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. 2023 Aug 18;102(33):e34815. doi: 10.1097/MD.0000000000034815

Astragaloside IV relieves IL-1β-induced human nucleus pulposus cells degeneration through modulating PI3K/Akt signaling pathway

Lu Zhang a, Junsheng Gao a, Zhentao Li a, Jun Liu a, Chong Zhang a, Jie Liu a, Hui Dong a, Wei Mei a,*
PMCID: PMC10443759  PMID: 37603510

Abstract

Background:

Intervertebral disc degeneration (IDD) is a multifactorial disease that is associated with nucleus pulposus (NP) apoptosis and extracellular matrix (ECM) degeneration and inflammation. Astragaloside IV (AS IV) has antioxidant, free radical scavenging, anti-inflammatory and anti-apoptosis effects. This study was to investigate whether AS IV could inhibit IL-1β-mediated apoptosis of HNP cells and its possible signal transduction pathway.

Methods:

Human nucleus pulposus cells (HNPCs) were stimulated with AS IV or LY294002 (PI3K inhibitor), followed by exposure to IL-1β for 24 hours. CCK8, TUNEL analysis and flow cytometry, ELISA and Western blotting were used to analyze the effects of AS IV on cell proliferation, apoptosis, inflammation, ECM and PI3K/Akt pathway signaling path-related proteins in IL-1β-induced HNPCs.

Results:

Compared with IL-1β-induced HNPCs, AS IV could improve the proliferation activity and the expressions of Collagen II, Aggrecan and Bcl-2 proteins, inhibit the apoptosis rate, inflammation and Bax and cleaved caspase-3 protein expression, and increase the activity of PI3K/Akt pathway. LY294002 attenuated the protective effect of AS IV against IL-1β-induced HNPCs degeneration.

Conclusion:

AS IV can inhibit IL-1β-induced HNPCs apoptosis inflammation and ECM degeneration by activating PI3K/Akt signaling pathway, which can be an effective drug to reduce disc degeneration.

Keywords: apoptosis, Astragaloside IV, degeneration, extracellular matrix, human nucleus pulposus cells, inflammation

1. Introduction

Intervertebral disc degeneration (IDD) is the pathological basis of a series of spinal degenerative diseases and is one of the common orthopedic diseases leading to decreased quality of life. However, there is no definitive drug available to address this condition.[1] The main structures of the intervertebral disc are the innermost nucleus pulposus (NP), the annulus fibrosus wrapped around the outer part of the NP, and the endplates, which are in contact with the upper and lower vertebral bodies.[2] Nucleus pulposus cells (NPCs) are the primary constituent cells of NP, which belong to the chondrocyte. They can secrete aggrecan and collagenII to synthesize extracellular matrix (ECM) to maintain the homeostasis of NP.[3] Under the stimulation of various factors in vivo and in vitro, proteoglycan depolymerization in NP increases, collagenII and ECM degradation, and the biological function of NPCs changes irreverently, leading to IDD diseases.[4] At the same time, apoptosis and inflammation of NPCs are also closely related to IDD.[5,6] Therefore, inhibition of inflammation, cell apoptosis and degradation of ECM of human nucleus pulposus cells (HNPCs) may be therapeutic targets for delaying IDD.

Astragaloside IV (AS IV, the chemical structure is shown in Fig. 1A) is one of the main active components extracted from Astragalus, and the molecular formula C41H68O14 and many pharmacological effects. Studies have shown that AS IV has antioxidant, free radical scavenging, anti-inflammatory and anti-apoptosis effects.[7,8] Currently, AS IV is used in the treatment of orthopedic diseases. AS IV can promote the differentiation of bone marrow mesenchymal stem cells into chondrocytes, and induce the proliferation of articular cartilage nuclear bone marrow mechanism cells.[9] Recent studies have shown that AS IV attenuates IDD,[10] but the mechanism of action is unclear.

Figure 1.

Figure 1.

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Effects of AS IV on cell viability of IL-1β-induced HNPCs. (A) Chemical structure of AS IV. (B) Cell viability of IL-1β-induced HNPCs detected by CCK-8. Data represent as mean ± S.D, n = 3. *P < .05 compared with control, #P < .05 compared with IL-1β treatment, &P < .05 compared with AS IV treatment. AS IV = astragaloside IV, HNPCs = human nucleus pulposus cells.

PI3K/AKT signaling pathway is an important intracellular signaling (including the release of inflammatory cytokines) pathway, which can regulate apoptosis, inflammatory response and ECM degradation.[11,12] AS IV can protect nerve and myocardial cells from damage by activating the PI3K/AKT signaling pathway.[13,14] However, it is unclear whether the mechanism of AS IV prevention against IDD is related to its activation of the PI3K/AKT signaling pathway. Therefore, in this study, IL-1β was used to induce the degeneration of HNPCs to prepare IDD models in vitro, To explore whether the effect of AS IV on HNPCs degeneration and its mechanism is related to the PI3K/AKT signaling pathway.

2. Materials and methods

2.1. HNPCs isolation and treatments

HNPCs (ScienCell Inc.) were continuously cultured in DMEM medium supplemented with 10% fetal bovine serum in an incubator containing 5% CO2 at 37°C. When the cells were grown and fused to about 80% of the bottom area of the dish, they were digested by trypsin and then cultured by passage. The second-generation cells were applied for subsequent experiments.

HNPCs were treated with IL-1β (10 ng/mL) for 24 hours as an IDD model in vitro. To investigate the effects of HNPCs on AS IV on IDD, HNPCs were pretreated with 100 μM AS IV (Shanghai Yuanye Biotechnology Co. Ltd, China) for 2 hours, followed by exposure to IL-1β (10 ng/mL) for 24 hours. The concentration of AS IV used here was based on our previous study.[10] Meanwhile, HNPCs were stimulated with 10 μM LY294002 (Sigma-Aldrich) to block the PI3K/Akt pathway. HNPCs treated only with DMEM/F12 medium with 15% FBS containing DMSO were a control.

2.2. CCK-8 assay

HNPCs were inoculated in 96-well plates (1 × 105 cells/well) with 5 duplicated wells. Culture for 24 hours, added 10 μL CCK-8 to each well following incubation at 37°C for 2 hours. The absorbance of each pore sample was measured by a multifunctional enzyme labeler at 450 nm. Cell viability was calculated with normal cells as control.

2.3. Apoptosis detection by TUNEL analysis and flow cytometry

HNPCs apoptosis was determined with the TUNEL apoptosis detection kit (Roche Applied Science, Switzerland) following the procedures. The cells in each group were treated with 0.2% Triton X-100 (Solarbio) for 10 minutes, cells were incubated with the TdT labeling reaction buffer for 60 minutes. The counterstain for cell nuclear was performed by interacting with 4′,6-diamidino-2-phenylindole (DAPI) (Solarbio) for 5 minutes. Cells were examined under fluorescence microscopy (Leica, Wetzlar, Germany), and the apoptosis rate was presented as the ratio of TUNEL-positive cells.

HNPCs apoptosis was also determined by flow cytometry. The cells in each group were digested by 0.25% trypsin, washed and resuspended with pre-cooling PBS buffer to adjust the cell density to 1 × 105 cells/mL. 5 μL Annexin V-FITC was added and incubated in darkness for 15 minutes at room temperature. Then propidium iodide was added and incubated for 5 minutes in darkness before the operation. The apoptosis rate of cells was detected by CytoFLEX flow cytometry.

2.4. ELISA

After digestion, cleavage and centrifugation, the supernatant was collected. ELISA kit (Solarbio) was used to detect IL-6 and TNF-α levels. The specific operations were conducted with the instructions of the ELISA kit.

2.5. Western blot

The total protein extraction kit was used to extract the total protein. The BCA method was used to detect the protein concentration. SDS-PAGE electrophoresis was used to transfer the membrane and block. The first antibody was incubated overnight at 4°C. The primary antibodies (Abcam) including anti-Bax (1:1000), anti-cleaved caspase-3, anti-Bcl-2 (1:1000), anti-Collagen II (1:5000), anti-Aggrecan (1:1000), anti-MMP-13 (1:1000), anti-Akt(1:1000), anti-p-Akt (1:500) and anti-GAPDH (1:1000) antibodies. After washing the membrane, HRP-labeled IgG secondary antibodies (1:5000) were incubated at room temperature for 1 hour. ECL was used as a developer. The software Image J was used for image analysis. GAPDH was used as an internal parameter to calculate the relative protein expression according to the gray value of the band.

2.6. Statistical analysis

All data were analyzed by SPSS19.0. The one-way ANOVA analysis was used for the comparison among the groups, and the LSD-t test was used for the pairwise comparison among the groups. P < .05 means the difference was statistically significant.

3. Results

3.1. Effects of AS IV on IL-1β-induced HNPCs’ viability

To estimate whether AS IV can alleviate the toxic effects of IL-1β on HNPCs, we determined the cell viability of IL-1β-induced HNPCs cells after 100 μM AS IV treatment by CCK-8 assay. As shown in Figure 1B, IL-1β treatment significantly decreased the cell viability, compared with the control HNPCs (P < .05). But AS IV treatment significantly increased the cell viability, compared with the IL-1β-induced HNPCs (P < .05). Additionally, the inhibitor LY294002 significantly decreased the cell viability, compared with the AS IV-treated HNPCs (P < .05).

3.2. Effects of AS IV on apoptosis of IL-1β-induced HNPCs

Abnormal apoptosis of HNPCs contributes to the progression of IDD. To elucidate the effect of AS IV on the apoptosis of IL-1β-induced HNPCs, we performed the TUNEL and FCM analysis. As shown in Figure 2A and B, IL-1β treatment significantly increased the apoptosis rate, compared with the control HNPCs (P < .05). AS IV treatment significantly decreased the cell apoptosis rate, compared with the IL-1β-induced HNPCs (P < .05). Moreover, the inhibitor LY294002 treatment significantly increased the apoptosis rate, compared with the AS IV-treated HNPCs (P < .05).

Figure 2.

Figure 2.

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Effects of AS IV on apoptosis in IL-1β-induced HNPCs. (A) Cell apoptosis was examined by TUNEL analysis. (B) Cell apoptosis was examined using flow cytometry. (C) The expressions of Bax, cleaved caspase-3 and Bcl-2 were examined with Western blot. Data represent as mean ± S.D, n = 3. *P < .05 compared with control, #P < .05 compared with IL-1β treatment, &P < .05 compared with AS IV treatment. AS IV = astragaloside IV, HNPCs = human nucleus pulposus cells.

To further evaluate the effect of AS IV on IL-1β-induced apoptosis, we also examined the anti-apoptosis proteins Bcl-2 and pro-apoptosis proteins Bax and cleaved caspase-3 by Western blot analysis. As shown in Figure 2C, IL-1β treatment significantly up-regulated the expression of Bax and cleaved caspase-3, and down-regulated the expression of Bcl-2, compared with the control (P < .05). However, AS IV treatment significantly down-regulated the expression of Bax and cleaved caspase-3, and up-regulated the expression of Bcl-2 compared with the IL-1β-induced HNPCs (P < .05). Moreover, the inhibitor LY294002 markedly reversed the effects treated by As IV (P < .05).

3.3. Effects of AS IV on IL-1β-induced inflammation in HNPCs

To evaluate the anti-inflammatory properties of AS IV, we measured the expression levels of TNF-α and IL-6 by ELISA test. As shown in Figure 3A, IL-1β treatment significantly increased the concentrations of TNF-α and IL-6, compared with the control HNPCs (P < .05). While AS IV treatment significantly decreased the concentrations of TNF-α and IL-6, compared with the IL-1β-induced HNPCs (P < .05). Moreover, the inhibitor LY294002 significantly increased the concentrations of TNF-α and IL-6, compared with the AS IV-treated HNPCs (P < .05).

Figure 3.

Figure 3.

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The effect of AS IV on inflammation and ECM in IL-1β-induced HNPCs. (A) The levels of IL-6 and TNF-α were detected by ELISA. (B) The expressions of Collagen II, Aggrecan and MMP-13 were measured by Western blot. Data represent as mean ± S.D, n = 3. *P < .05 compared with control, #P < .05 compared with IL-1β treatment, &P < .05 compared with AS IV treatment. AS IV = astragaloside IV, ECM = extracellular matrix, HNPCs = human nucleus pulposus cells.

3.4. Effects of AS IV on ECM in IL-1β-induced HNPCs

To elucidate the effects of AS IV on the ECM produced by HNPCs, we examined the effects of AS IV on the major proteins by Western blot analysis Aggrecan, Collagen II and MMP-13. As shown in Figure 3B, IL-1β treatment significantly up-regulated the expression of MMP-13 and down-regulated the expression of Aggrecan and Collagen II, compared with the control HNPCs (P < .05). However, AS IV treatment significantly down-regulated MMP-13 expression, and up-regulated Aggrecan and Collagen II expression, compared with the IL-1β-induced HNPCs (P < .05). Moreover, the inhibitor LY294002 significantly reversed changes in Aggrecan, Collagen II and MMP-13 proteins treated by AS IV (P < .05).

3.5. Effects of AS IV on PI3K/Akt pathway in IL-1β-induced HNPCs

To reveal the mechanisms of ECM degradation and apoptosis of HNPCs during IDD, we examined the proteins involved in the PI3K/Akt signaling pathway by Western blot analysis. As shown in Figure 4, IL-1β treatment significantly decreased the levels of phosphorylation of Akt, compared with the control HNPCs (P < .05). Additionally, AS IV treatment significantly upregulated the levels of phosphorylation of Akt, compared with the IL-1β-induced HNPCs (P < .05). Moreover, the inhibitor LY294002 markedly reversed the effects treated by AS IV (P < .05).

Figure 4.

Figure 4.

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The effect of AS IV on PI3K/Akt pathway in IL-1β-induced HNPCs. The expressions of Akt and p-Akt were measured by Western blot. Data represent as mean ± S.D, n = 3. *P < .05 compared with control, #P < .05 compared with IL-1β treatment, &P < .05 compared with AS IV treatment. AS IV = astragaloside IV, HNPCs = human nucleus pulposus cells.

4. Discussion

IDD can cause spinal stenosis, spinal instability and lumbar disc herniation in patients. IDD leads to low back pain and related complications, seriously damaging the labor force and bringing a heavy economic burden to society.[15] Current treatments for IDD only temporarily relieve pain, failing to eradicate the causes.[10] Therefore, it is of great significance to find a safer and more effective treatment for IDD. Studies have shown that during IDD, inflammatory cytokines such as IL-1β and TNF-α can induce NPCs apoptosis by stimulating NP, increase the expression of MMP13, decrease the expression of collagen II and aggrecan, and lead to the progressive deterioration of intervertebral disc.[16,17] Furthermore, Excessive apoptosis of NPCs leads to a decrease in the synthesis of ECM, and ultimately to IDD.[6,18] Therefore, inhibition of inflammation, apoptosis and ECM degradation may be therapeutic targets for delaying IDD.

Chinese medicine is well known to play a significant role in health in Chinese. In recent years, some Chinese herbs proved to be effective in treating a variety of diseases, which have been used as an additional and alternative therapy for IDD patients.[19] Many recent studies have partially established the usefulness of Chinese medicine in treating IDD, with the primary mechanisms including reduction of oxidative stress, regulation of inflammatory response, and decrease of myeloid cell death, among others.[20,21] AS IV is a natural saponin purified from the traditional Chinese medicine Astragalus membranaceus, which has anti-inflammatory, antioxidant, anti-apoptosis and anti-cancer pharmacological activities.[22] Previous studies have shown that AS IV inhibits IL-1β-induced chondrocyte inflammatory mediators, apoptosis and ECM degradation, and alleviates the progression of osteoarthritis.[23] Since NP and articular cartilage have similar histocytological composition and biomechanical function. NPCs and chondrocytes have similar phenotypes. Therefore, it is speculated that AS IV may be effective in treating IDD. In this study, IL-1β was used to stimulate HNPCs to simulate IDDs in vitro, and treated with AS IV. The results showed that AS IV significantly reduced the levels of inflammatory cytokines TNF-α and IL-6 in IL-1β-induced HNPCs, indicating that AS IV effectively inhibited IL-1β-induced inflammatory response in vitro. Meanwhile, AS IV significantly down-regulated the apoptosis rate and the expression of Bax and cleaved caspase-3 protein, and up-regulated the expression of Bcl-2 protein in IL-1β-induced HNPCs, suggesting that AS IV could alleviate IL-1β-induced apoptosis. Next, we evaluated the effect of AS IV on the ECM degradation of HNPCs. AS IV significantly down-regulated the expression of MMP-13, and up-regulated the expression of Aggrecan and Collagen II in IL-1β-induced HNPCs, suggesting that AS IV treatment alleviated IL-1β-induced ECM degradation. Taken together, these results suggest that AS IV alleviates IL-1β-induced inflammatory response, apoptosis, and ECM degradation in HNPCs, similar to previous research.

PI3K/Akt pathway is a major intracellular pathway that regulates cell proliferation, apoptosis, differentiation, autophagy and other processes under physiological and pathological conditions by interacting with multiple downstream target proteins.[24] Currently, studies on PI3K/Akt pathway play a very important role in the pathological development of IDD.[25] In this study, the results showed that IL-1β significantly inhibited activation of the PI3K/Akt pathway whereas in HNPCs. It is further proved that the PI3K/Akt pathway plays an important role in IDD, which is consistent with the results of previous studies.[26,27] More and more evidence shows that the targeted regulation of the PI3K/Akt pathway has become one of the effective methods to treat IDD.[26,28] Jiang et al[29] found that Resveratrol partly suppressed IL-1β-induced HNPCs apoptosis by activating the PI3K/Akt pathway. Zhu et al[30] found that higenamine suppressed cell apoptosis in IL-1β-induced HNPCs via activating ROS-mediated PI3K/Akt pathway. At the same time, studies have found that AS IV effectively alleviated IDD in vivo and in vitro.[10,31] In addition, AS IV ability to stimulate the PI3K/AKT pathway has been pointed out many times and is related to antiapoptosis, antioxidative stress and the protective effect of ischemia-reperfusion.[32,33] However, it is not clear whether AS IV can alleviate disc degeneration by interfering with PI3K/Akt pathway. Thus, we detected the levels of phosphorylation of Akt, and the results showed that AS IV significantly upregulated the levels of phosphorylation of Akt. LY294002, a PI3K-specific protein kinase inhibitor, has been widely used in the study of the PI3K/Akt pathway. In this study, LY294002 treatment significantly inhibited the levels of phosphorylation of Akt, reversed the protective effect treated by AS IV on degraded HNPCs. LY294002 treatment promoted the inflammatory response and apoptosis, markedly reversed the effects treated by AS IV. All of the results supported that AS IV had a strong protective effect on IL-1β-induced HNPCs, and that the PI3K/AKT pathway was, at least partly, involved in this protective effect. However, it remains unknown whether AS IV alleviates IDD by activating PI3K/Akt pathway in vivo. In our future experiments, we will evaluate the protective properties of AS IV using the vivo model. Moreover, we only explored the involvement of the PI3K/Akt pathway, while other pathways were not evaluated. This issue could be addressed in future studies to fully elucidate the mechanism of AS IV involvement in IDD treatment.

In conclusion, AS IV alleviates IL-1β-induced inflammation, apoptosis and ECM degeneration by activating PI3K/Akt pathway, suggesting that AS IV has therapeutic potential for treating IDD.

Author contributions

Conceptualization: Junsheng Gao, Jun Liu.

Data curation: Jie Liu.

Methodology: Chong Zhang.

Software: Zhentao Li.

Validation: Hui Dong.

Writing – original draft: Lu Zhang.

Writing – review & editing: Wei Mei.

Abbreviations:

AS IV
Astragaloside IV
ECM
extracellular matrix
HNPCs
human nucleus pulposus cells
IDD
intervertebral disc degeneration
NP
nucleus pulposus
NPCs
nucleus pulposus cells

This research was supported by Science and Technology Project of Henan Provincial Health Department (LHGJ20220790).

Not applicable. This article does not involve clinical or animal testing.

The authors declare no conflicts of interest.

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

How to cite this article: Zhang L, Gao J, Li Z, Liu J, Zhang C, Liu J, Dong H, Mei W. Astragaloside IV relieves IL-1β-induced human nucleus pulposus cells degeneration through modulating PI3K/Akt signaling pathway. Medicine 2023;102:33(e34815).

Contributor Information

Lu Zhang, Email: zhanggz_zy@163.com.

Junsheng Gao, Email: gaojunsheng_jz@163.com.

Zhentao Li, Email: lihailiangtg@163.com.

Jun Liu, Email: lkyypl@163.com.

Chong Zhang, Email: zhanggz_zy@163.com.

Jie Liu, Email: lkyypl@163.com.

Hui Dong, Email: dbzjjmz@163.com.

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