skeletal progenitors increased PHGDH and PSAT1 levels, whereas deletion of SOX9 in lineagecommitted chondrocytes reduced PHGDH and PSAT1 expression (Fig. 1c and Supplementary Fig. 1a)

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Summary

Introduction

During endochondral bone formation, multipotent mesenchymal progenitors condense and differentiate into chondrocytes Within this cartilaginous anlage, chondrocyte proliferation and hypertrophy control long bone growth, whereas the extracellular matrix they deposit is used as a template for bone formation by osteoblasts.[1] These processes have to be strictly coordinated, because disruption of these events is often associated with the development of skeletal dysplasia.[2,3] since the cellular and molecular processes that contribute to bone regeneration mirror those occurring during skeletal growth, impaired chondrocyte function is associated with delayed fracture healing or nonunion.[4,5] understanding the molecular mechanisms that endow chondrocyte anabolism is necessary to accelerate the development of novel therapies for cartilage-related pathologies. Whether glucose-derived carbon supports chondrocyte anabolism via other pathways is still not known

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