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Astragaloside IV modulates oxidative stress and osteoimmune-Wnt signaling in ovariectomized rats: an integrated study
Ya-Qing Li1,2, Xian-Ying Yao1, Yan Jing3
1First Clinical College, Shanxi University of Traditional Chinese Medicine, Jinzhong, China.
Background:
Postmenopausal osteoporosis (PMOP) is characterized by high-turnover bone loss and oxidative stress. Astragaloside IV (AS-IV) exhibits antioxidant and immunomodulatory activities, yet its skeletal effects and mechanistic basis in ovariectomized (OVX) models remain incompletely defined.
Methods:
Female Sprague-Dawley rats underwent bilateral ovariectomy. Six weeks after surgery, OVX rats were randomized to model, positive control, or AS-IV treatment (20/40/80 mg/kg, gavage, 8 weeks), with sham-operated controls. Serum bone-turnover markers (CTX-I, OCN, PTH) and oxidative stress markers (SOD, MDA) were measured by ELISA. Femora were assessed by micro-CT (BMD, BV/TV, Tb.N, Tb.Sp) and H&E staining. RNA sequencing was performed followed by GO/KEGG enrichment and WGCNA to identify hub genes, and molecular docking was used to evaluate AS-IV-target interactions. Multiplex immunofluorescence in the femoral trabecular bone quantified Lep, Ptgs2, Gfap, Igfbp2, Wnt1, β-catenin, and NF-κB p65 region (mean fluorescence intensity, normalized to Sham).
Results:
OVX rats developed a clear high-turnover phenotype with trabecular rarefaction, reflected by higher CTX-I and MDA and lower SOD. AS-IV produced a dose-related improvement in these readouts-CTX-I fell, oxidative stress was eased (SOD increased and MDA decreased), and OCN and PTH moved back toward control levels. Histological analysis showed AS-IV treatment partially mitigated the trabecular deterioration observed in OVX rats. However, micro-CT analysis showed no statistically significant differences in trabecular bone structure between AS-IV-treated groups and OVX controls (p > 0.05). RNA-seq identified osteoimmune and Wnt-centered programs and nominated hub genes including Lep, Ptgs2, Gfap, Igfbp2, Il22ra2, Wnt10a, and Wnt1. In femoral trabecular bone, multiplex immunofluorescence revealed increased NF-κB p65 and decreased Wnt1 and Gfap signals in OVX rats compared to Sham. High-dose AS-IV significantly reduced NF-κB p65 and partly restored Wnt1 and Gfap. However, Ptgs2 showed no significant differences across groups, and Igfbp2 and β-catenin were not significantly rescued within this sampling window. Molecular docking suggested favorable binding between AS-IV and selected targets, supporting its multitarget profile.
Conclusion:
AS-IV modulates oxidative stress and osteoimmune-Wnt signaling in OVX rats, with directional improvements in bone turnover markers but without significant micro-CT structural changes. This work provides a foundation for hypothesis-driven investigation of AS-IV in PMOP.
Insights
Astragaloside IV (AS-IV) improved bone turnover markers and eased oxidative stress in ovariectomized (OVX) rats, suggesting potential for postmenopausal osteoporosis (PMOP) treatment. Further research is needed to confirm structural bone benefits.
Area of Science:
- Biochemistry
- Pharmacology
- Bone Biology
Background:
- Postmenopausal osteoporosis (PMOP) involves high-turnover bone loss and oxidative stress.
- Astragaloside IV (AS-IV) has known antioxidant and immunomodulatory effects.
- Skeletal effects of AS-IV in ovariectomized (OVX) models require further elucidation.
Purpose of the Study:
- To investigate the skeletal effects and underlying mechanisms of AS-IV in an OVX rat model of PMOP.
- To assess AS-IV's impact on bone turnover, oxidative stress, and related signaling pathways.
- To explore AS-IV's potential as a therapeutic agent for PMOP.
Main Methods:
- OVX rats were treated with varying doses of AS-IV or controls for 8 weeks.
- Bone turnover markers (CTX-I, OCN, PTH) and oxidative stress markers (SOD, MDA) were measured.
- Femoral micro-CT, histology, RNA sequencing, and multiplex immunofluorescence were performed.
- Molecular docking evaluated AS-IV-target interactions.
Main Results:
- AS-IV treatment dose-dependently improved bone turnover markers and reduced oxidative stress.
- Histology showed partial mitigation of trabecular deterioration, but micro-CT revealed no significant structural changes.
- RNA-seq identified osteoimmune and Wnt-centered signaling pathways.
- AS-IV reduced NF-κB p65 and partially restored Wnt1 and Gfap levels in femoral bone.
Conclusions:
- AS-IV demonstrates potential in modulating oxidative stress and osteoimmune-Wnt signaling in OVX rats.
- Directional improvements in bone turnover markers were observed, but significant micro-CT structural changes were not detected.
- This study provides a basis for further investigation into AS-IV for PMOP treatment.
