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

  • BMC Musculoskelet Disord. 2025 Oct 14;26(1):961. doi: 10.1186/s12891-025-09167-w.
Yuting Cao  #  1 ,  Yifan Yu  #  1 ,  Feng Wang  1 ,  Kunqi Zhang  1 ,  Zengxin Jiang  2 ,  Qinglin Kang  3 ,  Jia Xu  4
Affiliations
  • 1. Department of Orthopedic Surgery, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
  • 2. Department of Orthopedic Surgery, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China. [email protected].
  • 3. Department of Orthopedic Surgery, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China. [email protected].
  • 4. Department of Orthopedic Surgery, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China. [email protected].
  • # Contributed equally.
PMID: 41088103 DOI: 10.1186/s12891-025-09167-w
Abstract

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.

Supplementary Information: The online version contains supplementary material available at 10.1186/s12891-025-09167-w.

Keywords
Glucocorticoid-induced osteoporosis; Osteoblast; PI3K/AKT signaling pathway; YS-49.
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