부산대학교 도서관

Bone formation is regulated by numerous factors, such as transcription factors, cytokines, and extracellular matrix molecules. Human hormone nuclear receptors (hHNR) are a family of ligand‐regulated transcription factors that are activated by steroid hormones, such as estrogen and progesterone, and various lipid‐soluble signals, including retinoic acid, oxysterols, and thyroid hormone. We found that an hHNR called NR4A1 was the most highly expressed after human MSC differentiation into osteoblasts by whole‐genome microarray. NR4A1 knockout decreased the osteoblastic differentiation of hMSCs in terms of ALPL expression and key marker gene expression. Whole‐genome microarray analysis further confirmed the decrease in key pathways when we knocked down NR4A1. Further studies with small molecule activators identified a novel molecule called Elesclomol (STA‐4783), which could activate and enhance osteoblast differentiation. Elesclomol activation of hMSCs also induced the gene expression of NR4A1 and rescued the phenotype of NR4A1 KD. In addition, Elesclomol activated the TGF‐ß pathway by regulating key marker genes. In conclusion, we first identified the role of NR4A1 in osteoblast differentiation and that Elesclomol is a positive regulator of NR4A1 through activation of the TGF‐ß signalling pathway. Significance statement: This paper investigates the role of the human hormone nuclear receptor (hHNR) NR4A1 in osteoblast differentiation and the effect of the small molecule activator Elesclomol (STA‐4783) on NR4A1 activation. This study found that NR4A1 plays a crucial role in osteoblast differentiation, with knockdown decreasing ALPL expression and key marker gene expression. This study further identified Elesclomol as a positive regulator of NR4A1 through the activation of the TGF‐ß signalling pathway. The temporal expression of NR4A1 during osteoblast differentiation was also studied, showing sporadic expression. This study provides valuable insights into the molecular mechanisms of osteoblast differentiation and potential therapeutic targets for bone‐related diseases. [ABSTRACT FROM AUTHOR]