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Background <p>Glucocorticoid-induced osteoporosis (GIOP) is a bone disorder marked by decreased bone density and an elevated risk of fracture. The Phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway plays a pivotal role in regulating osteoblast proliferation and differentiation, serving as a central molecular mechanism in bone homeostasis and making it a potential therapeutic target for GIOP. YS-49, an l-naphthylmethyl analog of higenamine, has demonstrated that it can influence various cellular processes through activating the PI3K/AKT signaling pathway.This study investigated the role and mechanism of YS-49 in osteoblast differentiation.</p> Methods <p>MC3T3-E1 cells were utilized to evaluate cell viability, apoptosis, reactive oxygen species (ROS) levels, malondialdehyde (MDA), superoxide dismutase (SOD) levels, Determinationosteogenic differentiation, and mineralization after treatment with YS-49 and dexamethasone (Dex). Osteogenic differentiation of MC3T3-E1 cells was assessed by Western blot and alkaline phosphatase (ALP) staining, with the former specifically analyzing YS-49-induced activation of the PI3K/AKT signaling pathway. Additionally, a GIOP mouse model was established, and the therapeutic effects of YS-49 were evaluated via bone mineral density (BMD), micro-computed tomography (micro-CT), enzyme linked immunosorbent assay (ELISA), and histopathological analysis.</p> Results <p>YS-49 enhanced cell viability, inhibited ROS production, and suppressed apoptosis in Dex-treated MC3T3-E1 cells. Moreover, it promoted osteogenic differentiation and mineralization by activating the PI3K/AKT signaling pathway. In vivo, YS-49 treatment significantly mitigated Dex-induced bone loss, as evidenced by the increased BMD, enhanced trabecular structure, and upregulation of the expression of osteogenic markers.</p> Conclusion <p>YS-49 promotes osteogenesis and prevents glucocorticoid-induced bone loss by activating the PI3K/AKT signaling pathway, collectively positioning it as a promising novel therapeutic agent for GIOP treatment.</p>

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YS-49 activates the PI3K/AKT signaling pathway in MC3T3-E1 cells to enhance osteoblast differentiation and inhibits glucocorticoid-induced bone loss in vivo

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月14日

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  • Yuting Cao,
  • Yifan Yu,
  • Feng Wang,
  • Kunqi Zhang,
  • Zengxin Jiang,
  • Qinglin Kang,
  • Jia Xu

摘要

Background

Glucocorticoid-induced osteoporosis (GIOP) is a bone disorder marked by decreased bone density and an elevated risk of fracture. The Phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway plays a pivotal role in regulating osteoblast proliferation and differentiation, serving as a central molecular mechanism in bone homeostasis and making it a potential therapeutic target for GIOP. YS-49, an l-naphthylmethyl analog of higenamine, has demonstrated that it can influence various cellular processes through activating the PI3K/AKT signaling pathway.This study investigated the role and mechanism of YS-49 in osteoblast differentiation.

Methods

MC3T3-E1 cells were utilized to evaluate cell viability, apoptosis, reactive oxygen species (ROS) levels, malondialdehyde (MDA), superoxide dismutase (SOD) levels, Determinationosteogenic differentiation, and mineralization after treatment with YS-49 and dexamethasone (Dex). Osteogenic differentiation of MC3T3-E1 cells was assessed by Western blot and alkaline phosphatase (ALP) staining, with the former specifically analyzing YS-49-induced activation of the PI3K/AKT signaling pathway. Additionally, a GIOP mouse model was established, and the therapeutic effects of YS-49 were evaluated via bone mineral density (BMD), micro-computed tomography (micro-CT), enzyme linked immunosorbent assay (ELISA), and histopathological analysis.

Results

YS-49 enhanced cell viability, inhibited ROS production, and suppressed apoptosis in Dex-treated MC3T3-E1 cells. Moreover, it promoted osteogenic differentiation and mineralization by activating the PI3K/AKT signaling pathway. In vivo, YS-49 treatment significantly mitigated Dex-induced bone loss, as evidenced by the increased BMD, enhanced trabecular structure, and upregulation of the expression of osteogenic markers.

Conclusion

YS-49 promotes osteogenesis and prevents glucocorticoid-induced bone loss by activating the PI3K/AKT signaling pathway, collectively positioning it as a promising novel therapeutic agent for GIOP treatment.