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RHEUMATOLOGY / BASIC RESEARCH
A network pharmacological study to unveil the mechanisms of xianlinggubao capsule in the treatment of osteoarthritis and osteoporosis
1
Department of Orthopaedics, Chengdu Integrated TCM and Western Medicine Hospital, Chengdu, China
Submission date: 2019-08-02
Final revision date: 2019-11-13
Acceptance date: 2019-11-24
Online publication date: 2020-02-12
Publication date: 2024-04-23
Arch Med Sci 2024;20(2):557-566
Article (PDF)
Supplementary files
References (43)
A network_Supplementary Table SI.pdf
A network_Supplementary Table SII.pdf
A network_Supplementary Table SIII.pdf
A network_Supplementary Table SIV.pdf
A network_Supplementary Table SV.pdf
A network_Supplementary Table SVI.pdf
A network_Supplementary Table SVII.pdf
A network_Supplementary Table SVIII.pdf
KEYWORDS
TOPICS
ABSTRACT
Introduction:
Xianlinggubao (XLGB) capsule is a traditional Chinese medicine, which is approved by the Chinese State Food and Drug Administration (CFDA) for osteoarthritis (OA) and osteoporosis (OP). However, as a capsule with complex ingredients, the molecular mechanisms supporting the therapeutic effects have not been explored.
Material and methods:
A network pharmacology-based approach was conducted to explore the complex interactome among the targets of the XLGB active compounds.
Results:
The herbs in the capsule contain 41 compounds with 246 high score targets, which cover four known OA targets (PTGS1, PTGS2, PTGER4 and TNF) and six known OP targets (AR, ESR1, PGR, PTGER2, TNFSF11 and VDR) of FDA-approved drugs or drugs undergoing clinical trials. The protein-protein interaction (PPI) network of the 246 targets had six key modules. Among the six modules, neuroactive ligand-receptor interaction, cAMP signaling pathway and calcium signaling pathway are the key pathways, which are all closely associated with the degeneration of joint cartilage and bone formation and resorption.
Conclusions:
Neuroactive ligand-receptor interaction, cAMP signaling pathway, and calcium signaling pathway might be the critical pathways upon which the capsule might act. The present study laid down a foundation to understand the molecular mechanisms of the XLGB capsule and also provided fundamental information for better improvement of the drug with the concept “less herbal materials for achieving equal treatment efficacy”.
Xianlinggubao (XLGB) capsule is a traditional Chinese medicine, which is approved by the Chinese State Food and Drug Administration (CFDA) for osteoarthritis (OA) and osteoporosis (OP). However, as a capsule with complex ingredients, the molecular mechanisms supporting the therapeutic effects have not been explored.
Material and methods:
A network pharmacology-based approach was conducted to explore the complex interactome among the targets of the XLGB active compounds.
Results:
The herbs in the capsule contain 41 compounds with 246 high score targets, which cover four known OA targets (PTGS1, PTGS2, PTGER4 and TNF) and six known OP targets (AR, ESR1, PGR, PTGER2, TNFSF11 and VDR) of FDA-approved drugs or drugs undergoing clinical trials. The protein-protein interaction (PPI) network of the 246 targets had six key modules. Among the six modules, neuroactive ligand-receptor interaction, cAMP signaling pathway and calcium signaling pathway are the key pathways, which are all closely associated with the degeneration of joint cartilage and bone formation and resorption.
Conclusions:
Neuroactive ligand-receptor interaction, cAMP signaling pathway, and calcium signaling pathway might be the critical pathways upon which the capsule might act. The present study laid down a foundation to understand the molecular mechanisms of the XLGB capsule and also provided fundamental information for better improvement of the drug with the concept “less herbal materials for achieving equal treatment efficacy”.
REFERENCES (43)
1.
Zhu HM, Qin L, Garnero P, et al. The first multicenter and randomized clinical trial of herbal Fufang for treatment of postmenopausal osteoporosis. Osteoporos Int 2012; 23: 1317-27.
2.
Cheng Y, Liu Y, Wang H, et al. A 26-week repeated dose toxicity study of Xian-ling-gu-bao in Sprague-Dawley rats. J Ethnopharmacol 2013; 145: 85-93.
3.
Qin L, Zhang G, Hung WY, et al. Phytoestrogen-rich herb formula “XLGB” prevents OVX-induced deterioration of musculoskeletal tissues at the hip in old rats. J Bone Miner Metab 2005; 23 Suppl: 55-61.
4.
Wang F, Shi L, Zhang Y, et al. A traditional herbal formula xianlinggubao for pain control and function improvement in patients with knee and hand osteoarthritis: a multicenter, randomized, open-label, controlled trial. Evid Based Complement Alternat Med 2018; 2018: 1827528.
6.
Liu Z, Guo F, Wang Y, et al. BATMAN-TCM: a bioinformatics analysis tool for molecular mechanism of traditional Chinese medicine. Sci Rep 2016; 6: 21146.
7.
Li YH, Yu CY, Li XX, et al. Therapeutic target database update 2018: enriched resource for facilitating bench-to-clinic research of targeted therapeutics. Nucleic Acids Res 2018; 46: D1121-7.
8.
Bader GD, Hogue CW. An automated method for finding molecular complexes in large protein interaction networks. BMC Bioinformatics 2003; 4: 2.
9.
Zhang G, Qin L, Shi Y. Epimedium-derived phytoestrogen flavonoids exert beneficial effect on preventing bone loss in late postmenopausal women: a 24-month randomized, double-blind and placebo-controlled trial. J Bone Miner Res 2007; 22: 1072-9.
10.
Van Hecken A, Schwartz JI, Depre M, et al. Comparative inhibitory activity of rofecoxib, meloxicam, diclofenac, ibuprofen, and naproxen on COX-2 versus COX-1 in healthy volunteers. J Clin Pharmacol 2000; 40: 1109-20.
11.
Atkinson MH, Menard HA, Kalish GH. Assessment of salsalate, a nonacetylated salicylate, in the treatment of patients with arthritis. Clin Ther 1995; 17: 827-37.
12.
Newman DJ, Cragg GM. Natural products as sources of new drugs over the last 25 years. J Nat Prod 2007; 70: 461-77.
13.
Edelstein D, Dobs A, Basaria S. Emerging drugs for hypogonadism. Expert Opin Emerg Drugs 2006; 11: 685-707.
14.
Archer DF, Pinkerton JV, Utian WH, et al. Bazedoxifene, a selective estrogen receptor modulator: effects on the endometrium, ovaries, and breast from a randomized controlled trial in osteoporotic postmenopausal women. Menopause 2009; 16: 1109-15.
15.
Silva-Fernandez L, Andreu JL. Lasofoxifene for postmenopausal women with osteoporosis. N Engl J Med 2010; 362: 2228.
16.
Genant HK, Lucas J, Weiss S, et al. Low-dose esterified estrogen therapy: effects on bone, plasma estradiol concentrations, endometrium, and lipid levels. Estratab/Osteoporosis Study Group. Arch Intern Med 1997; 157: 2609-15.
17.
Deal CL, Draper MW. Raloxifene: a selective estrogen-receptor modulator for postmenopausal osteoporosis – a clinical update on efficacy and safety. Womens Health 2006; 2: 199-210.
19.
Herber CB, Krause WC, Wang L, et al. Estrogen signaling in arcuate Kiss1 neurons suppresses a sex-dependent female circuit promoting dense strong bones. Nat Commun 2019; 10: 163.
20.
Wang X, He Y, Guo B, et al. In vivo screening for anti-osteoporotic fraction from extract of herbal formula Xianlinggubao in ovariectomized mice. PLoS One 2015; 10: e0118184.
21.
Wang X, Zhen L, Zhang G, Wong MS, Qin L, Yao X. Osteogenic effects of flavonoid aglycones from an osteoprotective fraction of Drynaria fortunei: an in vitro efficacy study. Phytomedicine 2011; 18: 868-72.
22.
Fisch KM, Gamini R, Alvarez-Garcia O, et al. Identification of transcription factors responsible for dysregulated networks in human osteoarthritis cartilage by global gene expression analysis. Osteoarthritis Cartilage 2018; 26: 1531-8.
23.
Xia B, Di C, Zhang J, Hu S, Jin H, Tong P. Osteoarthritis pathogenesis: a review of molecular mechanisms. Calcif Tissue Int 2014; 95: 495-505.
24.
Schiller M, Dennler S, Anderegg U, et al. Increased cAMP levels modulate transforming growth factor-beta/Smad-induced expression of extracellular matrix components and other key fibroblast effector functions. J Biol Chem 2010; 285: 409-21.
25.
Liu Q, Yang HX, Wan XH, et al. Calcium-/calmodulin-dependent protein kinase II in occlusion-induced degenerative cartilage of rat mandibular condyle. J Oral Rehabil 2018; 45: 442-51.
26.
Rong J, Pool B, Zhu M, et al. Basic calcium phosphate crystals induce osteoarthritis-associated changes in phenotype markers in primary human chondrocytes by a calcium/calmodulin kinase 2-dependent mechanism. Calcif Tissue Int 2019; 104: 331-43.
27.
Zhang Y, Liu P, Li J, et al. Communication factors-promising targets in osteoporosis treatment. Curr Drug Targets 2014; 15: 156-63.
28.
Tamma R, Zallone A. Osteoblast and osteoclast crosstalks: from OAF to Ephrin. Inflamm Allergy Drug Targets 2012; 11: 196-200.
29.
Giacobini P, Prevot V. Semaphorins in the development, homeostasis and disease of hormone systems. Semin Cell Dev Biol 2013; 24: 190-8.
30.
Yao Z, Xing L, Qin C, Schwarz EM, Boyce BF. Osteoclast precursor interaction with bone matrix induces osteoclast formation directly by an interleukin-1-mediated autocrine mechanism. J Biol Chem 2008; 283: 9917-24.
31.
Tintut Y, Parhami F, Le V, Karsenty G, Demer LL. Inhibition of osteoblast-specific transcription factor Cbfa1 by the cAMP pathway in osteoblastic cells. Ubiquitin/proteasome-dependent regulation. J Biol Chem 1999; 274: 28875-9.
32.
Fu Q, Jilka RL, Manolagas SC, O’Brien CA. Parathyroid hormone stimulates receptor activator of NFkappa B ligand and inhibits osteoprotegerin expression via protein kinase A activation of cAMP-response element-binding protein. J Biol Chem 2002; 277: 48868-75.
33.
Luo J, Zhou W, Zhou X, et al. Regulation of bone formation and remodeling by G-protein-coupled receptor 48. Development 2009; 136: 2747-56.
34.
Sharan K, Mishra JS, Swarnkar G, et al. A novel quercetin analogue from a medicinal plant promotes peak bone mass achievement and bone healing after injury and exerts an anabolic effect on osteoporotic bone: the role of aryl hydrocarbon receptor as a mediator of osteogenic action. J Bone Miner Res 2011; 26: 2096-111.
35.
Wu X, Li S, Xue P, Li Y. Liraglutide, a glucagon-like peptide-1 receptor agonist, facilitates osteogenic proliferation and differentiation in MC3T3-E1 cells through phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT), extracellular signal-related kinase (ERK)1/2, and cAMP/protein kinase A (PKA) signaling pathways involving beta-catenin. Exp Cell Res 2017; 360: 281-91.
36.
Kao R, Lu W, Louie A, Nissenson R. Cyclic AMP signaling in bone marrow stromal cells has reciprocal effects on the ability of mesenchymal stem cells to differentiate into mature osteoblasts versus mature adipocytes. Endocrine 2012; 42: 622-36.
37.
Rangaswami H, Schwappacher R, Tran T, et al. Protein kinase G and focal adhesion kinase converge on Src/Akt/beta-catenin signaling module in osteoblast mechanotransduction. J Biol Chem 2012; 287: 21509-19.
38.
Wegiel B, Persson JL. Effect of a novel botanical agent Drynol Cibotin on human osteoblast cells and implications for osteoporosis: promotion of cell growth, calcium uptake and collagen production. Phytother Res 2010; 24 Suppl 2: S139-47.
39.
Studer RK, Decker K, Melhem S, Georgescu H. Nitric oxide inhibition of IGF-1 stimulated proteoglycan synthesis: role of cGMP. J Orthop Res 2003; 21: 914-21.
40.
Koskinen A, Vuolteenaho K, Nieminen R, Moilanen T, Moilanen E. Leptin enhances MMP-1, MMP-3 and MMP-13 production in human osteoarthritic cartilage and correlates with MMP-1 and MMP-3 in synovial fluid from OA patients. Clin Exp Rheumatol 2011; 29: 57-64.
41.
Plebanczyk M, Radzikowska A, Burakowski T, et al. Different secretory activity of articular and subcutaneous adipose tissues from rheumatoid arthritis and osteoarthritis patients. Inflammation 2019; 42: 375-86.
42.
Kalyanaraman H, Ramdani G, Joshua J, et al. A Novel, direct NO donor regulates osteoblast and osteoclast functions and increases bone mass in ovariectomized mice. J Bone Miner Res 2017; 32: 46-59.
43.
Xi JC, Zang HY, Guo LX, et al. The PI3K/AKT cell signaling pathway is involved in regulation of osteoporosis. J Recept Signal Transduct Res 2015; 35: 640-5.
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