Work

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

Year: 2025

Type: article

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.

Source: BMC Musculoskeletal Disorders

DOI: 10.1186/s12891-025-09167-w