Download PDF
Planta Med 2023; 89(02): 218-230
DOI: 10.1055/a-1942-5428
Natural Product Chemistry & Analytical Studies
Original Papers

UPLC/Q-TOF-MS-based Metabolomics Study of the Antiosteoporosis Effects of Vaccarin in Ovariectomized Mice

Fangming Song   *
1   Research Centre of Regenerative Medicine, Guangxi Medical University, Nanning City, China
,
Tianyu Xie   *
2   Department of Traumatic Orthopaedic, the First Affiliated Hospital of Guangxi Medical University, Nanning City, China
,
Xi Liu   *
3   College of Chemistry and Chemical Engineering, Xiamen University, Nanning City, China
,
Bonnie Chin
4   School of Postgraduate Studies, International Medical University, Kuala Lumpur, Malaysia
,
Xiaoting Luo
5   Department of Pharmacy, the First Affiliated Hospital of Guangxi Medical University, Nanning City, China
,
Shijie Liao
1   Research Centre of Regenerative Medicine, Guangxi Medical University, Nanning City, China
,
Abu·Moro,
Wenyu Feng
2   Department of Traumatic Orthopaedic, the First Affiliated Hospital of Guangxi Medical University, Nanning City, China
,
Mingwei He
2   Department of Traumatic Orthopaedic, the First Affiliated Hospital of Guangxi Medical University, Nanning City, China
,
Nenggan Huang
2   Department of Traumatic Orthopaedic, the First Affiliated Hospital of Guangxi Medical University, Nanning City, China
,
Zhiheng Su
7   Pharmaceutical College, Guangxi Medical University, Nanning City, China
,
Yun Liu
6   Department of Spine and Bone Diseases, the First Affiliated Hospital of Guangxi Medical University, Nanning City, China
1   Research Centre of Regenerative Medicine, Guangxi Medical University, Nanning City, China
› Author AffiliationsSupported by: Natural Science Foundation of Guangxi Province 2017GXNSFBA198061
Supported by: Natural Science Foundation of Guangxi Province 2019JJA140408
Supported by: Youth Science and Technology Venus Project of the First Affiliated Hospital of Guangxi Medical University 201903038
Supported by: National Natural Science Foundation of China 81960768
Supported by: Project funded by China Postdoctoral Science Foundation 2018M633618XB
› Further Information
Also available at
    Permissions and Reprints

Abstract

Osteoporosis is a systemic and metabolic bone disease that usually occurs in postmenopausal women, which mainly manifests as bone loss and increased bone fragility that both facilitate fracture. However, few drugs for osteoporosis have shown good efficacy and limited side effects. Vaccarin has demonstrated its antiosteoporosis effects by inhibiting the formation and osteolytic activities of osteoclasts in our previous investigation. In this study, multivariate statistical analysis and ultrahigh-performance liquid chromatography and quadrupole time-of-flight tandem mass spectrometry were used to analyze the serum metabolites of ovariectomized mice treated with or without vaccarin. As a result, 9 serum metabolites were identified as biomarkers. The metabolic levels of 3 crucial biomarkers, namely, lysophosphatidylcholine [22 : 6, (4Z, 7Z, 10Z, 13Z, 16Z, 19Z)], 1-linoleoylglycerophosphocholine and 1-palmitoyl-Sn-glycero-3-phosphocholine, that were correlated with glycerophospholipid metabolism increased and then decreased significantly after vaccarin treatment. Molecular docking analysis and osteoclasts differentiation experiment further revealed that vaccarin may bind with phospholipase A2 and downregulated its activity to reduce the osteoclastogenesis. Therefore, the occurrence of osteoporosis is closely related with glycerophospholipid metabolism disorders, and vaccarin exerts antiosteoporosis effects by reducing the levels of glycerophospholipid metabolites.

Key words

postmenopausal osteoporosis - glycerophospholipids metabolism - phospholipase A2 - vaccarin - Vaccaria segetalis - Caryophyllaceae

* These authors have contributed equally to this work and share first authorship.


Supporting Information

    The overlapped ion chromatograms of all QC samples, the MS spectra of tested sample, the supplementary figures and the supplementary tables are available in Supporting Information.

  • Supporting Information


Publication History

Received: 10 February 2022

Accepted after revision: 13 September 2022

Accepted Manuscript online:
13 September 2022

Article published online:
10 January 2023

© 2022. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Compston J, McClung M, Leslie W. Osteoporosis. Lancet (London, England) 2019; 393: 364-376
    CrossrefPubMedSearch in Google Scholar
  • 2 Armas L, Recker R. Pathophysiology of osteoporosis: new mechanistic insights. Endocrinol Metab Clin North Am 2012; 41: 475-486
    CrossrefPubMedSearch in Google Scholar
  • 3 Heaney R, Recker R, Saville P. Nutrition classics. The journal of laboratory and clinical medicine, volume 92, 1978: Menopausal changes in calcium balance performance. Nutr Rev 1983; 41: 86-89
    CrossrefPubMedSearch in Google Scholar
  • 4 Black D, Rosen C. Clinical practice. Postmenopausal osteoporosis. N Engl J Med 2016; 374: 254-262
    CrossrefPubMedSearch in Google Scholar
  • 5 Pan S, Chen A, Han Z, Wang Y, Lu X, Yang Y. (1)H NMR-based metabonomic study on the effects of Epimedium on glucocorticoid-induced osteoporosis. J Chromatogr B Analyt Technol Biomed Life Sci 2016; 1038: 118-126
    CrossrefPubMedSearch in Google Scholar
  • 6 Luo D, Li J, Chen K, Rong X, Guo J. Untargeted metabolomics reveals the protective effect of Fufang Zhenshu Tiaozhi (FTZ) on aging-induced osteoporosis in mice. Front Pharmacol 2018; 9: 1483
    CrossrefPubMedSearch in Google Scholar
  • 7 Liu Y, Song FM, Ma ST, Moro A, Feng WY, Liao SJ, Lin XX, Zhao JM, Wang ZY, Xu J, Zhan XL, Liu Q. Vaccarin prevents titanium particle-induced osteolysis and inhibits RANKL-induced osteoclastogenesis by blocking NF-kappaB and MAPK signaling pathways. J Cell Physiol 2019; 234: 13832-13842
    CrossrefPubMedSearch in Google Scholar
  • 8 Gong L, Lei Y, Liu Y, Tan F, Li S, Wang X, Xu M, Cai W, Du B, Xu F, Zhou Y, Han H, Sun H, Qiu L. Vaccarin prevents ox-LDL-induced HUVEC EndMT, inflammation and apoptosis by suppressing ROS/p38 MAPK signaling. Am J Transl Res 2019; 11: 2140-2154
    PubMedSearch in Google Scholar
  • 9 Zhu X, Zhou Z, Zhang Q, Cai W, Zhou Y, Sun H, Qiu L. Vaccarin administration ameliorates hypertension and cardiovascular remodeling in renovascular hypertensive rats. J Cell Biochem 2018; 119: 926-937
    CrossrefPubMedSearch in Google Scholar
  • 10 Newgard C. Metabolomics and metabolic diseases: Where do we stand?. Cell Metab 2017; 25: 43-56
    CrossrefPubMedSearch in Google Scholar
  • 11 Bujak R, Struck-Lewicka W, Markuszewski M, Kaliszan R. Metabolomics for laboratory diagnostics. J Pharm Biomed Anal 2015; 113: 108-120
    CrossrefPubMedSearch in Google Scholar
  • 12 Zhang M, Wang Y, Zhang Q, Wang C, Zhang D, Wan JB, Yan C. UPLC/Q-TOF-MS-based metabolomics study of the anti-osteoporosis effects of Achyranthes bidentata polysaccharides in ovariectomized rats. Int J Biol Macromol 2018; 112: 433-441
    CrossrefPubMedSearch in Google Scholar
  • 13 Wu X, Huang Y, Sun J, Wen Y, Qin F, Zhao L, Xiong Z. A HILIC-UHPLC-MS/MS untargeted urinary metabonomics combined with quantitative analysis of five polar biomarkers on osteoporosis rats after oral administration of Gushudan. J Chromatogr B Analyt Technol Biomed Life Sci 2018; 1072: 40-49
    CrossrefPubMedSearch in Google Scholar
  • 14 Cai X, Zhang Z, Xiong J, Yang M, Wang Z. Experimental and molecular docking studies of estrogen-like and anti-osteoporosis activity of compounds in Fructus Psoraleae. J Ethnopharmacol 2021; 276: 114044
    CrossrefPubMedSearch in Google Scholar
  • 15 Coetzee M, Haag M, Kruger M. Effects of arachidonic acid, docosahexaenoic acid, prostaglandin E(2) and parathyroid hormone on osteoprotegerin and RANKL secretion by MC3T3-E1 osteoblast-like cells. J Nutr Biochem 2007; 18: 54-63
    CrossrefPubMedSearch in Google Scholar
  • 16 Zhang AH, Ma ZM, Sun H, Zhang Y, Liu JH, Wu FF, Wang XJ. High-throughput metabolomics evaluate the efficacy of total lignans from Acanthophanax senticosus stem against ovariectomized osteoporosis rat. Front Pharmacol 2019; 10: 553
    CrossrefPubMedSearch in Google Scholar
  • 17 Zhao X, Wu ZX, Zhang Y, Yan YB, He Q, Cao PC, Lei W. Anti-osteoporosis activity of Cibotium barometz extract on ovariectomy-induced bone loss in rats. J Ethnopharmacol 2011; 137: 1083-1088
    CrossrefPubMedSearch in Google Scholar
  • 18 Komori T. Animal models for osteoporosis. Eur J Pharmacol 2015; 759: 287-294
    CrossrefPubMedSearch in Google Scholar
  • 19 Moayyeri A, Cheung CL, Tan KC, Morris JA, Cerani A, Mohney RP, Richards JB, Hammond C, Spector TD, Menni C. Metabolomic pathways to osteoporosis in middle-aged women: A genome-metabolome-wide mendelian randomization study. J Bone Miner Res 2018; 33: 643-650
    CrossrefPubMedSearch in Google Scholar
  • 20 Liu X, Zhang S, Lu X, Zheng S, Li F, Xiong Z. Metabonomic study on the anti-osteoporosis effect of Rhizoma Drynariae and its action mechanism using ultra-performance liquid chromatography-tandem mass spectrometry. J Ethnopharmacol 2012; 139: 311-317
    Search in Google Scholar
  • 21 Fallah A, Pierre R, Abed E, Moreau R. Lysophosphatidylcholine-induced cytotoxicity in osteoblast-like MG-63 cells: involvement of transient receptor potential vanilloid 2 (TRPV2) channels. Mol Membr Biol 2013; 30: 315-326
    CrossrefPubMedSearch in Google Scholar
  • 22 Liu X, Liu Y, Cheng M, Zhang X, Xiao H. A metabolomics study of the inhibitory effect of 17-beta-estradiol on osteoclast proliferation and differentiation. Mol Biosyst 2015; 11: 635-646
    CrossrefPubMedSearch in Google Scholar
  • 23 Zhao H, Li X, Zhang D, Chen H, Chao Y, Wu K, Dong X, Su J. Integrative bone metabolomics-lipidomics strategy for pathological mechanism of postmenopausal osteoporosis mouse model. Sci Rep 2018; 8: 16456
    CrossrefPubMedSearch in Google Scholar
  • 24 Yuan X, Wen J, Jia H, Tong L, Zhao J, Zhao L, Xiong Z. Integrated metabolomic analysis for intervention effects of Gushudan on glucocorticoid-induced osteoporostic rat plasma based on RP/HILIC-UHPLC-Q-Orbitrap HRMS. Anal Biochem 2020; 591: 113559
    CrossrefPubMedSearch in Google Scholar
  • 25 Baek KH, Oh KW, Lee WY, Lee SS, Kim MK, Kwon HS, Rhee EJ, Han JH, Song KH, Cha BY, Lee KW, Kang MI. Association of oxidative stress with postmenopausal osteoporosis and the effects of hydrogen peroxide on osteoclast formation in human bone marrow cell cultures. Calcif Tissue Int 2010; 87: 226-235
    CrossrefPubMedSearch in Google Scholar
  • 26 Yin H, Shi ZG, Yu YS, Hu J, Wang R, Luan ZP, Guo DH. Protection against osteoporosis by statins is linked to a reduction of oxidative stress and restoration of nitric oxide formation in aged and ovariectomized rats. Eur J Pharmacol 2012; 674: 200-206
    CrossrefPubMedSearch in Google Scholar
  • 27 Wang J, Dong X, Ma F, Li C, Bu R, Lu J, Gao J, Xue P. Metabolomics profiling reveals Echinops latifolius Tausch improves the trabecular micro-architecture of ovariectomized rats mainly via intervening amino acids and glycerophospholipids metabolism. J Ethnopharmacol 2020; 260: 113018
    CrossrefPubMedSearch in Google Scholar
  • 28 Tao Y, Chen X, Li W, Cai B, Di L, Shi L, Hu L. Global and untargeted metabolomics evidence of the protective effect of different extracts of Dipsacus asper Wall. ex C.B. Clarke on estrogen deficiency after ovariectomia in rats. J Ethnopharmacol 2017; 199: 20-29
    CrossrefPubMedSearch in Google Scholar
  • 29 Wang J, Yan D, Zhao A, Hou X, Zheng X, Chen P, Bao Y, Jia W, Hu C, Zhang ZL, Jia W. Discovery of potential biomarkers for osteoporosis using LC-MS/MS metabolomic methods. Osteoporos Int 2019; 30: 1491-1499
    CrossrefPubMedSearch in Google Scholar
  • 30 Xiao HH, Sham TT, Chan CO, Li MH, Chen X, Wu QC, Mok DK, Yao XS, Wong MS. A Metabolomics study on the bone protective effects of a lignan-rich fraction from Sambucus Williamsii Ramulus in aged rats. Front Pharmacol 2018; 9: 932
    CrossrefPubMedSearch in Google Scholar
  • 31 El Refaey M, Watkins CP, Kennedy EJ, Chang A, Zhong Q, Ding KH, Shi XM, Xu J, Bollag WB, Hill WD, Johnson M, Hunter M, Hamrick MW, Isales CM. Oxidation of the aromatic amino acids tryptophan and tyrosine disrupts their anabolic effects on bone marrow mesenchymal stem cells. Mol Cell Endocrinol 2015; 410: 87-96
    CrossrefPubMedSearch in Google Scholar
  • 32 Pinzi L, Rastelli G. Molecular docking: Shifting paradigms in drug discovery. Int J Mol Sci 2019; 20: 4331
    CrossrefPubMedSearch in Google Scholar
  • 33 Murakami M, Kudo I. Phospholipase A2. J Biochem 2002; 131: 285-292
    CrossrefPubMedSearch in Google Scholar
  • 34 Jaworski K, Ahmadian M, Duncan RE, Sarkadi-Nagy E, Varady KA, Hellerstein MK, Lee HY, Samuel VT, Shulman GI, Kim KH, de Val S, Kang C, Sul HS. AdPLA ablation increases lipolysis and prevents obesity induced by high-fat feeding or leptin deficiency. Nat Med 2009; 15: 159-168
    CrossrefPubMedSearch in Google Scholar
  • 35 Yuan C, Rieke C, Rimon G, Wingerd B, Smith W. Partnering between monomers of cyclooxygenase-2 homodimers. Proc Natl Acad Sci U S A 2006; 103: 6142-6147
    CrossrefPubMedSearch in Google Scholar
  • 36 Murakami K, Kobayashi Y, Uehara S, Suzuki T, Koide M, Yamashita T, Nakamura M, Takahashi N, Kato H, Udagawa N, Nakamura Y. A Jak1/2 inhibitor, baricitinib, inhibits osteoclastogenesis by suppressing RANKL expression in osteoblasts in vitro. PLoS One 2017; 12: e0181126
    CrossrefPubMedSearch in Google Scholar
  • 37 Miyaura C, Inada M, Matsumoto C, Ohshiba T, Uozumi N, Shimizu T, Ito A. An essential role of cytosolic phospholipase A2alpha in prostaglandin E2-mediated bone resorption associated with inflammation. J Exp Med 2003; 197: 1303-1310
    CrossrefPubMedSearch in Google Scholar
  • 38 Cunningham T, Yao L, Lucena A. Product inhibition of secreted phospholipase A2 may explain lysophosphatidylcholinesʼ unexpected therapeutic properties. J Inflamm (Lond) 2008; 5: 17
    CrossrefPubMedSearch in Google Scholar
  • 39 Wi S, Seo S, Cho K, Nam M, Park K. Lysophosphatidylcholine enhances susceptibility in signaling pathway against pathogen infection through biphasic production of reactive oxygen species and ethylene in tobacco plants. Phytochemistry 2014; 104: 48-59
    CrossrefPubMedSearch in Google Scholar
  • 40 Lin C, Yu S, Jin R, Xiao Y, Pan M, Pei F, Zhu X, Huang H, Zhang Z, Chen S, Liu H, Chen Z. Circulating miR-338 cluster activities on osteoblast differentiation: Potential diagnostic and therapeutic targets for postmenopausal osteoporosis. Theranostics 2019; 9: 3780-3797
    CrossrefPubMedSearch in Google Scholar
  • 41 Jiang Y, Li Y, Zhou L, Zhang D. UPLC-MS metabolomics method provides valuable insights into the effect and underlying mechanisms of Rhizoma Drynariae protecting osteoporosis. J Chromatogr B Analyt Technol Biomed Life Sci 2020; 1152: 122262
    CrossrefPubMedSearch in Google Scholar
  • 42 Heitz M, Rupp J. Determining mushroom tyrosinase inhibition by imidazolium ionic liquids: A spectroscopic and molecular docking study. Int J Biol Macromol 2018; 107: 1971-1981
    CrossrefPubMedSearch in Google Scholar