Scholarlink

Background <p>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 <i>Akr1A1</i> expression during the lineage differentiation of human mesenchymal stem cells into osteoblasts and adipocytes.</p> Results <p>Our findings demonstrate that increased ROS levels enhance the expression of <i>C/EBP homology protein (CHOP)</i> and <i>Akr1A1</i> during adipogenic differentiation. Conversely, reduced ROS levels suppress <i>CHOP</i> and <i>Akr1A1</i> expression in osteogenically committed cells. Functional studies involving <i>Akr1A1</i> silencing and overexpression revealed that <i>Akr1A1</i> expression levels dictate MSC lineage commitment without altering ROS production or <i>CHOP</i> expression. Knockdown of <i>Akr1A1</i> suppressed adipogenesis while promoting osteoblastogenesis, accompanied by upregulation of <i>SIRT1</i>, <i>PGC-1α</i>, <i>TAZ</i>, and other osteogenic transcription factors. In contrast, overexpression of <i>Akr1A1</i> 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 <i>CHOP</i> and <i>Akr1A1</i> expression, preferentially driving differentiation into adipocytes over osteoblasts.</p> Conclusions <p>Our results reveal that intracellular ROS modulate <i>CHOP</i> and <i>Akr1A1</i> 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.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Reactive oxygen species regulate adipose-osteogenic lineage commitment of human mesenchymal stem cells by modulating gene expression of C/EBP homology protein and aldo-keto reductase family 1 member A1

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年7月18日

查看全文
  • Chen Hao Chiang,
  • Yu-Chieh Kao,
  • Yi-Hui Lin,
  • Yi-Shing Ma,
  • Yu-Ting Wu,
  • Bo-Yan Jian,
  • Yau-Huei Wei,
  • Chuan-Mu Chen,
  • Ying-Ming Liou

摘要

Background

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.

Results

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.

Conclusions

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.