Mechanism of action of total saponin Achyranthes in treating knee osteoarthritis explored using network pharmacology and animal experimentation

Document Type : Original Article

Authors

1 The Third Affiliated Hospital of Changchun University of Traditional Chinese Medicine, Changchun 130117, China

2 Institute of College of Pharmacy, Changchun University of Chinese Medicine, Changchun 130117, China

3 Jilin Cancer Hospital, Changchun, Changchun 130012, China

4 Affiliated Hospital of Changchun University of Chinese Medicine, Changchun 130021, China

10.22038/ijbms.2025.83153.17974

Abstract

Objective(s): Knee osteoarthritis (KOA) is a persistent degenerative disease affecting the joints, significantly reducing the quality of life for individuals afflicted. This study explores the therapeutic effects of total  saponin Achranthes (TSA) on KOA rats and its underlying mechanism. 
Materials and Methods: Forty-eight rats were randomly assigned to six experimental groups: a blank control group, a model group, a sham-operated group, and a TSA treatment group (low, medium, and high dose), with eight rats in each group. The rats were treated continuously for four weeks. The degree of joint swelling was quantified, and the Lequesne MG score was evaluated. Network pharmacology approaches were employed to pinpoint potential TSA targets and related pathways for managing KOA. Additionally, histopathological examinations were conducted on the knee cartilage of the rats. Serum levels of TNF-α and IL-1β were assessed through the ELISA assay. 
Results: The network pharmacology results indicate that TSA may effectively treat KOA through the MAPK and PI3K/Akt signaling pathways. Moreover, TSA significantly decreased the serum concentrations of pro-inflammatory cytokines such as TNF-α and IL-1β, and  TSA down-regulated the P38 MAPK, PI3K/Akt, and NF-κB pathways, whereas the KOA model showed up-regulation. The treatment also significantly reduced MMP-9, MMP-13, and ADAMTS-5 protein levels.
Conclusion: TSA can potentially ameliorate inflammation, safeguard knee cartilage tissue, and alleviate symptoms of KOA by inhibiting the MAPK/Akt/NF-κB signaling pathway.

Keywords

Main Subjects

References

1. Ma T, Wang XP, Qu WJ, Yang LS, Jing C, Zhu BR, et al. Osthole suppresses knee osteoarthritis development by enhancing autophagy activated via the AMPK/ULK1 pathway. Molecules 2022; 27: 8624-8640.
2. Liew JW, King LK, Mahmoudian A, Wang Q, Atkinson HF, Flynn DB, et al. A scoping review of how early-stage knee osteoarthritis has been defined. Osteoarthritis Cartilage 2023; 31: 1234-1241.
3. Giorgino R, Albano D, Fusco S, Peretti GM, Mangiavini L, Messina C. Knee osteoarthritis: Epidemiology, pathogenesis, and mesenchymal stem cells: What else is new? An update. Int J Mol Sci 2023; 24: 6405-6422.
4. Schreiner AJ, Stoker AM, Bozynski CC, Kuroki K, Stannard JP, Cook JL. Clinical application of the basic science of articular cartilage pathology and treatment. J Knee Surg 2020; 33: 1056-1068.
5. Zhang PW, Dong B, Yuan PW, Li X. Human umbilical cord mesenchymal stem cells promoting knee joint chondrogenesis for the treatment of knee osteoarthritis: A systematic review. J Orthop Surg Res 2023; 18: 639-651.
6. Zhu JM, Ruan GF, Cen H, Meng T, Zheng S, Wang Y, et al. Association of serum levels of inflammatory markers and adipokines with joint symptoms and structures in participants with knee osteoarthritis. Rheumatology 2022; 61: 1044-1052.
7. Rousset F, Hazane-Puch F, Pinosa C, Nguyen MVC, Grange L, Soldini A, et al. IL-1beta mediates MMP secretion and IL-1beta neosynthesis via upregulation of p22 phox and NOX4 activity in human articular chondrocytes. Osteoarthritis Cartilage 2015; 23: 1972-1980.
8. de Almeida LGN, Thode H, Eslambolchi Y, Chopra S, Young D, Gill S, et al. Matrix metalloproteinases: From molecular mechanisms to physiology, pathophysiology, and pharmacology. Pharmacol Rev 2022; 74: 712-768.
9. Alexander LC, McHorse G, Huebner JL, Bay-Jensen AC, Karsdal MA, Kraus VB. A matrix metalloproteinase-generated neoepitope of CRP can identify knee and multi-joint inflammation in osteoarthritis. Arthritis Res Ther 2021; 23: 226-235.
10. Kan HS, Chan PK, Chiu KY, Yan CH, Yeung SS, Ng YL, et al. Non-surgical treatment of knee osteoarthritis. Hong Kong Med J 2019; 25: 127-133.
11. Bindu S, Mazumder S, Bandyopadhyay U. Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: A current perspective. Biochem Pharmacol 2020; 180: 114147-114169.
12. He XR, Wang XX, Fang JC, Chang Y, Ning N, Guo H, et al. The genus achyranthes: A review on traditional uses, phytochemistry, and pharmacological activities. J Ethnopharmacol 2017; 203: 260-278.
13. Kiuchi F. Saponin constituents of Achyranthes root. J Nat Med 2022; 76: 343-351.
14. Li J, Li P, Li HJ, Song Y, Bi ZM, Li YJ. Simultaneous qualification and quantification of eight triterpenolds in Radix Achyranthis Bidentatae by high-performance liquid chromatography with evaporative light scattering detection and mass spectrometric detection. J Sep Sci 2007; 30: 843-850.
15. Xu XX, Zhang XH, Diao Y, Huang YX. Achyranthes bidentate saponins protect rat articular chondrocytes against interleukin-1β-induced inflammation and apoptosis in vitro. Kaohsiung J Med Sci 2017; 33: 62-68.
16. Tao Y, Huang SR, Yan JZ, Cai BC. Determination of major components from Radix Achyranthes bidentate using ultra high performance liquid chromatography with triple quadrupole tandem mass spectrometry and an evaluation of their anti-osteoporosis effect in vitro. J Sep Sci 2019; 42: 2214-2221.
17. Khan N, Akhtar MS, Khan BA, Braga VD, Reich A. Antiobesity, hypolipidemic, antioxidant and hepatoprotective effects of Achyranthes aspera seed saponins in high cholesterol fed Albino rats. Arch Med Sci 2015; 11: 1261-1271.
18. Shi Y, Zhang ZW, Du MM, Wu J, Li JX. Saponin extract from Achyranthes bidentata Blume alleviates disuse-induced muscle atrophy through PI3K/Akt signaling pathway. J Ethnopharmacol 2023; 312: 116458.
19. Zeng MN, Feng AZ, Wang L, Li K, Zhou JH. Aralia saponin A isolated from Achyranthes bidentata Bl. ameliorates LPS/D-GalN induced acute liver injury via SPHK1/S1P/S1PR1 pathway in vivo and in vitro. Int Immunopharmacol 2023; 124: 110912-110927.
20. Xie WP, Qi SF, Dou LM, Wang L, Wang XP, Bi RX, et al. Achyranthoside D attenuates chondrocyte loss and inflammation in osteoarthritis via targeted regulation of Wnt3a. Phytomedicine 2023; 111: 154663.
21. Zhao L, Zhang H, Li N, Chen JM, Xu H, Wang YJ, et al. Network pharmacology, a promising approach to reveal the pharmacology mechanism of Chinese medicine formula. J Ethnopharmacol 2023; 309: 116306.
22. Li Q, Xu J-Y, Hu X, Li J, Huang X-J, Wu Z-Y, et al. The protective effects and mechanism of Ruyi Zhenbao Pill, a Tibetan medicinal compound, in a rat model of osteoarthritis. J Ethnopharmacol 2023; 308: 116255.
23. Shi XW, Yu WJ, Wang T, Battulga O, Wang CJ, Shu Q, et al. Electroacupuncture alleviates cartilage degradation: Improvement in cartilage biomechanics via pain relief and potentiation of muscle function in a rabbit model of knee osteoarthritis. Biomed  Pharmacother 2020; 123: 109724-109738.
24. Jang S, Lee K, Ju JH. Recent updates of diagnosis, pathophysiology, and treatment on osteoarthritis of the knee. Int J Mol Sci 2021; 22: 2619-2634.
25. Luyten FP, Bierma-Zeinstra S, Dell’Accio F, Kraus VB, Nakata K, Sekiya I, et al. Toward classification criteria for early osteoarthritis of the knee. Semin Arthritis Rheum 2018; 47: 457-463.
26. Fu J, Wu H, Wu H, Deng R, Sun MH. Deciphering the metabolic profile and pharmacological mechanisms of Achyranthes bidentata blume saponins using ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry coupled with network pharmacology-based investigation. J Ethnopharmacol 2021; 274: 114067.
27. Murat N, Karadam B, Ozkal S, Karatosun V, Gidener S. Quantification of papain-induced rat osteoarthritis in relation to time with the Mankin score. Acta Orthop Traumatol Turc 2007; 41: 233-237.
28. Li L, Li ZX, Li YY, Hu X, Zhang Y, Fan P. Profiling of inflammatory mediators in the synovial fluid related to pain in knee osteoarthritis. Bmc Musculoskelet Disord 2020; 21: 99-109.
29. Geng RZ, Li JY, Yu C, Zhang CQ, Chen F, Chen J, et al. Knee osteoarthritis: Current status and research progress in treatment (Review). Exp Ther Med 2023; 26: 481-492.
30. Wojdasiewicz P, Poniatowski LA, Szukiewicz D. The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of osteoarthritis. Mediators Inflamm 2014; 2014: 561459-561478.
31. Bollmann M, Pinno K, Ehnold LI, Märtens N, Martson A, Pap T, et al. MMP-9 mediated Syndecan-4 shedding correlates with osteoarthritis severity. Osteoarthritis Cartilage 2021; 29: 280-289.
32. Makki MS, Haqqi TM. Histone deacetylase inhibitor vorinostat (SAHA) suppresses IL-1β-induced matrix metallopeptidase-13 expression by inhibiting IL-6 in osteoarthritis chondrocyte. Am J Pathol 2016; 186: 2701-2708.
33. Wang PE, Xu JB, Sun Q, Ge QW, Qiu M, Zou KA, et al. Chondroprotective mechanism of Eucommia ulmoides oliv.-Glycyrrhiza uralensis fisch. couplet medicines in knee osteoarthritis via experimental study and network pharmacology analysis. Drug Des Devel Ther 2023; 17: 633-646.
34. Zhao CW, Song WX, Liu B, Gao YH, Ding L, Huang YF, et al. Resistin induces chemokine and matrix metalloproteinase production via CAP1 receptor and activation of p38-MAPK and NF-κB signalling pathways in human chondrocytes. Clin Exp Rheumatol 2022; 40: 501-513.
35. Xu XT, Li NP, Wu YR, Yan K, Mi YL, Yi NX, et al. Zhuifeng tougu capsules inhibit the TLR4/MyD88/NF-κB signaling pathway and alleviate knee osteoarthritis: In vitro and in vivo experiments. Front Pharmacol 2022; 13: 951860-951880.
36. Jing N, Fang B, Li Z, Tian AY. Exogenous activation of cannabinoid-2 receptor modulates TLR4/MMP9 expression in a spinal cord ischemia reperfusion rat model. J Neuroinflammation 2020; 17: 101-115.
37. Li J, Jiang MQ, Yu ZT, Xiong CW, Pan JE, Cai ZH, et al. Artemisinin relieves osteoarthritis by activating mitochondrial autophagy through reducing TNFSF11 expression and inhibiting PI3K/AKT/mTOR signaling in cartilage. Cell Mol Biol Lett 2022; 27: 62-81.
38. Hossain MA, Alam MJ, Kim B, Kang CW, Kim JH. Ginsenoside-Rb1 prevents bone cartilage destruction through down-regulation of p-Akt, p-P38, and p-P65 signaling in rabbit. Phytomedicine 2022; 100: 154039.
39. Qian YQ, Feng ZH, Li XB, Hu ZC, Xuan JW, Wang XY, et al. Downregulating PI3K/Akt/NF-B signaling with allicin for ameliorating the progression of osteoarthritis: In vitro and vivo studies. Food Funct 2018; 9: 4865-4875.
Iranian Journal of Basic Medical Sciences
Volume 28, Issue 6
June 2025
Pages 762-771

Files

Share

How to cite

Statistics