Top

BMC Complementary Medicine and Therapies

Published in:

01-12-2020 | Ovariectomy | Research article

A circRNA-miRNA-mRNA network plays a role in the protective effect of diosgenin on alveolar bone loss in ovariectomized rats

Authors: Zhiguo Zhang, Lifeng Yue, Yuhan Wang, Yanhua Jiang, Lihua Xiang, Yin Cheng, Dahong Ju, Yanjing Chen

Published in: BMC Complementary Medicine and Therapies | Issue 1/2020

Abstract

Background

The present study aimed to assess the perturbation in circular RNA (circRNA)/mRNA expression profiles and a circRNA-miRNA-mRNA coexpression network involved in the potential protective effect of diosgenin (DIO) on alveolar bone loss in rats subjected to ovariectomy (OVX).

Methods

The Wistar rats (female) manipulated with sham operation were classified as the SHAM group and the grouping of OVX rats administered with DIO, estradiol valerate or vehicle for 12 weeks was DIO group, EV group and OVX group respectively. Following treatments, the plasmatic levels of osteocalcin and tumor necrosis factor-alpha and the microstructure of alveolar bone were assayed. Based on microarray analyses, we identified differentially expressed (DE) circRNAs and mRNAs in alveolar bone of rats in both OVX and DIO group. The DE circRNAs and DE mRNAs involved in the bone metabolism pathway validated by RT-qPCR were considered key circRNAs/mRNAs. On the basis of these key circRNAs/mRNAs, we predicted the overlapping relative miRNAs of key circRNAs/mRNAs, and a circRNA-miRNA-mRNA network was built.

Results

DIO showed an anti-osteopenic effect on the rat alveolar bone loss induced by OVX. In total, we found 10 DE circRNAs (6 downregulated and 4 upregulated) and 614 DE mRNAs (314 downregulated and 300 upregulated) in samples of the DIO group compared with those of the OVX group. However, only one circRNA (rno_circRNA_016717) and seven mRNAs (Sfrp1, Csf1, Il1rl1, Nfatc4, Tnfrsf1a, Pik3c2g, and Wnt9b) were validated by qRT-PCR and therefore considered key circRNA/mRNAs. According to these key circRNA/mRNAs and overlapping predicted miRNAs, a coexpression network was constructed. After network analysis, one circRNA-miRNA-mRNA axis (circRNA_016717/miR-501-5p/Sfrp1) was identified.

Conclusion

The mechanism of DIO inhibiting alveolar bone loss after OVX is possibly relevant to the simultaneous inhibition of osteogenesis and osteoclastogenesis by mediating the expression of important molecules in the Wnt, PI3K, RANK/RANKL or osteoclastogenic cytokine pathways. The circRNA_016717/miR-501-5p/Sfrp1 axis may play important roles in these processes.

Available only for authorised users

Taguchi A, Tanimoto K, Suei Y, Wada T. Tooth loss and mandibular osteopenia. Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics. 1995;79:127–32.PubMed

Krall EA, Garcia RI, Dawson-Hughes B. Increased risk of tooth loss is related to bone loss at the whole body, hip, and spine. Calcif Tissue Int. 1996;59:433–7.PubMed

Ikeo T, Goda S, Domae E. Metabolism of alveolar bone. Clinical calcium. 2006;16:117–21.PubMed

Du Z, Steck R, Doan N, Woodruff MA, Ivanovski S, Xiao Y. Estrogen deficiency-associated bone loss in the maxilla: a methodology to quantify the changes in the maxillary intra-radicular alveolar bone in an Ovariectomized rat osteoporosis model. Tissue engineering Part C, Methods. 2015;21:458–66.PubMed

Payne JB, Zachs NR, Reinhardt RA, Nummikoski PV, Patil K. The association between estrogen status and alveolar bone density changes in postmenopausal women with a history of periodontitis. J Periodontol. 1997;68:24–31.PubMed

Duarte PM, Goncalves P, Casati MZ, de Toledo S, Sallum EA, Nociti FH Jr. Estrogen and alendronate therapies may prevent the influence of estrogen deficiency on the tooth-supporting alveolar bone: a histometric study in rats. J Periodontal Res. 2006;41:541–6.PubMed

Turner JV, Agatonovic-Kustrin S, Glass BD. Molecular aspects of phytoestrogen selective binding at estrogen receptors. J Pharm Sci. 2007;96:1879–85.PubMed

Sirotkin AV, Alexa R, Alwasel S, Harrath AH. The phytoestrogen, diosgenin, directly stimulates ovarian cell functions in two farm animal species. Domest Anim Endocrinol. 2019;69:35–41.PubMed

Shen M, Qi C, Kuang YP, Yang Y, Lyu QF, Long H, Yan ZG, Lu YY. Observation of the influences of diosgenin on aging ovarian reserve and function in a mouse model. Eur J Med Res. 2017;22:42.PubMedPubMedCentral

10.

Zhang Z, Chen Y, Xiang L, Wang Z, Xiao GG, Ju D. Diosgenin protects against alveolar bone loss in ovariectomized rats via regulating long non-coding RNAs. Experimental and therapeutic medicine. 2018;16:3939–50.PubMedPubMedCentral

11.

Medigovic I, Ristic N, Zivanovic J, Sosic-Jurjevic B, Filipovic B, Milosevic V, Nestorovic N. Diosgenin does not express estrogenic activity: a uterotrophic assay. Can J Physiol Pharmacol. 2014;92:292–8.PubMed

12.

Aradhana, Rao AR, Kale RK. Diosgenin--a growth stimulator of mammary gland of ovariectomized mouse. Indian journal of experimental biology. 1992;30:367–70.

13.

Zhang Z, Song C, Fu X, Liu M, Li Y, Pan J, Liu H, Wang S, Xiang L, Xiao GG, et al. High-dose diosgenin reduces bone loss in ovariectomized rats via attenuation of the RANKL/OPG ratio. Int J Mol Sci. 2014;15:17130–47.PubMedPubMedCentral

14.

Salzman J, Gawad C, Wang PL, Lacayo N, Brown PO. Circular RNAs are the predominant transcript isoform from hundreds of human genes in diverse cell types. PLoS One. 2012;7:e30733.PubMedPubMedCentral

15.

Wilusz JE, Sharp PA. Molecular biology. A circuitous route to noncoding RNA. Science. 2013;340:440–1.PubMedPubMedCentral

16.

Chen X, Ouyang Z, Shen Y, Liu B, Zhang Q, Wan L, Yin Z, Zhu W, Li S, Peng D. CircRNA_28313/miR-195a/CSF1 axis modulates osteoclast differentiation to affect OVX-induced bone absorption in mice. RNA Biol. 2019:1–14.

17.

Yu L, Liu Y. circRNA_0016624 could sponge miR-98 to regulate BMP2 expression in postmenopausal osteoporosis. Biochemical and biophysical research communications. 2019.

18.

Li CM, Dong XL, Fan XD, Wu JH, Wang QH, Tian XL, Guo DJ, Wong MS, Qiu TQ, Chan SW. Aqueous extract of danshen (Salvia miltiorrhiza Bunge) protects ovariectomized rats fed with high-fat diet from endothelial dysfunction. Menopause. 2013;20:100–9.PubMed

19.

Maimoun L, Brennan-Speranza TC, Rizzoli R, Ammann P. Effects of ovariectomy on the changes in microarchitecture and material level properties in response to hind leg disuse in female rats. Bone. 2012;51:586–91.PubMed

20.

Lane NE, Yao W, Kinney JH, Modin G, Balooch M, Wronski TJ. Both hPTH(1-34) and bFGF increase trabecular bone mass in osteopenic rats but they have different effects on trabecular bone architecture. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2003;18:2105–15.

21.

Hsu KH, Chang CC, Tsai HD, Tsai FJ, Hsieh YY. Effects of yam and diosgenin on calpain systems in skeletal muscle of ovariectomized rats. Taiwanese journal of obstetrics & gynecology. 2008;47:180–6.

22.

Ma Y, Zeng R, Hu QQ, Yan HX, Yang LX, Dong Y, Qu Y. Preventive effects of Polygonum orientale L. on ovariectomy-induced osteoporosis in rats. Climacteric : the journal of the International Menopause Society. 2020;1–9.

23.

Tang YQ, Li C, Sun XJ, Liu Y, Wang XT, Guo YB, Wang LL, Ma RF, Niu JZ, Fu M, et al. Fructus Ligustri Lucidi modulates estrogen receptor expression with no uterotrophic effect in ovariectomized rats. BMC Complement Altern Med. 2018;18:118.PubMedPubMedCentral

24.

Yang J, Pham SM, Crabbe DL. High-resolution micro-CT evaluation of mid- to long-term effects of estrogen deficiency on rat trabecular bone. Acad Radiol. 2003;10:1153–8.PubMed

25.

Bouxsein ML, Boyd SK, Christiansen BA, Guldberg RE, Jepsen KJ, Muller R. Guidelines for assessment of bone microstructure in rodents using micro-computed tomography. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2010;25:1468–86.

26.

Betel D, Wilson M, Gabow A, Marks DS, Sander C. The microRNA.org resource: targets and expression. Nucleic Acids Res. 2008;36:D149–53.PubMed

27.

Agarwal V, Bell GW, Nam JW, Bartel DP. Predicting effective microRNA target sites in mammalian mRNAs. eLife. 2015;4.

28.

Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003;13:2498–504.PubMedPubMedCentral

29.

Hung YT, Tikhonova MA, Ding SJ, Kao PF, Lan HH, Liao JM, Chen JH, Amstislavskaya TG, Ho YJ. Effects of chronic treatment with diosgenin on bone loss in a d-galactose-induced aging rat model. The Chinese journal of physiology. 2014;57:121–7.PubMed

30.

Zhao S, Niu F, Xu CY, Liu Y, Ye L, Bi GB, Chen L, Tian G, Nie TH. Diosgenin prevents bone loss on retinoic acid-induced osteoporosis in rats. Ir J Med Sci. 2016;185:581–7.PubMed

31.

Hansen TB, Jensen TI, Clausen BH, Bramsen JB, Finsen B, Damgaard CK, Kjems J. Natural RNA circles function as efficient microRNA sponges. Nature. 2013;495:384–8.PubMed

32.

Alikhani M, Alikhani M, Alansari S, Almansour A, Hamidaddin MA, Khoo E, Lopez JA, Nervina JM, Nho JY, Oliveira SM, et al. Therapeutic effect of localized vibration on alveolar bone of osteoporotic rats. PLoS One. 2019;14:e0211004.PubMedPubMedCentral

33.

Wang L, Cheng L, Zhang B, Wang N, Wang F. Tanshinone prevents alveolar bone loss in ovariectomized osteoporosis rats by up-regulating phosphoglycerate dehydrogenase. Toxicol Appl Pharmacol. 2019;376:9–16.PubMed

34.

Rao YQ, Li J, Wang WJ. Effects of Gengnianchun on learning and memory ability, neurotransmitter, cytokines, and leptin in ovariectomized rats. Int J Clin Exp Med. 2015;8:8648–60.PubMedPubMedCentral

35.

Cheng M, Wang Q, Fan Y, Liu X, Wang L, Xie R, Ho CC, Sun W. A traditional Chinese herbal preparation, Er-Zhi-Wan, prevent ovariectomy-induced osteoporosis in rats. J Ethnopharmacol. 2011;138:279–85.PubMed

36.

Marcellini S, Henriquez JP, Bertin A. Control of osteogenesis by the canonical Wnt and BMP pathways in vivo: cooperation and antagonism between the canonical Wnt and BMP pathways as cells differentiate from osteochondroprogenitors to osteoblasts and osteocytes. BioEssays : news and reviews in molecular, cellular and developmental biology. 2012;34:953–62.

37.

Lin GL, Hankenson KD. Integration of BMP, Wnt, and notch signaling pathways in osteoblast differentiation. J Cell Biochem. 2011;112:3491–501.PubMedPubMedCentral

38.

Amin N, Boccardi V, Taghizadeh M, Jafarnejad S. Probiotics and bone disorders: the role of RANKL/RANK/OPG pathway. Aging Clin Exp Res. 2019.

39.

Hanada R, Hanada T, Penninger JM. Physiology and pathophysiology of the RANKL/RANK system. Biol Chem. 2010;391:1365–70.PubMed

40.

Li Y, Rankin SA, Sinner D, Kenny AP, Krieg PA, Zorn AM. Sfrp5 coordinates foregut specification and morphogenesis by antagonizing both canonical and noncanonical Wnt11 signaling. Genes Dev. 2008;22:3050–63.PubMedPubMedCentral

41.

Satoh W, Matsuyama M, Takemura H, Aizawa S, Shimono A. Sfrp1, Sfrp2, and Sfrp5 regulate the Wnt/beta-catenin and the planar cell polarity pathways during early trunk formation in mouse. Genesis. 2008;46:92–103.PubMed

42.

Hausler KD, Horwood NJ, Chuman Y, Fisher JL, Ellis J, Martin TJ, Rubin JS, Gillespie MT. Secreted frizzled-related protein-1 inhibits RANKL-dependent osteoclast formation. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2004;19:1873–81.

43.

Bhuvanalakshmi G, Basappa, Rangappa KS, Dharmarajan A, Sethi G, Kumar AP, Warrier S. Breast Cancer Stem-Like Cells Are Inhibited by Diosgenin, a Steroidal Saponin, by the Attenuation of the Wnt beta-Catenin Signaling via the Wnt Antagonist Secreted Frizzled Related Protein-4. Frontiers in pharmacology. 2017;8:124.

44.

Cantley LC. The phosphoinositide 3-kinase pathway. Science. 2002;296:1655–7.PubMed

45.

Ling L, Dombrowski C, Foong KM, Haupt LM, Stein GS, Nurcombe V, van Wijnen AJ, Cool SM. Synergism between Wnt3a and heparin enhances osteogenesis via a phosphoinositide 3-kinase/Akt/RUNX2 pathway. J Biol Chem. 2010;285:26233–44.PubMedPubMedCentral

46.

Moon JB, Kim JH, Kim K, Youn BU, Ko A, Lee SY, Kim N. Akt induces osteoclast differentiation through regulating the GSK3beta/NFATc1 signaling cascade. J Immunol. 2012;188:163–9.PubMed

47.

Kang H, Chang W, Hurley M, Vignery A, Wu D. Important roles of PI3Kgamma in osteoclastogenesis and bone homeostasis. Proc Natl Acad Sci U S A. 2010;107:12901–6.PubMedPubMedCentral

48.

Hattersley G, Owens J, Flanagan AM, Chambers TJ. Macrophage colony stimulating factor (M-CSF) is essential for osteoclast formation in vitro. Biochem Biophys Res Commun. 1991;177:526–31.PubMed

49.

Kudo O, Fujikawa Y, Itonaga I, Sabokbar A, Torisu T, Athanasou NA. Proinflammatory cytokine (TNFalpha/IL-1alpha) induction of human osteoclast formation. J Pathol. 2002;198:220–7.PubMed

50.

Kwan Tat S, Padrines M, Theoleyre S, Heymann D, Fortun Y. IL-6, RANKL, TNF-alpha/IL-1: interrelations in bone resorption pathophysiology. Cytokine Growth Factor Rev. 2004;15:49–60.PubMed

51.

Takayanagi H. Mechanistic insight into osteoclast differentiation in osteoimmunology. J Mol Med (Berl). 2005;83:170–9.

52.

Sitara D, Aliprantis AO. Transcriptional regulation of bone and joint remodeling by NFAT. Immunol Rev. 2010;233:286–300.PubMedPubMedCentral

53.

Kuroda Y, Hisatsune C, Mizutani A, Ogawa N, Matsuo K, Mikoshiba K. Cot kinase promotes Ca2+ oscillation/calcineurin-independent osteoclastogenesis by stabilizing NFATc1 protein. Mol Cell Biol. 2012;32:2954–63.PubMedPubMedCentral

54.

Fan D, Ren B, Yang X, Liu J, Zhang Z. Upregulation of miR-501-5p activates the wnt/beta-catenin signaling pathway and enhances stem cell-like phenotype in gastric cancer. Journal of experimental & clinical cancer research : CR. 2016;35:177.PubMedCentral

Title: A circRNA-miRNA-mRNA network plays a role in the protective effect of diosgenin on alveolar bone loss in ovariectomized rats
Authors: Zhiguo Zhang
Lifeng Yue
Yuhan Wang
Yanhua Jiang
Lihua Xiang
Yin Cheng
Dahong Ju
Yanjing Chen
Publication date: 01-12-2020
Publisher: BioMed Central
Keyword: Ovariectomy
Published in: BMC Complementary Medicine and Therapies / Issue 1/2020
Electronic ISSN: 2662-7671
DOI: https://doi.org/10.1186/s12906-020-03009-z

2024 ASCO Annual Meeting

Springer Medicine

A circRNA-miRNA-mRNA network plays a role in the protective effect of diosgenin on alveolar bone loss in ovariectomized rats

Abstract

Background

Methods

Results

Conclusion

2024 ASCO Annual Meeting

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2020

Isatis root polysaccharide promotes maturation and secretory function of monocyte-derived dendritic cells

The toxicity assessment of extract of Peganum harmala L. seeds in Caenorhabditis elegans

The effects of the Xijiao Dihuang decoction combined with Yinqiao powder on miRNA-mRNA profiles in mice infected with influenza a virus

Effectiveness of herbal oral care products in reducing dental plaque & gingivitis – a systematic review and meta-analysis

The risk of coronary artery disease in patients with rheumatoid arthritis using Chinese herbal products and conventional medicine in parallel: a population-based cohort study

Cost-effectiveness analysis of combining traditional Chinese medicine in the treatment of hypertension: compound Apocynum tablets combined with Nifedipine sustained-release tablets vs Nifedipine sustained-release tablets alone