4.7 Article

Phospholipid peroxidation-driven modification of chondrogenic transcription factor mediates alkoxyl radicals-induced impairment of embryonic bone development

Journal

REDOX BIOLOGY
Volume 56, Issue -, Pages -

Publisher

ELSEVIER
DOI: 10.1016/j.redox.2022.102437

Keywords

Lipid peroxidation; Ferroptosis; Alkoxyl radicals; Chondrogenic transcription factor; Embryonic bone development; Chondrogenesis

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The study demonstrates that maternal stress may lead to abnormal embryo bone development through oxidative stress damage, specifically by inducing ferroptosis-related signals in chondrocytes with alkoxyl radicals. This process causes accumulation of oxidized phospholipids in chondrocytes and dampens chondrogenesis through adduct formation with the SOX9 transcription factor.
Maternal stress has been associated with poor birth outcomes, including preterm birth, infant mortality, and low birth weight. Bone development disorders in the embryo as a result of maternal stress are believed to be mediated through oxidative stress damage. Various species of free radicals, such as alkoxyl radicals, can be formed through endogenous redox response or exogenous stimuli in the womb and transmitted to embryos. Yet, whether these free radicals lead to abnormal fetal bone development is unclear. Here, we demonstrate prenatal bone growth retardation and ferroptosis-related signals of chondrocytes were induced by classic alkoxyl radical generators. We also show that alkoxyl radicals lead to significant accumulation of oxidized phospholipids in chondrocytes, through the iron-mediated Fenton reaction in embryos. We further demonstrate a role for the lipid peroxidation end product, 4-HNE, which forms adducts with the pivotal chondrogenesis transcription factor SOX9, leading to its degradation, therefore dampening chondrogenesis. Our data define a critical role for phospholipid peroxi-dation in alkoxyl radicals-evoked abnormal chondrogenesis, and pinpoint it being a precise target for treating oxidative stress-related bone development disorders.

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