Skip to main content

Advertisement

SpringerLink
Log in

Ursolic Acid Prevents Retinoic Acid-Induced Bone Loss in Rats

  • Original Article
  • Published:
Chinese Journal of Integrative Medicine Aims and scope Submit manuscript

Abstract

Objective

To examine the effects of ursolic acid (UA) on mitigating retinoic acid (RA)-induced osteoporosis in rats.

Methods

Fifty female Sprague-Dawley rats were randomly divided into the control group (n=10) and the osteoporosis group (n=40). The 40 osteoporosis rats were induced by 75 mg/(kg•d) RA once daily for 2 weeks, and then were randomly assigned to vehicle control (model), low-, middle-, and high-dose UA [(UA-L, UA-M, UA-H; 30, 60, 120 mg/(kg•d), respectively] groups (10 rats each). UA were administered once daily to the rats from the 3rd weeks for up to 4 weeks by gavage. Bone turnover markers [serum alkaline phosphatase (ALP), osteocalcin (OCN), urine deoxypyridinoline (DPD)] and other parameters, including serum calcium (S-Ca), serum phosphorus (S-P), urine calcium (U-Ca), urine phosphorus (U-P), and bone mineral density (BMD) of the femur, 4th lumbar vertebra and tibia, bone biomechanical properties and trabecular microarchitecture, were measured.

Results

The osteoporosis in rats was successfully induced by RA. Compared with the model group, UA-M and UA-H significantly reversed the RA-induced changes in S-P, U-Ca, U-P, ALP, OCN and urine DPD ratio and markedly enhanced the BMD of right femur, 4th lumbar vertebra and tibia (Plt;0.05 or Plt;0.01). Further, biomechanical test and microcomputed tomography evaluation also showed that UA-H drastically improved biomechanical properties and trabecular microarchitecture (Plt;0.05 or Plt;0.01).

Conclusion

UA could promote bone formation, increase osteoblastic activity and reduce osteoclastic activity in rats, indicating that UA might be a potential therapeutic of RA-induced acute osteoporosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Hough S, Avioli LV, Muir H, Gelderblom D, Jenkins G, Kurasi H, et al. Effects of hypervitaminosis A on the bone and mineral metabolism of the rat. Endocrinology 1988;122:2933–2939.

    Article  PubMed  CAS  Google Scholar 

  2. Lind PM, Johansson S, Rönn M, Melhus H. Subclinical hypervitaminosis A in rat: measurements of bone mineral density (BMD) do not reveal adverse skeletal changes. Chem Biol Interact 2006;159:73–80.

    Article  PubMed  CAS  Google Scholar 

  3. Fahmy SR, Soliman AM. Oxidative stress as a risk factor of osteoporotic model induced by vitamin A in rats. Aust J Basic Appl Sci 2009;3:1559–1568.

    CAS  Google Scholar 

  4. Chen W, Jia W, Wang K, Zhou Q, Leng Y, Duan T, et al. Retinoic acid regulates germ cell differentiation in mouse embryonic stem cells through a Smad–dependent pathway. Biochem Biophys Res Commun 2012;418:571–577.

    Article  PubMed  CAS  Google Scholar 

  5. Broulík PD, Raška I, Brouliková K. Prolonged overdose of all–trans retinoic acid enhances bone sensitivity in castrated mice. Nutrition 2013;29:1166–1169.

    Article  PubMed  CAS  Google Scholar 

  6. Oršoli N, Goluža E, Diki D, Lisi i D, Sašilo K, Rodak E, et al. Role of flavonoids on oxidative stress and mineral contents in the retinoic acid–induced bone loss model of rat. Eur J Nutr 2014;53:1217–1227.

    Article  CAS  Google Scholar 

  7. Zhao S, Niu F, Xu CY, Liu Y, Ye L, Bi GB, et al. Diosgenin prevents bone loss on retinoic acid–induced osteoporosis in rats. Ir J Med Sci 2016;185:581–587.

    Article  PubMed  CAS  Google Scholar 

  8. Ge JR, Xie LH, Chen J, Li SQ. Liuwei Dihuang Pill treats postmenopausal osteoporosis with Shen (Kidney) yin deficiency via Janus kinase/signal transducer and activator of transcription signal pathway by up–regulating cardiotrophin–like cytokine factor 1 expression. Chin J Integr Med 2018;24:415–422.

    Article  PubMed  Google Scholar 

  9. Ueda H, Yamazaki C, Yamazaki M. Luteolin as an antiinflammatory and anti–allergic constituent of Perilla frutescens. Biol Pharm Bull 2002;25:1197–1202.

    Article  PubMed  CAS  Google Scholar 

  10. Chiba H, Uehara M, Wu J, Wang XX, Masuyama R, Suzuki K, et al. Hesperidin, a citrus flavonoid, inhibits bone loss and decreases serum and hepatic lipids in ovariectomized mice. J Nutr 2003;133:1892–1897.

    Article  PubMed  CAS  Google Scholar 

  11. Zhang G, Qin L, Hung WY, Shi YY, Leung PC, Yeung KS. Flavonoids derived from herbal Epimedium Brevicornum Maxim prevent OVX–induced osteoporosis in rats independent of its enhancement in intestinal calcium absorption. Bone 2006;38:818–825.

    Article  PubMed  CAS  Google Scholar 

  12. The Pharmacopoeia Committee of the People’s Republic of China. Chinese Pharmacopoeia. Volume. Beijing: Chemical Industry Press;2015:27–28.

  13. Lee SU, Park SJ, Kwak HB, Oh J, Min YK, Kim SH. Anabolic activity of ursolic acid in bone: stimulating osteoblast differentiation in vitro and inducing new bone formation in vivo. Pharmacol Res 2008;58:290–296.

    Article  PubMed  CAS  Google Scholar 

  14. Zang LL, Wu BN, Lin Y, Tang ZY. Research progress of ursolic acid’s anti–tumor actions. Chin J Integr Med 2014;20:72–79.

    Article  PubMed  CAS  Google Scholar 

  15. Saraswat B, Visen PK, Agarwal DP. Ursolic acid isolated from Eucalyptus tereticomis protects against ethanol toxicity in isolated rat hepatocytes. Phytother Res 2000;14:163–166.

    Article  PubMed  CAS  Google Scholar 

  16. Martin–Aragon S, de Las HB, Sanchez–Reus MI, Benedi J. Pharmacological modification of endogenous antioxidant enzymes by ursolic acid on tetrachloride–induced liver damage in rats and primary cultures of rat hepatocytes. Exp Toxicol Pathol 2001;53:199–206.

    Article  PubMed  Google Scholar 

  17. Jin YR, Jin JL, Li CH, Piao XX, Jin NG. Ursolic acid enhances mouse liver regeneration after partial hepatectomy. Pharm Biol 2012;50:523–528.

    Article  PubMed  CAS  Google Scholar 

  18. Lee HY, Chung HY, Lim KH, Lee JJ, Kim KW. Induction of differentiation in the cultured F9 teratocarcinoma stem cells by triterpene acids. J Cancer Res Clin Oncol 1994;120:513–518.

    Article  PubMed  CAS  Google Scholar 

  19. Quéré L, Wenger T, Schramm HJ. Triterpenes as potential dimerization inhibitors of HIV–1 protease. Biochem Biophys Res Commun 1996;227:484–488.

    Article  PubMed  Google Scholar 

  20. Chiang LC, Chiang W, Chang MY, Ng LT, Lin CC. Antileukemic activity of selected natural products in Taiwan. Am J Chin Med 2003;31:37–46.

    Article  PubMed  CAS  Google Scholar 

  21. Cunha WR, de Matos GX, Souza MG, Tozatti MG, Andrade e Silva ML, Martins CH, et al. Evaluation of the antibacterial activity of the methylene chloride extract of Miconia ligustroides, isolated triterpene acids, and ursolic acid derivatives. Pharm Biol 2010;48:166–169.

    Article  PubMed  CAS  Google Scholar 

  22. Cha HJ, Park MT, Chung HY, Kim ND, Sato H, Seiki M, et al. Ursolic acid–induced down–regulation of MMP–9 gene is mediated through the nuclear translocation of glucocorticoid receptor in HT1080 human fibrosarcoma cells. Oncogene 1998;16:771–778.

    Article  PubMed  CAS  Google Scholar 

  23. Liu RH, Kang X, Xu LP, Nian HL, Yang XW, Shi HT, et al. Effects of the combined extracts of Herba Epimedii and Fructus Ligustri Lucidi on bone mineral content and bone turnover in osteoporotic rats. BMC Complement Altern Med 2015;15:112.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Zhang Y, Diao TY, Wang L, Che CT, Wong MS. Protective effects of water fraction of Fructus Ligustri Lucidi extract against hypercalciuria and trabecular bone deterioration in experimentally type 1 diabetic mice. J Ethnopharmacol 2014;158:239–245.

    Article  PubMed  Google Scholar 

  25. Arjmandi BH, Lucas EA, Juma S, Soliman A, Stoecker BJ, Khalil DA, et al. Dried plums prevent ovariectomy–induced bone loss in rats. J Am Nutraceut Assoc 2001;4:50–56.

    Google Scholar 

  26. Peng Z, Tuukkanen J, Zhang H, Jämsä T, Väänänen HK. The mechanical strength of bone in different rat models of experimental osteoporosis. Bone 1994;15:523–532.

    Article  PubMed  CAS  Google Scholar 

  27. Turner CH, Burr CB. Basic mechanical measurements of bone: a tutorial. Bone 1993;14:595–608.

    Article  PubMed  CAS  Google Scholar 

  28. Zhang Y, Lai WP, Leung PC, Wu CF, Yao XS, Wong MS. Effects of Fructus Ligustri Lucidi extract on bone turnover and calcium balance in ovariectomized rats. Biol Pharm Bull 2006;29:291–296.

    Article  PubMed  Google Scholar 

  29. Huang JH, Huang XH, Chen ZY, Zheng QS, Sun RY. Dose conversion among different animals and healthy volunteers in pharmacological study. Chin J Clin Pharmacol Ther (Chin) 2004;9:1069–1072.

    Google Scholar 

  30. Laib A, Barou O, Vico L, Lafage–Proust MH, Alexandre C, Rugsegger P. 3D micro–computed tomography of trabecular and cortical bone architecture with application to a rat model of immobilisation osteoporosis. Med Biol Eng Comput 2000;38:326–332.

    Article  PubMed  CAS  Google Scholar 

  31. Gabet Y, Müller R, Regev E, Sela J, Shteyer A, Salisbury K, et al. Osteogenic growth peptide modulates fracture callus structural and mechanical properties. Bone 2004;35:65–73.

    Article  PubMed  CAS  Google Scholar 

  32. Johansson S, Melhus H. Vitamin A antagonizes calcium response to vitamin D in man. J Bone Miner Res 2001;16:1899–1905.

    Article  PubMed  CAS  Google Scholar 

  33. Bharti AC, Takada Y, Aggarwal BB. Curcumin (diferuloylmethane) inhibits receptor activator of NF–kappa B ligand–induced NF–kappa B activation in osteoclast precursors and suppresses osteoclastogenesis. J Immunol 2004;172:5940–5947.

    Article  PubMed  CAS  Google Scholar 

  34. Li YJ, Kim TH, Kwak HB, Lee ZH, Lee SY, Jhon GJ. Chloroform extract of deer antler inhibits osteoclast differentiation and bone resorption. J Ethnopharmacol 2007;113:191–198.

    Article  PubMed  Google Scholar 

  35. Zhang Y, Leung PC, Che CT, Chow HK, Wu CF, Wong MS. Improvement of bone properties and enhancement of mineralization by ethanol extract of Fructus Ligustri Lucidi. Br J Nutr 2008;99:494–502.

    Article  PubMed  CAS  Google Scholar 

  36. Kyoko T, Shinji F, Kazutoshi N, Satoshi K, Koichiro T. Comparison of incadronate and alfacalcidol on increased bone turnover caused by ovariectomy in rats. Eur J Pharmacol 2002;449:191–196.

    Article  Google Scholar 

  37. Brown JP, Delmas PD, Malaval L, Edouard C, Chapuy MC, Meunier PJ. Serum bone GLA–protein: a specific marker for bone formation in postmenopausal osteoporosis. Lancet 1984;1:1091–1093.

    Article  PubMed  CAS  Google Scholar 

  38. Meyer–Sabellek W, Sinha P, Köttgen E. Alkaline phosphatase. Laboratory and clinical implications. J Chromatogr 1988;429:419–444.

    PubMed  Google Scholar 

  39. Farley JR, Stilt–Coffing B. Apoptosis may determine the release of skeletal alkaline phosphatase activity from human osteoblast–line cells. Calcif Tissue Int 2001;68:43–52.

    Article  PubMed  CAS  Google Scholar 

  40. Bahlous A, Kalai E, Hadj Salah M, Bouzid K, Zerelli L. Biochemical markers of bone remodeling: recent data of their applications in managing postmenopausal osteoporosis. Tunis Med 2006;84:751–757.

    PubMed  Google Scholar 

  41. Lerner UH. Bone remodeling in post–menopausal osteoporosis. J Dent Res 2006;85:584–595.

    Article  PubMed  CAS  Google Scholar 

  42. Wada S, Fukawa T, Kamiya S. Osteocalcin and bone. Clin Calcium 2007;17:1673–1677.

    PubMed  CAS  Google Scholar 

  43. Bharadwaj S, Naidu AG, Betageri GV, Prasadarao NV, Naidu AS. Milk ribonuclease–enriched lactoferrin induces positive effects on bone turnover markers in postmenopausal women. Osteoporos Int 2009;20:1603–1611.

    Article  PubMed  CAS  Google Scholar 

  44. Hotchkiss CE, Latendresse J, Ferguson SA. Oral treatment with retinoic acid decreases bone mass in rats. Comp Med 2006;56:502–511.

    PubMed  CAS  Google Scholar 

  45. Yang J, Wu NN, Peng J, Yang XQ, Guo J, Yin SW, et al. Prevention of retinoic acid–induced osteoporosis in mice by isoflavone–enriched soy protein. J Sci Food Agric 2016;96:331–338.

    Article  PubMed  CAS  Google Scholar 

  46. Reddy NP, Lakshmana M. Assessment of experimental osteoporosis using CT–scanning, quantitative X–ray analysis and impact test in calcium deficient ovariectomized rats. J Pharmacol Toxicol 2005;52:350–355.

    Article  CAS  Google Scholar 

  47. Liu ZG, Zhang R, Li C, Ma X, Liu L, Wang JP, et al. The osteoprotective effect of Radix Dipsaci extract in ovariectomized rats. J Ethnopharmacol 2009;123:74–81.

    Article  PubMed  Google Scholar 

  48. Zhang R, Liu ZG, Li C, Hu SJ, Liu L, Wang JP, et al. Du–Zhong (Eucommia ulmoides Oliv.) cortex extract prevent OVX–induced osteoporosis in rats. Bone 2009;45:553–559.

    Article  PubMed  CAS  Google Scholar 

  49. Cheng M, Wang Q, Fan Y, Liu X, Wang L, Xie R, et al. A traditional Chinese herbal preparation, Er–Zhi–Wan, prevent ovariectomy–induced osteoporosis in rat. J Ethnopharmacol 2011;138:279–285.

    Article  PubMed  Google Scholar 

  50. Ederveen AGH, Spanjers CPM, Quaijtaal JHM, Kloosterboer HJ. Effect of 16 months of treatment with tibolone on bone mass, turnover, and biomechanical quality in mature ovariectomized rats. J Bone Miner Res 2001;16:1674–1681.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. College of Biology Pharmacy and Food Engineering, Shangluo University, Shangluo, Shaanxi Province, 726000, China

    Min Cheng, Xu-hua Liang & Zhi-xin Zhao

  2. Department of Pharmacy, The Second Affiliated Hospital, Fourth Military Medical University, Xi’an, 710038, China

    Qing-wei Wang

  3. Department of Pharmacology, Xi’an Medical College, Xi’an, 710021, China

    Ya-ting Deng

  4. Department of Medicinal Chemistry, Fourth Military Medical University, Xi’an, 710032, China

    Xue-ying Liu

Authors
  1. Min Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xu-hua Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Qing-wei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ya-ting Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhi-xin Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xue-ying Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Min Cheng.

Additional information

Supported by Qinling-Bashan Mountains Bioresources Comprehensive Development Collaborative Innovation Center (No. QBXT-Z(Z)-15-4)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cheng, M., Liang, Xh., Wang, Qw. et al. Ursolic Acid Prevents Retinoic Acid-Induced Bone Loss in Rats. Chin. J. Integr. Med. 25, 210–215 (2019). https://doi.org/10.1007/s11655-018-3050-y

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11655-018-3050-y

Keywords

Search

Navigation