Chiang Chen Hao, Kao Yu-Chieh, Lin Yi-Hui, Ma Yi-Shing, Wu Yu-Ting, Jian Bo-Yan, Wei Yau-Huei, Chen Chuan-Mu, Liou Ying-Ming
Department of Orthopaedics, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, 600, Taiwan.
Department of Microbiology, Immunology and Biopharmaceuticals, College of Life Sciences, National Chiayi University, Chiayi City, 600, Taiwan.
Cell Biosci. 2025 Jul 18;15(1):104. doi: 10.1186/s13578-025-01448-0.
Bone-derived mesenchymal stem cells (BMSCs) are multipotent stem cells capable of differentiating into adipocytes and osteoblasts. Dysfunctional differentiation, characterized by a shift from osteoblastogenesis to adipogenesis, is closely associated with metabolic and senile osteoporosis. The Aldo-keto reductase family 1 member A1 (Akr1A1) enzyme, which utilizes NADPH to reduce aldehyde groups to alcohols, has emerged as a potential regulator. This study investigates the role of reactive oxygen species (ROS) in modulating Akr1A1 expression during the lineage differentiation of human mesenchymal stem cells into osteoblasts and adipocytes.
Our findings demonstrate that increased ROS levels enhance the expression of C/EBP homology protein (CHOP) and Akr1A1 during adipogenic differentiation. Conversely, reduced ROS levels suppress CHOP and Akr1A1 expression in osteogenically committed cells. Functional studies involving Akr1A1 silencing and overexpression revealed that Akr1A1 expression levels dictate MSC lineage commitment without altering ROS production or CHOP expression. Knockdown of Akr1A1 suppressed adipogenesis while promoting osteoblastogenesis, accompanied by upregulation of SIRT1, PGC-1α, TAZ, and other osteogenic transcription factors. In contrast, overexpression of Akr1A1 reduced SIRT1, PGC-1α, and TAZ levels, thereby enhancing adipogenesis and inhibiting osteogenesis. These findings position Akr1A1 as a downstream target of the ROS/CHOP signaling pathway. Using an oxidative stress cell model induced by D-galactose in BMSCs, we confirmed that elevated ROS levels upregulate CHOP and Akr1A1 expression, preferentially driving differentiation into adipocytes over osteoblasts.
Our results reveal that intracellular ROS modulate CHOP and Akr1A1 expression, which regulate commitment to adipogenic and osteogenic lineages. This regulation appears to occur through inhibiting SIRT1-dependent pathways, shedding light on potential therapeutic targets for metabolic and age-related osteoporosis.
骨源性间充质干细胞（BMSCs）是能够分化为脂肪细胞和成骨细胞的多能干细胞。功能失调的分化，其特征是从成骨细胞生成向脂肪生成转变，与代谢性和老年性骨质疏松密切相关。醛酮还原酶家族1成员A1（Akr1A1）酶利用NADPH将醛基还原为醇，已成为一种潜在的调节因子。本研究调查了活性氧（ROS）在人骨髓间充质干细胞向成骨细胞和脂肪细胞谱系分化过程中调节Akr1A1表达的作用。
我们的研究结果表明，在脂肪生成分化过程中，ROS水平升高会增强C/EBP同源蛋白（CHOP）和Akr1A1的表达。相反，ROS水平降低会抑制成骨细胞中CHOP和Akr1A1的表达。涉及Akr1A1沉默和过表达的功能研究表明，Akr1A1表达水平决定了间充质干细胞的谱系定向，而不会改变ROS产生或CHOP表达。敲低Akr1A1可抑制脂肪生成，同时促进成骨细胞生成，并伴有SIRT1、PGC-1α、TAZ和其他成骨转录因子的上调。相反，Akr1A1的过表达降低了SIRT1、PGC-1α和TAZ水平，从而增强了脂肪生成并抑制了成骨。这些发现将Akr1A1定位为ROS/CHOP信号通路的下游靶点。使用BMSCs中由D-半乳糖诱导的氧化应激细胞模型，我们证实ROS水平升高会上调CHOP和Akr1A1表达，优先驱动分化为脂肪细胞而非成骨细胞。
我们的结果表明，细胞内ROS调节CHOP和Akr1A1表达，进而调节脂肪生成和成骨细胞谱系的定向。这种调节似乎是通过抑制SIRT1依赖的途径发生的，这为代谢性和年龄相关性骨质疏松症的潜在治疗靶点提供了线索。
