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Journal of Bone and Mineral Metabolism

, Volume 31, Issue 3, pp 262–273 | Cite as

Glycyrrhizic acid (GCA) as 11β-hydroxysteroid dehydrogenase inhibitor exerts protective effect against glucocorticoid-induced osteoporosis

  • Elvy Suhana Mohd Ramli
  • Farihah Suhaimi
  • Siti Fadziyah Mohamad Asri
  • Fairus Ahmad
  • Ima Nirwana SoelaimanEmail author
Original Article

Abstract

Rapid onset of bone loss is a frequent complication of systemic glucocorticoid therapy which may lead to fragility fractures. Glucocorticoid action in bone depends upon the activity of 11β-hydroxysteroid dehydrogenase type 1 enzyme (11β-HSD1). Regulations of 11β-HSD1 activity may protect the bone against bone loss due to excess glucocorticoids. Glycyrrhizic acid (GCA) is a potent inhibitor of 11β-HSD. Treatment with GCA led to significant reduction in bone resorption markers. In this study we determined the effect of GCA on 11β-HSD1 activity in bones of glucocorticoid-induced osteoporotic rats. Thirty-six male Sprague–Dawley rats (aged 3 months and weighing 250–300 g) were divided randomly into groups of ten. (1) G1, sham operated group; (2) G2, adrenalectomized rats administered with intramuscular dexamethasone 120 μg/kg/day and oral vehicle normal saline vehicle; and (3) G3, adrenalectomized rats administered with intramuscular dexamethasone 120 μg/kg/day and oral GCA 120 mg/kg/day The results showed that GCA reduced plasma corticosterone concentration. GCA also reduced serum concentration of the bone resorption marker, pyridinoline and induced 11β-HSD1 dehydrogenase activity in the bone. GCA improved bone structure, which contributed to stronger bone. Therefore, GCA has the potential to be used as an agent to protect the bone against glucocorticoid induced osteoporosis.

Keywords

Glycyrrhizic acid 11β-Hydroxysteroid dehydrogenase type 1 Dexamethasone Glucocorticoids Osteoporosis 

Notes

Acknowledgments

This work was supported by the Malaysian Ministry of Science Technology and Innovation (MOSTI) and Universiti Kebangsaan Malaysia (UKM) Research Grant. The authors gratefully acknowledge the technical assistance of the staffs of the Anatomy and Pharmacology Department of Universiti Kebangsaan Malaysia; especially Mrs Azizah Othman, Mrs Mazlidiyana and Mr Rafizul.

Conflict of interest

The authors declare that they have no conflict of interest regarding this paper.

References

  1. 1.
    Raisz LG (2005) Pathogenesis of osteoporosis: concepts, conflicts, and prospects. J Clin Invest 115:3318–3325PubMedCrossRefGoogle Scholar
  2. 2.
    Melton LJ III (2003) Adverse outcomes of osteoporotic fractures in the general population. J Bone Miner Res 18:1139–1141PubMedCrossRefGoogle Scholar
  3. 3.
    Cheng SL, Zhang SF, Avioli LV (1996) Expression of bone matrix proteins during dexamethasone-induced mineralization of human bone marrow stromal cells. J Cell Biochem 61:182–193PubMedCrossRefGoogle Scholar
  4. 4.
    Iba K, Chiba H, Sawada N, Hirota S, Ishii S, Mori M (1995) Glucocorticoids induce mineralization coupled with bone protein expression without influence on growth of a human osteoblastic cell line. Cell Struct Funct 20:319–330PubMedCrossRefGoogle Scholar
  5. 5.
    Canalis E, Mazziotti G, Giustina A, Bilezikian JP (2007) Glucocorticoid-induced osteoporosis: pathophysiology and therapy. Osteoporos Int 18:1319–1328PubMedCrossRefGoogle Scholar
  6. 6.
    Van der Meulen MC, Jepsen KJ, Mikić B (2001) Understanding bone strength: size isn’t everything. Bone 29:101–104PubMedCrossRefGoogle Scholar
  7. 7.
    Carter DR, Beaupré GS (1990) Effects of fluoride treatment on bone strength. J Bone Miner Res Suppl 1:S177–S184Google Scholar
  8. 8.
    Turner CH (2002) Biomechanics of bone: determinants of skeletal fragility and bone quality. Osteoporos Int 13:97–104PubMedCrossRefGoogle Scholar
  9. 9.
    Lo Cascio V, Bonucci E, Imbimbo B, Ballanti P, Tartarotti D, Galvanini G, Fuccella L, Adami S (1984) Bone loss after glucocorticoid therapy. Calcif Tissue Int 36:435–438PubMedCrossRefGoogle Scholar
  10. 10.
    Lo Cascio V, Kanis JA, Beneton MN, Bertoldo F, Adami S, Poggi G, Zanolin ME (1995) Acute effects of deflazacort and prednisone on rates of mineralization and bone formation. Calcif Tissue Int 56:109–912PubMedCrossRefGoogle Scholar
  11. 11.
    Dalle Carbonare L, Arlot ME, Chavassieux PM et al (2001) Comparison of trabecular bone microarchitecture and remodeling in glucocorticoid-induced and postmenopausal osteoporosis. J Bone Miner Res 16:77–103Google Scholar
  12. 12.
    Canalis E (2005) Mechanisms of glucocorticoid action in bone. Curr Osteoporos Rep 3:98–102 (review)PubMedCrossRefGoogle Scholar
  13. 13.
    Pereira RM, Delany AM, Canalis E (2001) Cortisol inhibits the differentiation and apoptosis of osteoblasts in culture. Bone 28:484–490PubMedCrossRefGoogle Scholar
  14. 14.
    Pereira RC, Delany AM, Canalis M (2002) Effects of cortisol and bone morphogenetic protein-2 on stromal cell differentiation: correlation with CCAAT-enhancer binding protein expression. Bone 30:685–691PubMedCrossRefGoogle Scholar
  15. 15.
    Sciaudone M, Gazzerro E, Priest L, Delany AM, Canalis E (2003) Notch 1 impairs osteoblastic cell differentiation. Endocrinology 144:5631–5639PubMedCrossRefGoogle Scholar
  16. 16.
    Dempster DW, Arlott MA, Meunier PJ (1983) Mean wall thickness and formation periods of trabecular bone packets in corticosteroid-induced osteoporosis. Calcif Tissue Int 35:410–417PubMedCrossRefGoogle Scholar
  17. 17.
    Chavassieux PM, Arlot ME, Roux JP, Portero N, Daifotis A, Yates AJ, Hamdy NA, Malice MP, Freedholm D, Meunier PJ (2000) Effects of alendronate on bone quality and remodeling in glucocorticoid-induced osteoporosis: a histomorphometric analysis of transiliac biopsies. J Bone Miner Res 15:754–762PubMedCrossRefGoogle Scholar
  18. 18.
    Weinstein R, Jilka R, Parfitt A, Manolagas S (1998) Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. Potential mechanisms of their deleterious effects on bone. J Clin Invest 102:274–282PubMedCrossRefGoogle Scholar
  19. 19.
    Weinstein RS, Chen JR, Powers CC, Stewart SA, Landes RD, Bellido T, Jilka RL, Parfitt AM, Manolagas SC (2002) Promotion of osteoclast survival and antagonism of bisphosphonate-induced osteoclast apoptosis by glucocorticoids. J Clin Invest 109:1041–1048PubMedGoogle Scholar
  20. 20.
    Jia D, O’Brien CA, Stewart SA, Manolagas SC, Weinstein RS (2006) Glucocorticoids act directly on osteoclasts to increase their life span and reduce bone density. Endocrinology 147:5592–5599PubMedCrossRefGoogle Scholar
  21. 21.
    Kim CH, Cheng SL, Kim GS (2006) Effects of dexamethasone on proliferation, activity, and cytokine secretion of normal human bone marrow stromal cells: possible mechanisms of glucocorticoid-induced bone loss. J Endocrinol 162:371–379CrossRefGoogle Scholar
  22. 22.
    Delany AM, Durant D, Canalis E (2001) Glucocorticoid suppression of IGF I transcription in osteoblasts. Mol Endocrinol 15:1781–1789PubMedCrossRefGoogle Scholar
  23. 23.
    Hofbauer LC, Gori F, Riggs BL, Lacey DL, Dunstan CR, Spelsberg TC (1999) Stimulation of osteoprotegerin ligand and inhibition of osteoprotegerin production by glucocorticoids in human osteoblastic lineage cells: potential paracrine mechanisms of glucocorticoid-induced osteoporosis. Endocrinology 140:4382–4389PubMedCrossRefGoogle Scholar
  24. 24.
    Rubin J, Biskobing DM, Jadhav L, Fan D, Nanes MS, Perkins S, Fan X (1998) Dexamethasone promotes expression of membrane-bound macrophage colony-stimulating factor in murine osteoblast-like cells. Endocrinology 139:1006–1012PubMedCrossRefGoogle Scholar
  25. 25.
    White PC, Mune T, Agarwal AK (1997) 11 beta-Hydroxysteroid dehydrogenase and the syndrome of apparent mineralocorticoid excess. Endocr Rev 18:135–156PubMedCrossRefGoogle Scholar
  26. 26.
    Stewart PM, Krozowski ZS (1999) 11 beta-Hydroxysteroid dehydrogenase. Vitam Horm 57:249–324PubMedCrossRefGoogle Scholar
  27. 27.
    Stewart PM, Whorwood CB (1994) 11 beta-Hydroxysteroid dehydrogenase activity and corticosteroid hormone action. Steroids 59:90–95PubMedCrossRefGoogle Scholar
  28. 28.
    Cooper MS, Walker EA, Bland R, Fraser WD, Hewison M, Stewart PM (2000) Expression and functional consequences of 11beta-hydroxysteroid dehydrogenase activity in human bone. Bone 27:375–381PubMedCrossRefGoogle Scholar
  29. 29.
    Phillipov G, Palermo M, Shackleton CH (1996) Apparent cortisone reductase deficiency: a unique form of hypercortisolism. J Clin Endocrinol Metab 81:3855–3860PubMedCrossRefGoogle Scholar
  30. 30.
    Cooper MS, Blumsohn A, Goddard PE, Bartlett WA, Shackleton CH, Eastell R, Hewison M, Stewart PM (2003) 11beta-hydroxysteroid dehydrogenase type 1 activity predicts the effects of glucocorticoids on bone. J Clin Endocrinol Metab 88:3874–3877PubMedCrossRefGoogle Scholar
  31. 31.
    Ploeger B, Mensinga T, Sips A, Seinen W, Meulenbelt J, DeJongh J (2001) The pharmacokinetics of glycyrrhizic acid evaluated by physiologically based pharmacokinetic modeling. Drug Metab 33:125–147CrossRefGoogle Scholar
  32. 32.
    Stewart PM, Wallace AM, Atherden SM, Shearing CH, Edwards CR (1990) Mineralocorticoid activity of carbenoxolone: contrasting effects of carbenoxolone and liquorice on 11 beta-hydroxysteroid dehydrogenase activity in man. Clin Sci (Lond) 78:49–54Google Scholar
  33. 33.
    Lems WF, Van Veen GJ, Gerrits MI, Jacobs JW, Houben HH, Van Rijn HJ, Bijlsma JW (1998) Effect of low-dose prednisone (with calcium and calcitriol supplementation) on calcium and bone metabolism in healthy volunteers. Br J Rheumatol 37:27–33PubMedCrossRefGoogle Scholar
  34. 34.
    Prummel MF, Wiersinga WM, Lips P, Sanders GT, Sauerwein HP (1991) The course of biochemical parameters of bone turnover during treatment with corticosteroids. J Clin Endocrinol Metab 72:382–386PubMedCrossRefGoogle Scholar
  35. 35.
    Eijken M, Hewison M, Cooper MS, de Jong FH, Chiba H, Stewart PM, Uitterlinden AG, Pols HA, van Leeuwen JP (2005) 11beta-Hydroxysteroid dehydrogenase expression and glucocorticoid synthesis are directed by a molecular switch during osteoblast differentiation. Mol Endocrinol 19:621–631PubMedCrossRefGoogle Scholar
  36. 36.
    Moisan MP, Seckl JR, Edwards CRW (1990) 11β-hydroxysteroid dehydrogenase bioactivity and messanger RNA expression in rat forebrain: localization in hypothalamus, hippocampus and cortex. Endocrinology 127:1450–1455PubMedCrossRefGoogle Scholar
  37. 37.
    Moisan MP, Seckl JR, Monder C, Agarwal PC, Edwards CRW (1990) 11β-hydroxysteroid dehydrogenase mRNA expression, bioactivity and immunoreactivity in rat cerebellum. Neuroendocrinology 2:853–858CrossRefGoogle Scholar
  38. 38.
    Haque T, Mandu-Hrit M, Rauch F, Lauzier D (2006) Immunohistochemical localization of Bone Morphogenetic protein-signaling Smads during Long-bone Distraction Osteogenesis. J Histochem Cytochem 54:407–415PubMedCrossRefGoogle Scholar
  39. 39.
    Haffa A, Krueger D, Bruner J, Engelke J, Gundberg C, Akhter M, Binkley N (2000) Diet- or warfarin-induced vitamin K insufficiency elevates circulating undercarboxylated osteocalcin without altering skeletal status in growing female rats. J Bone Miner Res 15:872–878PubMedCrossRefGoogle Scholar
  40. 40.
    Parfitt AM, Drezner MK, Glorieux FH, Kanis JA, Malluche H, Meunier PJ, Ott SM, Recker RR (1987) Bone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res 2:595–610PubMedCrossRefGoogle Scholar
  41. 41.
    Ima Nirwana S, Suhaniza S (2004) Effects of tocopherols and tocotrienols on Body composition and bone calcium content in adrenalectomized rats replaced with Dexamethasone. J Med Food 7:45–51PubMedCrossRefGoogle Scholar
  42. 42.
    Elvy Suhana MR, Farihah HS, Faizah O, Nazrun AS, Norazlina M, Norliza M, Ima-Nirwana S (2011) Effect of 11β-HSD1 dehydrogenase activity on bone histomorphometry of glucocorticoid-induced osteoporotic male Sprague–Dawley rats. Singap Med J 52:786–793Google Scholar
  43. 43.
    Al-Wahaibi A, Nazaimoon WWM, Farihah HS, Azian AL (2007) Effects of water extract of Labisia pumila var alata on 11beta-hydroxysteroid dehydrogenase activity induced fat deposition in the Sprague Dawley rats. Trop Med Plants 8:21–26Google Scholar
  44. 44.
    Cooper MS, Rabbit EH, Goddard PE, Bartiett WA, Hewison M, Stewart PM (2002) Osteoblastic 11beta-hydroxysteroid dehydrogenase type 1 activity increases with age and glucocorticoid exposure. J Bone Miner Res 17:979–986PubMedCrossRefGoogle Scholar
  45. 45.
    Yao W, Cheng Z, Busse C, Pham A, Nakamura MC, Lane NE (2008) Glucocorticoid excess in mice results in early activation of osteoclastogenesis and adipogenesis and prolonged suppression of osteogenesis: a longitudinal study of gene expression in bone tissue from glucocorticoid-treated mice. Arthritis Rheum 58:1674–1686PubMedCrossRefGoogle Scholar
  46. 46.
    Delany AM, Gabbitas BY, Canalis E (1995) Cortisol downregulates osteoblast alpha 1 (I) procollagen mRNA by transcriptional and posttranscriptional mechanisms. J Cell Biochem 57:488–494PubMedCrossRefGoogle Scholar
  47. 47.
    Strömstedt PE, Poellinger L, Gustafsson JA, Carlstedt-Duke J (1991) The glucocorticoid receptor binds to a sequence overlapping the TATA box of the human osteocalcin promoter: a potential mechanism for negative regulation. Mol Cell Biol 11:3379–3383PubMedGoogle Scholar
  48. 48.
    Lacey DL, Timms E, Tan HL, Kelley MJ, Dunstan CR et al (1998) Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93:165–176PubMedCrossRefGoogle Scholar
  49. 49.
    Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS et al (1997) Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89:309–319PubMedCrossRefGoogle Scholar
  50. 50.
    Cohen S (2006) Role of RANK ligand in normal and pathologic bone remodeling and the therapeutic potential of novel inhibitory molecules in musculoskeletal diseases. Arthritis Rheum 55:15–18PubMedCrossRefGoogle Scholar
  51. 51.
    Sivagurunathan S, Muir MM, Brennan TC, Seale JP, Mason RS (2005) Influence of glucocorticoids on human osteoclast generation and activity. J Bone Miner Res 20:390–398PubMedCrossRefGoogle Scholar

Copyright information

© The Japanese Society for Bone and Mineral Research and Springer Japan 2012

Authors and Affiliations

  • Elvy Suhana Mohd Ramli
    • 1
  • Farihah Suhaimi
    • 1
  • Siti Fadziyah Mohamad Asri
    • 1
  • Fairus Ahmad
    • 1
  • Ima Nirwana Soelaiman
    • 2
    Email author
  1. 1.Department of Anatomy, Faculty of MedicineUniversiti Kebangsaan MalaysiaKuala LumpurMalaysia
  2. 2.Department of Pharmacology, Faculty of MedicineUniversiti Kebangsaan MalaysiaKuala LumpurMalaysia

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