Quercetagetin Alleviates Inflammatory Osteoclastogenesis and Collagen Antibody-induced Arthritis Via Nrf2 Signaling and Pten/AKT/Nfatc1 Axis

Overview

Journal Arthritis Res Ther

Publisher Biomed Central

Specialty Rheumatology

Date 2025 Mar 8

PMID 40057805

Authors

Haojue Wang

Tao Yuan

Jingpeng Wang

Dengju Li

Wayne Yuk-Wai Lee

Ziqing Li

Shui Sun

Affiliations

Soon will be listed here.

Abstract

Purpose: Quercetagetin, a flavonoid derived from the natural herb Flos eriocauli, is used in traditional Chinese medicine for its fire-purging (anti-inflammation) and wind-expelling (pain-alleviating) properties. However, its potential effects concerning rheumatoid arthritis (RA) remain underexplored. This study was designed to elucidate the potential associations between Quercetagetin and RA, establishing the therapeutic potential of Quercetagetin and related mechanisms in RA treatment.

Methods: Network pharmacology was conducted to decipher related targets and signaling pathways between Quercetagetin and RA. In vitro assays were then conducted to explore the effects of Quercetagetin on osteoclast cell behaviors and corresponding signaling pathways. In vivo study further validated the therapeutic effect of Quercetagetin in collagen antibody-induced arthritis (CAIA) mice.

Results: The network pharmacological analysis indicated an intimate correlation of Quercetagetin with RA-related inflammatory osteolysis treatment. Pertaining to biological validations, 2 µM of Quercetagetin successfully inhibited LPS-driven osteoclast differentiation and function. qPCR assay and Western blot analyses denoted parallel changes in osteoclastic marker genes and proteins. Further mechanism study uncovered the effect of Quercetagetin in stimulating the Nrf2/Keap1 signaling pathway and moderating the Pten/AKT/Nfatc1 axis in osteoclasts. In vivo study revealed 40 mg/kg Quercetagetin every day could significantly relief joint destruction in CAIA mice.

Conclusions: Our study presents Quercetagetin 's therapeutic potential in treating RA, outlining its effects and potential mechanisms in suppressing LPS-induced osteoclast activity, and alleviating inflammatory bone destruction in CAIA model, thereby laying the groundwork for further translational research on Quercetagetin and Flos eriocauli in RA treatment.

References

Ko M, Kim Y, Kim H, Jeong S, Ahn D, Chung S . Network pharmacology and molecular docking approaches to elucidate the potential compounds and targets of Saeng-Ji-Hwang-Ko for treatment of type 2 diabetes mellitus. Comput Biol Med. 2022; 149:106041. DOI: 10.1016/j.compbiomed.2022.106041. View

Siebert S, Pratt A, Stocken D, Morton M, Cranston A, Cole M . Targeting the rheumatoid arthritis synovial fibroblast via cyclin dependent kinase inhibition: An early phase trial. Medicine (Baltimore). 2020; 99(26):e20458. PMC: 7328978. DOI: 10.1097/MD.0000000000020458. View

Figus F, Piga M, Azzolin I, McConnell R, Iagnocco A . Rheumatoid arthritis: Extra-articular manifestations and comorbidities. Autoimmun Rev. 2021; 20(4):102776. DOI: 10.1016/j.autrev.2021.102776. View

Komatsu N, Takayanagi H . Mechanisms of joint destruction in rheumatoid arthritis - immune cell-fibroblast-bone interactions. Nat Rev Rheumatol. 2022; 18(7):415-429. DOI: 10.1038/s41584-022-00793-5. View

Zhang W, Jiang G, Zhou X, Huang L, Meng J, He B . α-Mangostin inhibits LPS-induced bone resorption by restricting osteoclastogenesis via NF-κB and MAPK signaling. Chin Med. 2022; 17(1):34. PMC: 8898470. DOI: 10.1186/s13020-022-00589-5. View

Di Matteo A, Bathon J, Emery P . Rheumatoid arthritis. Lancet. 2024; 402(10416):2019-2033. DOI: 10.1016/S0140-6736(23)01525-8. View

Singh M, Divakaran R, Kumar Konda L, Kristam R . A classification model for blood brain barrier penetration. J Mol Graph Model. 2020; 96:107516. DOI: 10.1016/j.jmgm.2019.107516. View

Cutolo M, Shoenfeld Y, Bogdanos D, Gotelli E, Salvato M, Gunkl-Toth L . To treat or not to treat rheumatoid arthritis with glucocorticoids? A reheated debate. Autoimmun Rev. 2023; 23(1):103437. DOI: 10.1016/j.autrev.2023.103437. View

Yan G, Guo Y, Guo J, Wang Q, Wang C, Wang X . N-Acetylcysteine Attenuates Lipopolysaccharide-Induced Osteolysis by Restoring Bone Remodeling Balance via Reduction of Reactive Oxygen Species Formation During Osteoclastogenesis. Inflammation. 2020; 43(4):1279-1292. DOI: 10.1007/s10753-020-01207-y. View

10.

Thakur P, Kumar R, Choudhary N, Sharma R, Chaudhary A . Network pharmacology on mechanistic role of Thymus linearis Benth. against gastrointestinal and neurological diseases. Phytomedicine. 2023; 121:155098. DOI: 10.1016/j.phymed.2023.155098. View

11.

Chu M, Wu P, Hong M, Zeng H, Wong C, Feng Y . Lingzhi and San-Miao-San with hyaluronic acid gel mitigate cartilage degeneration in anterior cruciate ligament transection induced osteoarthritis. J Orthop Translat. 2021; 26:132-140. PMC: 7773973. DOI: 10.1016/j.jot.2020.07.008. View

12.

Dong Y, Kang H, Peng R, Liu Z, Liao F, Hu S . A clinical-stage Nrf2 activator suppresses osteoclast differentiation via the iron-ornithine axis. Cell Metab. 2024; 36(8):1679-1695.e6. DOI: 10.1016/j.cmet.2024.03.005. View

13.

Berman H, Henrick K, Nakamura H . Announcing the worldwide Protein Data Bank. Nat Struct Biol. 2003; 10(12):980. DOI: 10.1038/nsb1203-980. View

14.

Kensler T, Wakabayashi N, Biswal S . Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol. 2006; 47:89-116. DOI: 10.1146/annurev.pharmtox.46.120604.141046. View

15.

Rangasamy T, Guo J, Mitzner W, Roman J, Singh A, Fryer A . Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice. J Exp Med. 2005; 202(1):47-59. PMC: 2212893. DOI: 10.1084/jem.20050538. View

16.

Sherman B, Hao M, Qiu J, Jiao X, Baseler M, Lane H . DAVID: a web server for functional enrichment analysis and functional annotation of gene lists (2021 update). Nucleic Acids Res. 2022; 50(W1):W216-W221. PMC: 9252805. DOI: 10.1093/nar/gkac194. View

17.

Kim S, Chen J, Cheng T, Gindulyte A, He J, He S . PubChem in 2021: new data content and improved web interfaces. Nucleic Acids Res. 2020; 49(D1):D1388-D1395. PMC: 7778930. DOI: 10.1093/nar/gkaa971. View

18.

Sato K, Suematsu A, Okamoto K, Yamaguchi A, Morishita Y, Kadono Y . Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J Exp Med. 2006; 203(12):2673-82. PMC: 2118166. DOI: 10.1084/jem.20061775. View

19.

Tu J, Chen W, Fang Y, Han D, Chen Y, Jiang H . PU.1 promotes development of rheumatoid arthritis via repressing FLT3 in macrophages and fibroblast-like synoviocytes. Ann Rheum Dis. 2022; 82(2):198-211. PMC: 9887374. DOI: 10.1136/ard-2022-222708. View

20.

Gutierrez-Venegas G, Torras-Ceballos A, Gomez-Mora J, Fernandez-Rojas B . Luteolin, quercetin, genistein and quercetagetin inhibit the effects of lipopolysaccharide obtained from in H9c2 cardiomyoblasts. Cell Mol Biol Lett. 2017; 22:19. PMC: 5583969. DOI: 10.1186/s11658-017-0047-z. View