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Gegen Qinlian Decoction ameliorates type 2 diabetes osteoporosis via IGFBP3/MAPK/NFATc1 signaling pathway based on
Junzheng Yang1, Qi He1, Yunhan Wang2
1First School of Clinical Medicine, Guangzhou University of Chinese Medicine, 12 Jichang Road, Baiyun District, Guangzhou 510405, PR China; The Laboratory of Orthopaedics and Traumatology of Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, 12 Jichang Road, Baiyun District, Guangzhou 510405, PR China.
Background:
Osteoporosis affects more than half the patients with type 2 diabetes mellitus (T2DM). Up to data, there is no effective clinical practice in managing type 2 diabetes osteoporosis (T2DOP) because of its complex pathogenesis. Gegen Qinlian Decoction (GQD) has been used for the long-term management of T2DM. However, the underlying mechanism of GQD in the treatment of T2DOP remains unknown.
Purpose:
To reveal the role of GQD in T2DOP and its potential therapeutic targets in the management of T2DOP.
Study Design:
The effect of GQD on T2DOP was observed in db/db mice in four groups: model group, GQD low-dose group (GQD-L), GQD high-dose group (GQD-H), and metformin (positive control) group. C57BL/6J mice were used as the negative control group.
Methods:
Quantitative phytochemical analysis of GQD was performed using high-performance liquid chromatography (HPLC). Micro-CT and hematoxylin-eosin (H&E) staining were used to evaluate bone histomorphometry. To screen for candidate targets of GQD, a cytokine antibody array was used, followed by bioinformatics analysis. Quantitative real-time PCR (qRT-PCR) and western blotting (WB) were used to determine expression levels.
Results:
The major active components of GQD were confirmed by HPLC. Micro-CT and H&E staining showed that bone mass was significantly increased in the GQD-H group compared with the model group. Antibody arrays revealed that the expression of insulin-like growth factor binding protein 3 (IGFBP3) was elevated in the GQD-H group. The MAPK pathway was identified using bioinformatics analysis. Additionally, the levels of osteoclastogenesis-related genes, including cathepsin K (Ctsk), acid phosphatase 5 (Acp5), matrix metallopeptidase 9 (Mmp9), and ATPase H+ transporting V0 subunit D2 (Atp6v0d2) were significantly decreased in the GQD-H group. Compared with the model group, high-dosage GQD inhibited phosphorylation of extracellular signal-regulated kinases (ERKs) and P38 mitogen-activated protein kinase (MAPK) and the expression of c-Fos and nuclear factor of activated T cells 1 (NFATc1).
Conclusion:
GQD plays a protective role in T2DOP by upregulating IGFBP3 expression and downregulating the IGFBP3/MAPK/NFATc1 signaling pathway. IGFBP3 in serum may also be a novel biomarker in the treatment of T2DOP. Our current findings not only expand the application of GQD, but also provide a theoretical basis and guidance for T2DOP.
Insights
Gegen Qinlian Decoction (GQD) shows promise in treating type 2 diabetes osteoporosis (T2DOP) by increasing bone mass. It works by upregulating IGFBP3 and downregulating the IGFBP3/MAPK/NFATc1 pathway, suggesting IGFBP3 as a potential biomarker.
Area of Science:
- Endocrinology
- Pharmacology
- Orthopedics
Background:
- Osteoporosis is a common comorbidity in type 2 diabetes mellitus (T2DM), affecting over half of patients.
- The complex pathogenesis of type 2 diabetes osteoporosis (T2DOP) lacks effective clinical management strategies.
- Gegen Qinlian Decoction (GQD) is traditionally used for T2DM, but its mechanism in T2DOP is unknown.
Purpose of the Study:
- To investigate the role of GQD in T2DOP.
- To identify potential therapeutic targets of GQD for T2DOP management.
- To elucidate the underlying mechanism of GQD in T2DOP.
Main Methods:
- GQD's efficacy was assessed in a mouse model of T2DOP (db/db mice) with groups for low-dose GQD, high-dose GQD, and metformin control.
- Bone histomorphometry was evaluated using Micro-CT and H&E staining.
- Candidate targets were screened via cytokine antibody arrays and bioinformatics, with validation using qRT-PCR and Western blotting.
Main Results:
- GQD treatment, particularly high-dose, significantly increased bone mass in T2DOP mice.
- Insulin-like growth factor binding protein 3 (IGFBP3) expression was upregulated by GQD.
- GQD inhibited the IGFBP3/MAPK pathway, reducing osteoclastogenesis-related gene expression and key signaling molecules like ERK, p38 MAPK, c-Fos, and NFATc1.
Conclusions:
- GQD demonstrates a protective effect in T2DOP by modulating the IGFBP3/MAPK/NFATc1 signaling pathway.
- Elevated serum IGFBP3 may serve as a novel biomarker for T2DOP treatment.
- Findings support GQD's expanded application and provide a theoretical basis for T2DOP management.
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