Department of Orthopedics, Liyang People's Hospital, Liyang City, Jiangsu Province, PR China.
Histol Histopathol. 2024 Aug;39(8):1017-1024. doi: 10.14670/HH-18-680. Epub 2023 Nov 27.
FOXO4 was previously identified as a potential biomarker and therapeutic target for postmenopausal osteoporosis (PMO) using bioinformatic analysis, but its specific function and molecular mechanism in the progression of osteoporosis was not reported. The current study was designed to investigate the biological function and underlying mechanism of FOXO4 in PMO. Our results showed that FOXO4 expression was significantly upregulated in the serum samples of PMO patients, which was also negatively correlated with the expression of osteogenesis genes (OCN and ALP). In addition, FOXO4 depletion alleviated osteoporosis by facilitating osteogenic differentiation and inhibiting adipogenic differentiation in human bone marrow mesenchymal stem cells (hBMSCs). Overexpression of FOXO4 exerted the opposite effects on the osteogenic/adipogenic differentiation in hBMSCs. Moreover, FOXO4 knockdown activated the Wnt/β-catenin signaling whereas the inhibition of Wnt/β-catenin signaling overturned the effects of FOXO4 deficiency on osteoporosis. Furthermore, FOXO4 upregulation in PMO was caused by CBP-induced acetylation. In summary, our data demonstrated that FOXO4 was a potent biomarker for PMO and mediated the balance between osteogenesis and adipogenesis in hBMSCs by regulating Wnt/β-catenin signaling.
FOXO4 先前曾通过生物信息学分析被鉴定为绝经后骨质疏松症 (PMO) 的潜在生物标志物和治疗靶点，但它在骨质疏松症进展中的具体功能和分子机制尚未报道。本研究旨在研究 FOXO4 在 PMO 中的生物学功能和潜在机制。我们的结果表明，PMO 患者的血清样本中 FOXO4 的表达显著上调，并且与成骨基因（OCN 和 ALP）的表达呈负相关。此外，FOXO4 的耗竭通过促进人骨髓间充质干细胞 (hBMSCs) 中的成骨分化和抑制成脂分化来缓解骨质疏松症。FOXO4 的过表达对 hBMSCs 中的成骨/成脂分化产生相反的影响。此外，FOXO4 的敲低激活了 Wnt/β-catenin 信号通路，而 Wnt/β-catenin 信号通路的抑制则推翻了 FOXO4 缺乏对骨质疏松症的影响。此外，PMO 中 FOXO4 的上调是由 CBP 诱导的乙酰化引起的。总之，我们的数据表明，FOXO4 是 PMO 的一个有力的生物标志物，并通过调节 Wnt/β-catenin 信号通路介导 hBMSCs 中成骨和成脂之间的平衡。
