Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Oncology Letters
      • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Biomedical Reports
      • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • Information for Authors
    • Information for Reviewers
    • Information for Librarians
    • Information for Advertisers
    • Conferences
  • Language Editing
Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • For Authors
    • For Reviewers
    • For Librarians
    • For Advertisers
    • Conferences
  • Language Editing
Login Register Submit
  • This site uses cookies
  • You can change your cookie settings at any time by following the instructions in our Cookie Policy. To find out more, you may read our Privacy Policy.

    I agree
Search articles by DOI, keyword, author or affiliation
Search
Advanced Search
presentation
Molecular Medicine Reports
Join Editorial Board Propose a Special Issue
Print ISSN: 1791-2997 Online ISSN: 1791-3004
Journal Cover
September-2015 Volume 12 Issue 3

Full Size Image

Sign up for eToc alerts
Recommend to Library

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

Medicine International

An International Open Access Journal Devoted to General Medicine.

Journal Cover
September-2015 Volume 12 Issue 3

Full Size Image

Sign up for eToc alerts
Recommend to Library

  • Article
  • Citations
    • Cite This Article
    • Download Citation
    • Create Citation Alert
    • Remove Citation Alert
    • Cited By
  • Similar Articles
    • Related Articles (in Spandidos Publications)
    • Similar Articles (Google Scholar)
    • Similar Articles (PubMed)
  • Download PDF
  • Download XML
  • View XML
Article

Increase in osteoclastogenesis in an obese Otsuka Long-Evans Tokushima fatty rat model

  • Authors:
    • Tomoyo Ootsuka
    • Atsuko Nakanishi
    • Ikuyo Tsukamoto
  • View Affiliations / Copyright

    Affiliations: Department of Food Science and Nutrition, Nara Women's University, Nara 630‑8506, Japan
  • Pages: 3874-3880
    |
    Published online on: May 21, 2015
       https://doi.org/10.3892/mmr.2015.3811
  • Expand metrics +
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
Cited By (CrossRef): 0 citations Loading Articles...

This article is mentioned in:



Abstract

In the present study, the effects of obesity on bone metabolism were investigated using a hyperphagic and obese rat model, the Otsuka Long‑Evans Tokushima fatty (OLETF) rat, which exhibits normal glycemic control at 8 weeks of age. Body weight, food intake, fat mass, markers of bone resorption, the activities of tartrate‑resistant acid phosphatase (TRAP) and cathepsin K, the number of osteoclasts in the proximal tibia, and the serum C‑terminal crosslinking telopeptide level were higher in OLETF rats than those in control rats (Long‑Evans Tokushima Otsuka; LETO). However, no differences in markers of bone formation, alkaline phosphatase activity, the number of osteoblasts in the proximal tibia or the serum osteocalcin level were observed. mRNA and protein levels of c‑fms, receptor for activation of nuclear factor‑κB (RANK), RANK ligand (RANKL), TRAP and cathepsin K were significantly increased in OLETF rats, although those levels of macrophage colony‑stimulating factor (M‑CSF) and osteoprotegerin (OPG) were similar to those in LETO rats. The level of serum tumor necrosis factor α (TNFα), and that of TNFα mRNA in bone, increased in association with the activation of NFκB. Furthermore, a frequency analysis and a colony formation assay respectively showed that the number of osteoclast precursors and the number of colony‑forming cells induced by M‑CSF each increased in OLETF rats compared with the control group. These results suggested that hyperphagia‑induced obesity with normal glycemic control induces the upregulation of osteoclastogenesis that is associated with an increase in the expression of c‑fms, RANK and RANKL, which is induced by TNFα, via the activation of NFκB.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

View References

1 

Hsu YH, Venners SA, Terwedow HA, et al: Relation of body composition, fat mass and serum lipids to osteoporotic fractures and bone mineral density in Chinese men and women. Am J Clin Nutr. 83:146–154. 2006.PubMed/NCBI

2 

Zhao LJ, Jiang H, Papasian CJ, et al: Correlation of obesity and osteoporosis: Effect of fat mass on the determination of osteoporosis. J Bone Miner Res. 23:17–29. 2008. View Article : Google Scholar

3 

Cao JJ, Gregoire BR and Gao H: High-fat diet decreases cancellous bone mass but has no effect on cortical bone mass in the tibia in mice. Bone. 44:1097–1104. 2009. View Article : Google Scholar : PubMed/NCBI

4 

Fehrendt H, Linn T, Hartmann S, et al: Negative influence of a long-term high-fat diet on murine bone architecture. Int J Endocrinol. 2014:3189242014.PubMed/NCBI

5 

Kyung TW, Lee JE, Phan TV, Yu R and Choi HS: Osteoclastogenesis by bone marrow-derived macrophages is enhanced in obese mice. J Nutr. 139:502–506. 2009. View Article : Google Scholar : PubMed/NCBI

6 

Halade GV, Rahman MM, Williams PJ and Fernandes G: High fat diet-induced animal model of age-associated obesity and osteoporosis. J Nutr Biochem. 21:1162–1169. 2010. View Article : Google Scholar : PubMed/NCBI

7 

Patsch JM, Kiefer FW, Varga P, et al: Increased bone resorption and impaired bone microarchitecture in short-term and extended high-fat diet-induced obesity. Metabolism. 60:243–249. 2011. View Article : Google Scholar

8 

Baek K, Hwang HR, Park HJ, et al: TNF-α upregulates sclerostin expression in obese mice fed a high-fat diet. J Cell Physiol. 229:640–650. 2014. View Article : Google Scholar : PubMed/NCBI

9 

Xiao Y, Cui J, Shi YH, Sun J, Wang ZP and Le GW: Effects of duodenal redox status on calcium absorption and related genes expression in high-fat diet-fed mice. Nutrition. 26:1188–1194. 2010. View Article : Google Scholar : PubMed/NCBI

10 

Chen JR, Lazarenko OP, Wu X, et al: Obesity reduces bone density associated with activation of PPARγ and suppression of Wnt/β-catenin in rapidly growing male rats. PLoS One. 5:e137042010. View Article : Google Scholar

11 

Kawano K, Hirashima T, Mori S, Saitoh Y, Kurosumi M and Natori T: Spontaneous long-term hyperglycemic rat with diabetic complications. Otsuka Long-Evans Tokushima Fatty (OLETF) strain. Diabetes. 41:1422–1428. 1992. View Article : Google Scholar : PubMed/NCBI

12 

Kawano K, Hirashima T, Mori S and Natori T: OLETF (Otsuka Long-Evans Tokushima Fatty) rat: A new NIDDM rat strain. Diabetes Res Clin Pract. (Suppl 24): S317–S320. 1994. View Article : Google Scholar : PubMed/NCBI

13 

Moran TH and Bi S: Hyperphagia and obesity of OLETF rats lacking CCK1 receptors: Developmental aspects. Dev Psychobiol. 48:360–367. 2006. View Article : Google Scholar : PubMed/NCBI

14 

Gibbs J, Young RC and Smith GP: Cholecystokinin elicits satiety in rats with open gastric fistulas. Nature. 245:323–325. 1973. View Article : Google Scholar : PubMed/NCBI

15 

Schroeder M, Zagoory-Sharon O, Shbiro L, et al: Development of obesity in the Otsuka Long-Evans Tokushima Fatty rat. Am J Physiol Regul Integr Comp Physiol. 297:R1749–R1760. 2009. View Article : Google Scholar : PubMed/NCBI

16 

Bi S, Ladenheim EE, Schwartz GJ and Moran TH: A role for NPY overexpression in the dorsomedial hypothalamus in hyperphagia and obesity of OLETF rats. Am J Physiol Regul Integr Comp Physiol. 281:R254–R260. 2001.PubMed/NCBI

17 

Man ZW, Hirashima T, Mori S and Kawano K: Decrease in triglyceride accumulation in tissues by restricted diet and improvement of diabetes in Otsuka Long-Evans Tokushima fatty rats, a non-insulin-dependent diabetes model. Metabolism. 49:108–114. 2000. View Article : Google Scholar : PubMed/NCBI

18 

Park SY, Choi GH, Choi HI, Ryu J, Jung CY and Lee W: Calorie restriction improves whole-body glucose disposal and insulin resistance in association with the increased adipocyte-specific GLUT4 expression in Otsuka Long-Evans Tokushima fatty rats. Arch Biochem Biophys. 436:276–284. 2005. View Article : Google Scholar : PubMed/NCBI

19 

Bajotto G, Murakami T, Nagasaki M, et al: Downregulation of the skeletal muscle pyruvate dehydrogenase complex in the Otsuka Long-Evans Tokushima Fatty rat both before and after the onset of diabetes mellitus. Life Sci. 75:2117–2130. 2004. View Article : Google Scholar : PubMed/NCBI

20 

Laye MJ, Rector RS, Warner SO, et al: Changes in visceral adipose tissue mitochondrial content with type 2 diabetes and daily voluntary wheel running in OLETF rats. J Physiol. 587:3729–3739. 2009. View Article : Google Scholar : PubMed/NCBI

21 

Omi N, Nakamura T and Ezawa I: Modulation of bone mass and turnover in growing rats by voluntary weight-bearing exercise and glucose supplementation. J Nutr Sci Vitaminol (Tokyo). 44:409–421. 1998. View Article : Google Scholar

22 

Hie M, Shimono M, Fujii K and Tsukamoto I: Increased cathepsin K and tartrate-resistant acid phosphatase expression in bone of streptozotocin-induced diabetic rats. Bone. 41:1045–1050. 2007. View Article : Google Scholar : PubMed/NCBI

23 

Bergman I and Loxley R: The determination of hydroxyproline in urine hydrolysates. Clin Chim Acta. 27:347–349. 1970. View Article : Google Scholar : PubMed/NCBI

24 

Goto A and Tsukamoto I: Increase in tartrate-resistant acid phosphatase of bone at the early stage of ascorbic acid deficiency in the ascorbate-requiring Osteogenic Disorder Shionogi (ODS) rat. Calcif Tissue Int. 73:180–185. 2003. View Article : Google Scholar : PubMed/NCBI

25 

Parfitt AM, Drezner MK, Glorieux FH, et al: Bone histomorphometry: Standardization of nomenclature, symbols and units. Report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res. 2:595–610. 1987. View Article : Google Scholar : PubMed/NCBI

26 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar

27 

Hie M, Yamazaki M and Tsukamoto I: Curcumin suppresses increased bone resorption by inhibiting osteoclastogenesis in rats with streptozotocin-induced diabetes. Eur J Pharmacol. 621:1–9. 2009. View Article : Google Scholar : PubMed/NCBI

28 

Sato T, Shibata T, Ikeda K and Watanabe K: Generation of bone-resorbing osteoclasts from B220+ cells: its role in accelerated osteoclastogenesis due to estrogen deficiency. J Bone Miner Res. 16:2215–2221. 2001. View Article : Google Scholar

29 

Hie M, Iitsuka N, Otsuka T, Nakanishi A and Tsukamoto I: Zinc deficiency decreases osteoblasts and osteoclasts associated with the reduced expression of Runx2 and RANK. Bone. 49:1152–1159. 2011. View Article : Google Scholar : PubMed/NCBI

30 

Hie M and Tsukamoto I: Increased expression of the receptor for activation of NF-κB and decreased runt-related transcription factor 2 expression in bone of rats with streptozotocin-induced diabetes. Int J Mol Med. 26:611–618. 2010.PubMed/NCBI

31 

Hayashi S, Miyamoto A, Yamane T, et al: Osteoclast precursors in bone marrow and peritoneal cavity. J Cell Physiol. 170:241–247. 1997. View Article : Google Scholar : PubMed/NCBI

32 

Manolagas SC: Birth and death of bone cells: Basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev. 21:115–137. 2000.PubMed/NCBI

33 

Suda T, Takahashi N, Udagawa N, Jimi E, Gillespie MT and Martin TJ: Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocr Rev. 20:345–357. 1999. View Article : Google Scholar : PubMed/NCBI

34 

Riggs BL: The mechanisms of estrogen regulation of bone resorption. J Clin Invest. 106:1203–1204. 2000. View Article : Google Scholar : PubMed/NCBI

35 

Hofbauer LC, Khosla S, Dunstan CR, Lacey DL, Boyle WJ and Riggs BL: The roles of osteoprotegerin and osteoprotegerin ligand in the paracrine regulation of bone resorption. J Bone Miner Res. 15:2–12. 2000. View Article : Google Scholar : PubMed/NCBI

36 

Arai F, Miyamoto T, Ohneda O, et al: Commitment and differentiation of osteoclast precursor cells by the sequential expression of c-Fms and receptor activator of nuclear factor kappaB (RANK) receptors. J Exp Med. 190:1741–1754. 1999. View Article : Google Scholar : PubMed/NCBI

37 

Ishii J, Kitazawa R, Mori K, et al: Lipopolysaccharide suppresses RANK gene expression in macrophages by down-regulating PU.1 and MITF. J Cell Biochem. 105:896–904. 2008. View Article : Google Scholar : PubMed/NCBI

38 

Zhang DE, Hetherington CJ, Chen HM and Tenen DG: The macrophage transcription factor PU.1 directs tissue-specific expression of the macrophage colony-stimulating factor receptor. Mol Cell Biol. 14:373–381. 1994.PubMed/NCBI

39 

Yao Z, Li P, Zhang Q, et al: Tumor necrosis factor-alpha increases circulating osteoclast precursor numbers by promoting their proliferation and differentiation in the bone marrow through up-regulation of c-Fms expression. J Biol Chem. 281:11846–11855. 2006. View Article : Google Scholar : PubMed/NCBI

40 

Manolagas SC, Kousteni S and Jilka RL: Sex steroids and bone. Recent Prog Horm Res. 57:385–409. 2002. View Article : Google Scholar : PubMed/NCBI

41 

Fujita D, Yamashita N, Iita S, Amano H, Yamada S and Sakamoto K: Prostaglandin E2 induced the differentiation of osteoclasts in mouse osteoblast-depleted bone marrow cells. Prostaglandins Leukot Essent Fatty Acids. 68:351–358. 2003. View Article : Google Scholar : PubMed/NCBI

42 

Singer P, Shapiro H, Theilla M, Anbar R, Singer J and Cohen J: Anti-inflammatory properties of omega-3 fatty acids in critical illness: Novel mechanisms and an integrative perspective. Intensive Care Med. 34:1580–1592. 2008. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Ootsuka T, Nakanishi A and Tsukamoto I: Increase in osteoclastogenesis in an obese Otsuka Long-Evans Tokushima fatty rat model. Mol Med Rep 12: 3874-3880, 2015.
APA
Ootsuka, T., Nakanishi, A., & Tsukamoto, I. (2015). Increase in osteoclastogenesis in an obese Otsuka Long-Evans Tokushima fatty rat model. Molecular Medicine Reports, 12, 3874-3880. https://doi.org/10.3892/mmr.2015.3811
MLA
Ootsuka, T., Nakanishi, A., Tsukamoto, I."Increase in osteoclastogenesis in an obese Otsuka Long-Evans Tokushima fatty rat model". Molecular Medicine Reports 12.3 (2015): 3874-3880.
Chicago
Ootsuka, T., Nakanishi, A., Tsukamoto, I."Increase in osteoclastogenesis in an obese Otsuka Long-Evans Tokushima fatty rat model". Molecular Medicine Reports 12, no. 3 (2015): 3874-3880. https://doi.org/10.3892/mmr.2015.3811
Copy and paste a formatted citation
x
Spandidos Publications style
Ootsuka T, Nakanishi A and Tsukamoto I: Increase in osteoclastogenesis in an obese Otsuka Long-Evans Tokushima fatty rat model. Mol Med Rep 12: 3874-3880, 2015.
APA
Ootsuka, T., Nakanishi, A., & Tsukamoto, I. (2015). Increase in osteoclastogenesis in an obese Otsuka Long-Evans Tokushima fatty rat model. Molecular Medicine Reports, 12, 3874-3880. https://doi.org/10.3892/mmr.2015.3811
MLA
Ootsuka, T., Nakanishi, A., Tsukamoto, I."Increase in osteoclastogenesis in an obese Otsuka Long-Evans Tokushima fatty rat model". Molecular Medicine Reports 12.3 (2015): 3874-3880.
Chicago
Ootsuka, T., Nakanishi, A., Tsukamoto, I."Increase in osteoclastogenesis in an obese Otsuka Long-Evans Tokushima fatty rat model". Molecular Medicine Reports 12, no. 3 (2015): 3874-3880. https://doi.org/10.3892/mmr.2015.3811
Follow us
  • Twitter
  • LinkedIn
  • Facebook
About
  • Spandidos Publications
  • Careers
  • Cookie Policy
  • Privacy Policy
How can we help?
  • Help
  • Live Chat
  • Contact
  • Email to our Support Team