Bone lengthening and fracture repair depend on the anabolic properties of chondrocytes that function in an avascular milieu. The limited supply of oxygen and nutrients calls into question how biosynthesis and redox homeostasis are guaranteed. Here we show that glucose metabolism by the pentose phosphate pathway (PPP) is essential for endochondral ossification. Loss of glucose-6-phosphate dehydrogenase in chondrocytes does not affect cell proliferation because reversal of the non-oxidative PPP produces ribose-5-phosphate. However, the decreased NADPH production reduces glutathione recycling, resulting in decreased protection against the reactive oxygen species (ROS) produced during oxidative protein folding. The disturbed proteostasis activates the unfolded protein response and protein degradation. Moreover, the oxidative stress induces ferroptosis, which, together with altered matrix properties, results in a chondrodysplasia phenotype. Collectively, these data show that in hypoxia, the PPP is crucial to produce reducing power that confines ROS generated by oxidative protein folding and thereby controls proteostasis and prevents ferroptosis.

Center for Biotechnology Khalifa University of Science and Technology Abu Dhabi United Arab Emirates

Laboratory of Angiogenesis and Vascular Metabolism Department of Oncology and Leuven Cancer Institute KU Leuven VIB Center for Cancer Biology VIB Leuven Belgium

Laboratory of Cellular Metabolism Institute of Biotechnology of the Czech Academy of Sciences Vestec Czechia

Laboratory of Clinical and Experimental Endocrinology Department of Chronic Diseases and Metabolism KU Leuven Leuven Belgium

Laboratory of Translational Genetics Department of Human Genetics and Leuven Cancer Institute KU Leuven Leuven Belgium

Laboratory of Translational Genetics VIB Center for Cancer Biology Leuven Belgium

VIB Bioimaging Core Leuven Center for Brain and Disease Research Leuven Belgium

VIB Bioimaging Core Leuven Department of Neurosciences KU Leuven Leuven Belgium

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