Kurarinone, a Flavonoid from Radix Sophorae Flavescentis, Inhibits RANKL-induced Osteoclastogenesis in Mouse Bone Marrow-derived Monocyte/macrophages

Overview

Journal Naunyn Schmiedebergs Arch Pharmacol

Specialty Pharmacology

Date 2024 Apr 21

PMID 38643449

Authors

Ling Long

Hao Luo

Yi Wang

Jiaxiang Gu

Jiachao Xiong

Xiaokai Tang

Hao Lv

Faxin Zhou

Kai Cao

Sijian Lin

Affiliations

Soon will be listed here.

Abstract

Inflammation-induced osteoclast proliferation is a crucial contributor to impaired bone metabolism. Kurarinone (KR), a flavonoid extracted from the Radix Sophorae Flavescentis, exhibits notable anti-inflammatory properties. Nevertheless, the precise influence of KR on osteoclast formation remains unclear. This study's objective was to assess the impact of KR on osteoclast activity in vitro and unravel its underlying mechanism. Initially, a target network for KR-osteoclastogenesis-osteoporosis was constructed using network pharmacology. Subsequently, the intersecting targets were identified through the Venny platform and a PPI network was created using Cytoscape 3.9.1. Key targets within the network were identified employing topological algorithms. GO enrichment and KEGG pathway analysis were then performed on these targets to explore their specific functions and pathways. Additionally, molecular docking of potential core targets of KR was conducted, and the results were validated through cell experiments. A total of 83 target genes overlapped between KR and osteoclastogenesis-osteoporosis targets. Enrichment analysis revealed their role in inflammatory response, protein tyrosine kinase activity, osteoclast differentiation, and MAPK and NF-κB signaling pathways. PPI analysis and molecular docking demonstrate that key targets MAPK14 and MAPK8 exhibit more stable binding with KR compared to other proteins. In vitro experiments demonstrate that KR effectively inhibits osteoclast differentiation and bone resorption without cellular toxicity. It suppresses key osteoclast genes (NFATc1, c-Fos, TRAP, MMP9, Ctsk, Atp6v2), hinders IκB-α degradation, and inhibits ERK and JNK phosphorylation, while not affecting p38 phosphorylation. The results indicate that KR may inhibit osteoclast maturation and bone resorption by blocking NF-κB and MAPK signaling pathways, suggesting its potential as a natural therapeutic agent for osteoporosis.

References

Adler R . MANAGEMENT OF ENDOCRINE DISEASE: Atypical femoral fractures: risks and benefits of long-term treatment of osteoporosis with anti-resorptive therapy. Eur J Endocrinol. 2018; 178(3):R81-R87. DOI: 10.1530/EJE-17-1002. View

Adler R, Fuleihan G, Bauer D, Camacho P, Clarke B, Clines G . Managing Osteoporosis in Patients on Long-Term Bisphosphonate Treatment: Report of a Task Force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2015; 31(1):16-35. PMC: 4906542. DOI: 10.1002/jbmr.2708. View

Anastasilakis A, Polyzos S, Makras P . THERAPY OF ENDOCRINE DISEASE: Denosumab vs bisphosphonates for the treatment of postmenopausal osteoporosis. Eur J Endocrinol. 2018; 179(1):R31-R45. DOI: 10.1530/EJE-18-0056. View

Black D, Bauer D, Schwartz A, Cummings S, Rosen C . Continuing bisphosphonate treatment for osteoporosis--for whom and for how long?. N Engl J Med. 2012; 366(22):2051-3. PMC: 4015798. DOI: 10.1056/NEJMp1202623. View

Cosman F . Long-term treatment strategies for postmenopausal osteoporosis. Curr Opin Rheumatol. 2018; 30(4):420-426. DOI: 10.1097/BOR.0000000000000509. View

Xie W, Ji L, Zhao T, Gao P . Identification of transcriptional factors and key genes in primary osteoporosis by DNA microarray. Med Sci Monit. 2015; 21:1333-44. PMC: 4436946. DOI: 10.12659/MSM.894111. View

Gfeller D, Grosdidier A, Wirth M, Daina A, Michielin O, Zoete V . SwissTargetPrediction: a web server for target prediction of bioactive small molecules. Nucleic Acids Res. 2014; 42(Web Server issue):W32-8. PMC: 4086140. DOI: 10.1093/nar/gku293. View

Goel D, Vohora D . Liver X receptors and skeleton: Current state-of-knowledge. Bone. 2020; 144:115807. DOI: 10.1016/j.bone.2020.115807. View

Han J, Jin Y, Kim H, Park K, Lee W, Jeong T . Lavandulyl flavonoids from Sophora flavescens suppress lipopolysaccharide-induced activation of nuclear factor-kappaB and mitogen-activated protein kinases in RAW264.7 cells. Biol Pharm Bull. 2010; 33(6):1019-23. DOI: 10.1248/bpb.33.1019. View

10.

He Y, Zhang Q, Shen Y, Chen X, Zhou F, Peng D . Schisantherin A suppresses osteoclast formation and wear particle-induced osteolysis via modulating RANKL signaling pathways. Biochem Biophys Res Commun. 2014; 449(3):344-50. DOI: 10.1016/j.bbrc.2014.05.034. View

11.

Jeong T, Ryu Y, Kim H, Curtis-Long M, An S, An S . Low density lipoprotein (LDL)-antioxidant flavonoids from roots of Sophora flavescens. Biol Pharm Bull. 2008; 31(11):2097-102. DOI: 10.1248/bpb.31.2097. View

12.

Jin H, Wang Q, Chen K, Xu K, Pan H, Chu F . Astilbin prevents bone loss in ovariectomized mice through the inhibition of RANKL-induced osteoclastogenesis. J Cell Mol Med. 2019; 23(12):8355-8368. PMC: 6850941. DOI: 10.1111/jcmm.14713. View

13.

Kim H, Lee K, Kim J, Kim M, Kim J, Lee H . Selenoprotein W ensures physiological bone remodeling by preventing hyperactivity of osteoclasts. Nat Commun. 2021; 12(1):2258. PMC: 8050258. DOI: 10.1038/s41467-021-22565-7. View

14.

Kim J, Kim N . Regulation of NFATc1 in Osteoclast Differentiation. J Bone Metab. 2014; 21(4):233-41. PMC: 4255043. DOI: 10.11005/jbm.2014.21.4.233. View

15.

Kitaura H, Marahleh A, Ohori F, Noguchi T, Shen W, Qi J . Osteocyte-Related Cytokines Regulate Osteoclast Formation and Bone Resorption. Int J Mol Sci. 2020; 21(14). PMC: 7404053. DOI: 10.3390/ijms21145169. View

16.

La V, Tanabe S, Grenier D . Naringenin inhibits human osteoclastogenesis and osteoclastic bone resorption. J Periodontal Res. 2008; 44(2):193-8. DOI: 10.1111/j.1600-0765.2008.01107.x. View

17.

Lan J, Dou X, Li J, Yang Y, Xue C, Wang C . l-Arginine Ameliorates Lipopolysaccharide-Induced Intestinal Inflammation through Inhibiting the TLR4/NF-κB and MAPK Pathways and Stimulating β-Defensin Expression in Vivo and in Vitro. J Agric Food Chem. 2020; 68(9):2648-2663. DOI: 10.1021/acs.jafc.9b07611. View

18.

Li T, Hou X, Huang Y, Wang C, Chen H, Yan C . In vitro and in silico anti-osteoporosis activities and underlying mechanisms of a fructan, ABW90-1, from Achyranthes bidentate. Carbohydr Polym. 2021; 276:118730. DOI: 10.1016/j.carbpol.2021.118730. View

19.

Li Z, Lin M, Li Y, Shao J, Huang R, Qiu Y . Total flavonoids of Sophora flavescens and kurarinone ameliorated ulcerative colitis by regulating Th17/Treg cell homeostasis. J Ethnopharmacol. 2022; 297:115500. DOI: 10.1016/j.jep.2022.115500. View

20.

Liu Z, Guo F, Wang Y, Li C, Zhang X, Li H . BATMAN-TCM: a Bioinformatics Analysis Tool for Molecular mechANism of Traditional Chinese Medicine. Sci Rep. 2016; 6:21146. PMC: 4754750. DOI: 10.1038/srep21146. View