Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility, Jinan University, Guangzhou, 510632, China; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), Jinan University, Guangzhou, 510632, China; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, 510632, China; Joint Laboratory of Dalian Runsheng Kangtai and Jinan University, Jinan University, China.
Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility, Jinan University, Guangzhou, 510632, China; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), Jinan University, Guangzhou, 510632, China; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, 510632, China; Huizhou Health Sciences Polytechnic, Huizhou, 516025, China.
Redox Biol. 2022 Oct;56:102437. doi: 10.1016/j.redox.2022.102437. Epub 2022 Aug 20.
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 peroxidation in alkoxyl radicals-evoked abnormal chondrogenesis, and pinpoint it being a precise target for treating oxidative stress-related bone development disorders.
母体应激与不良出生结局有关，包括早产、婴儿死亡率和低出生体重。母体应激导致胚胎骨骼发育障碍被认为是通过氧化应激损伤介导的。各种自由基，如烷氧基自由基，可以通过内源性氧化还原反应或子宫内的外源性刺激形成，并传递到胚胎中。然而，这些自由基是否导致胎儿骨骼发育异常尚不清楚。在这里，我们证明了经典烷氧基自由基生成剂诱导了产前骨生长迟缓和软骨细胞铁死亡相关信号。我们还表明，烷氧基自由基通过胚胎中的铁介导的芬顿反应导致软骨细胞中氧化磷脂的大量积累。我们进一步证明了脂质过氧化终产物 4-HNE 的作用，它与关键的软骨生成转录因子 SOX9 形成加合物，导致其降解，从而抑制软骨生成。我们的数据定义了磷脂过氧化在烷氧基自由基引起的异常软骨生成中的关键作用，并指出它是治疗与氧化应激相关的骨骼发育障碍的精确靶点。
