Abstract
Objective
To explore the mechanism of paeoniflorin (PF) on osteoarthritis (OA) synovial inflammation from network pharmacology to experimental pharmacology.
Methods
Targets of OA were constructed by detecting the database of network database platforms (Therapeutic Target database, DrugBank and GeneCards), and the targets of PF were constructed by PubChem and Herbal Ingredients’ Targets database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of these co-targeted genes were conducted via Database for Annotation, Visualization, and Integrated Discovery (DAVID) database, and protein-protein interaction (PPI) networks were conducted via the search tool for the retrieval of interacting genes (STRING) database. Cell counting kit-8 (CCK-8) assay was performed to assess the potential toxicity of PF on human OA fibroblast-like synoviocytes (FLS), quantitative real-time polymerase chain reaction (qPCR), enzyme-linked immunosorbent assay (ELISA) and Western blot were used to verify the potential mechanism of PF in synovial inflammation.
Results
Twenty-six co-targeted genes were identified. GO enrichment results showed that these co-targeted genes were most likely localized in the cytoplasm, and the biological processes mainly involved ‘cellular response to hypoxia’ ‘lipopolysaccharide (LPS)-mediated signaling pathway’ and ‘positive regulation of gene expression’. KEGG pathway analysis indicated that these co-targeted genes may function through pathways associated with ‘hypoxia-inducible factor-1 (HIF-1) signaling pathway’ and ‘tumor-necrosis factor (TNF) signaling pathway’. The PPI network showed that the top 3 hub genes were TP53, TNF, and CASP3. Molecular docking results showed that PF was well docking with TNF. CCK-8 showed no potential toxicity of 10, 20 and 50 µmol/L PF on human OA FLS. And PF significantly decreased the expression levels of interleukin-1 β, interleukin-6, TNF-α matrix metalloproteinase 13 (MMP13), and a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) and TNF-α in LPS-induced OA FLS.
Conclusion
PF exhibited potent anti-inflammatory effect in OA synovial inflammation.
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References
GBD 2021 Other Musculoskeletal Disorders Collaborators. Global, regional, and national burden of other musculoskeletal disorders, 1990–2020, and projections to 2050: a systematic analysis of the Global Burden of Disease Study 2021. Lancet Rheumatol 2023;5:e670–e682.
Chen P, Huang L, Ma Y, Zhang D, Zhang X, Zhou J, et al. Intraarticular platelet-rich plasma injection for knee osteoarthritis: a summary of meta-analyses. J Orthop Surg Res 2019;14:385.
Chen P, Huang L, Zhang D, Zhang X, Ma Y, Wang Q. Mobile bearing versus fixed bearing for total knee arthroplasty: meta-analysis of randomized controlled trials at minimum 10-year follow-up. J Knee Surg 2022;35:135–144.
Zhuang SZ, Chen PJ, Han J, Xiao WH. Beneficial Effects and potential mechanisms of Tai Chi on lower limb osteoarthritis: a biopsychosocial perspective. Chin J Integr Med 2023;29:368–376.
Wang H, Wang Q, Yang M, Yang L, Wang W, Ding H, et al. Histomorphology and innate immunity during the progression of osteoarthritis: Does synovitis affect cartilage degradation? J Cell Physiol 2018;233:1342–1358.
Yang Y, Wang Y, Kong Y, Zhang X, Zhang H, Gang Y, et al. Carnosine prevents type 2 diabetes-induced osteoarthritis through the ROS/NF-κ B pathway. Front Pharmacol 2018;9:598–611.
Guo JM, Xiao Y, Cai TY, Wang JH, Li BL, Huang LL, et al. Chinese medicine involving triple rehabilitation therapy for knee osteoarthritis in 696 outpatients: a multi-Center, randomized controlled trial. Chin J Integr Med 2021;27:729–736.
Wang XY, Nie ZY, Yu QQ, Chen W, Zhang XN, Wang HY, et al. Acupuncture enhances signals at sensitized acupoints to elevate pressure pain threshold in knee osteoarthritis patients. Chin J Integr Med 2022;28:1105–1110.
Silverstein AM, Stefani RM, Sobczak E, Tong EL, Attur MG, Shah RP, et al. Toward understanding the role of cartilage particulates in synovial inflammation. Osteoarthritis Cartilage 2017;25:1353–1361.
Kuo SJ, Yang WH, Liu SC, Tsai CH, Hsu HC, Tang CH. Transforming growth factor beta1 enhances heme oxygenase 1 expression in human synovial fibroblasts by inhibiting microRNA 519b synthesis. PLoS One 2017;12: e0176052–0176066.
Chen P, Ruan A, Zhou J, Huang L, Zhang X, Ma Y, et al. Extraction and identification of synovial tissue-derived exosomes by different separation techniques. J Orthop Surg Res 2020;15:97–106.
Chen P, Zhou J, Ruan A, et al. Synovial tissue-derived extracellular vesicles induce chondrocyte inflammation and degradation via NF- κ B signalling pathway: an in vitro study. J Cell Mol Med 2022;26:2038–2048.
Chen Z, Li XP, Li ZJ, Xu L, Li XM. Reduced hepatotoxicity by total glucosides of paeony in combination treatment with leflunomide and methotrexate for patients with active rheumatoid arthritis. Int Immunopharmacol 2013;15:474–477.
Jia XY, Chang Y, Sun XJ, Wu HX, Wang C, Xu HM, et al. Total glucosides of paeony inhibit the proliferation of fibroblast-like synoviocytes through the regulation of G proteins in rats with collagen-induced arthritis. Int Immunopharmacol 2014;18:1–6.
Xu H, Cai L, Zhang L, Wang G, Xie R, Jiang Y, et al. Paeoniflorin ameliorates collagen-induced arthritis via suppressing nuclear factor-kappa B signalling pathway in osteoclast differentiation. Immunology 2018;17:593–603.
Liu H, Wang J, Wang J, Wang P, Xue Y. Paeoniflorin attenuates Abeta1–42-induced inflammation and chemotaxis of microglia in vitro and inhibits NF-kappa B and VEGF/ Flt-1 signaling pathways. Brain Res 2015;1618:149–158.
Xing D, Ma Y, Lu M, Liu W, Zhou H. Paeoniflorin alleviates hypoxia/reoxygenation injury in HK-2 cells by inhibiting apoptosis and repressing oxidative damage via Keap1/Nrf2/ HO-1 pathway. BMC Nephrol 2023;24:314–325.
Zhai W, Ma Z, Wang W, Song L, Yi J. Paeoniflorin inhibits Rho kinase activation in joint synovial tissues of rats with collagen-induced rheumatoid arthritis. Biomed Pharmacother 2018;106:255–259.
Wang Y, Zhang S, Li F, Zhou Y, Zhang Y, Wang Z, et al. Therapeutic target database 2020: enriched resource for facilitating research and early development of targeted therapeutics. Nucleic Acids Res 2020;48:1031–1041.
Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, et al. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res 2018;46:1074–1082.
Stelzer G, Rosen N, Plaschkes I, Zimmerman S, Twik M, Fishilevich S, et al. The genecards suite: from gene data mining to disease genome sequence analyses. Curr Protoc Bioinformatics 2016;54:1–33.
Xu HY, Zhang YQ, Liu ZM, Chen T, Lv CY, Tang SH, et al. ETCM: an encyclopaedia of traditional Chinese medicine. Nucleic Acids Res 2019;47:976–982.
Ye H, Ye L, Kang H, Zhang D, Tao L, Tang K, et al. HIT: linking herbal active ingredients to targets. Nucleic Acids Res 2011;39:1055–1059.
Huang da W, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 2009;4:44–57.
The Gene Ontology C. Expansion of the gene ontology knowledgebase and resources. Nucleic Acids Res 2017;45:331–338.
Du J, Yuan Z, Ma Z, Song J, Xie X, Chen Y. Kegg-Path: kyoto encyclopedia of genes and genomes-based pathway analysis using a path analysis model. Mol Biosyst 2014;10:2441–2447.
Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, et al. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res 2019;47:607–613.
Bader GD, Hogue CW. An automated method for finding molecular complexes in large protein interaction networks. BMC Bioinformatics 2003;4:2–29.
Wang H, Wang Q, Yang M, Yang L, Wang W, Ding H, et al. Histomorphology and innate immunity during the progression of osteoarthritis: does synovitis affect cartilage degradation? J Cell Physiol 2018;233:1342–1358.
Yang Y, Wang Y, Kong Y, Zhang X, Zhang H, Feng X, et al. Moderate mechanical stimulation protects rats against osteoarthritis through the regulation of TRAIL via the NF- κ B/NLRP3 Pathway. Oxid Med Cell Longev 2020;2020:6196398–6196409.
Lu J, Feng X, Zhang H, Wei Y, Yang Y, Tian Y, et al. Maresin-1 suppresses IL-1 β -induced MMP-13 secretion by activating the PI3K/AKT pathway and inhibiting the NF- κ B pathway in synovioblasts of an osteoarthritis rat model with treadmill exercise. Connect Tissue Res 2021;62:508–518.
Chen J, Yu X, Zhang X. Advances on biological functions of exosomal non-coding RNAs in osteoarthritis. Cell Biochem Funct 2022;40:49–59.
Sharif B, Garner R, Hennessy D, Sanmartin C, Flanagan WM, Marshall DA. Productivity costs of work loss associated with osteoarthritis in Canada from 2010 to 2031. Osteoarthr Cartil 2017;25:249–258.
Atukorala I, Kwoh CK, Guermazi A, Roemer FW, Boudreau RM, Hannon MJ, et al. Synovitis in knee osteoarthritis: a precursor of disease? Ann Rheum Dis 2016;75:390–395.
Yin N, Gao Q, Tao W, Chen J, Bi J, Ding F, et al. Paeoniflorin relieves LPS-induced inflammatory pain in mice by inhibiting NLRP3 inflammasome activation via transient receptor potential vanilloid 1. J Leukoc Biol 2020;108:229–241.
Wang T, Xu L, Gao L, Zhao L, Liu XH, Chang YY, et al. Paeoniflorin attenuates early brain injury through reducing oxidative stress and neuronal apoptosis after subarachnoid hemorrhage in rats. Metab Brain Dis 2020;35:959–970.
Zhou S, Ai Z, Li W, You P, Wu C, Li L, et al. Deciphering the pharmacological mechanisms of Taohe-Chengqi decoction extract against renal fibrosis through integrating network pharmacology and experimental validation in vitro and in vivo. Front Pharmacol 2020;11:425–443.
Wang P, Dai L, Zhou W, Meng J, Zhang M, Wu Y, et al. Intermodule coupling analysis of Huang-Lian-Jie-Du decoction on stroke. Front Pharmacol 2019;10:1288–1302.
Ran J, Ma C, Xu K, Xu L, He Y, Moqbel SAA, et al. Schisandrin B ameliorated chondrocytes inflammation and osteoarthritis via suppression of NF- κ B and MAPK signal pathways. Drug Des Devel Ther 2018;12:1195–1204.
Xu Z, Yang H, Zhou X, Li J, Jiang L, Li D, et al. Genetic variants in mTOR-pathway-related genes contribute to osteoarthritis susceptibility. Int Immunopharmacol 2019;77:105960–105967.
Wan Y, Lv Y, Li L, Yin Z. 15-Lipoxygenase-1 in osteoblasts promotes TGF-β 1 expression via inhibiting autophagy in human osteoarthritis. Biomed Pharmacother 2020;121:109548–109556.
Kamiya N, Kuroyanagi G, Aruwajoye O, Kim HKW. IL6 receptor blockade preserves articular cartilage and increases bone volume following ischemic osteonecrosis in immature mice. Osteoarthr Cartil 2019;27:326–335.
Li G, Tan W, Fang Y, Wu X, Zhou W, Zhang C, et al. circFADS2 protects LPS-treated chondrocytes from apoptosis acting as an interceptor of miR-498/mTOR cross-talking. Aging (Albany NY). 2019;11:3348–3361.
Zhu X, Wang L, Teng X, Chen Q, Pan C. N-Methyl Pyrrolidone (NMP) alleviates lipopolysaccharide (LPS)-induced inflammatory injury in articular chondrocytes. Med Sci Monit 2018;24:6480–6488.
Fernández-Torres J, Martínez-Nava GA, Gutiérrez-Ruíz MC, Gómez-Quiroz LE, Gutiérrez M. Role of HIF-1 α signaling pathway in osteoarthritis: a systematic review. Rev Bras Reumatol (Engl ed) 2017;57:162–173.
Yang Q, Zhou Y, Cai P, Fu W, Wang J, Wei Q, et al. Up-regulated HIF-2α contributes to the osteoarthritis development through mediating the primary cilia loss. Int Immunopharmacol 2019;75:105762–105768.
Guo Y, Feng Y, Liu H, Luo S, Clarke JW, Moorman PG, et al. Potentially functional genetic variants in the TNF/TNFR signaling pathway genes predict survival of patients with non-small cell lung cancer in the PLCO cancer screening trial. Mol Carcinog 2019;58:1094–1104.
Tang M, Zhu WJ, Yang ZC, He CS. Brucine inhibits TNF-α -induced HFLS-RA cell proliferation by activating the JNK signaling pathway. Exp Ther Med 2019;18:735–740.
Li M, Ren CX, Zhang JM, Xin XY, Hua T, Wang HB, et al. The effects of miR-195-5p/MMP14 on proliferation and invasion of cervical carcinoma cells through TNF signaling pathway based on bioinformatics analysis of microarray profiling. Cell Physiol Biochem 2018;50:1398–1413.
Huan X, Jinhe Y, Rongzong Z. Identification of pivotal genes and pathways in osteoarthritic degenerative meniscallesions via bioinformatics analysis of the GSE52042 dataset. Med Sci Monit 2019;25:8891–8904.
Zhu X, Yang S, Lin W, Wang L, Ying J, Ding Y, et al. Roles of cell cyle regulators Cyclin D1, CDK4, and p53 in knee osteoarthritis. Genet Test Mol Biomarkers 2016;20:529–534.
Prokhorova EA, Kopeina GS, Lavrik IN, Zhivotovsky B. Apoptosis regulation by subcellular relocation of caspases. Sci Rep 2018;8:12199–12210.
Wei Y, Bai L. Recent advances in the understanding of molecular mechanisms of cartilage degeneration, synovitis and subchondral bone changes in osteoarthritis. Connect Tissue Res 2016;57:245–261.
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Wang QF contributed to the conception of the study; Chen P, Ruan AM, Zhou J and MA YF conducted the experiment; Chen P wrote the manuscript; Chen P and Zhou J analyzed the data. All author read the paper and approved the final version for publication.
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Supported by the National Natural Science Foundation of China (No. 81373662 and No. 81874475), Capacity Building Project of Chinese and Western Medicine Clinical Collaboration on Major Difficult Disease (No. 201803190106)
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Chen, P., Zhou, J., Ruan, Am. et al. Paeoniflorin, the Main Monomer Component of Paeonia lactiflora, Exhibits Anti-inflammatory Properties in Osteoarthritis Synovial Inflammation. Chin. J. Integr. Med. 30, 433–442 (2024). https://doi.org/10.1007/s11655-023-3653-9
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DOI: https://doi.org/10.1007/s11655-023-3653-9