Advances in Clinical and Experimental Medicine

Adv Clin Exp Med
Impact Factor (IF) – 1.227
Index Copernicus (ICV 2018) – 157.72
MNiSW – 40
Average rejection rate – 84.38%
ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
Periodicity – monthly

Download PDF

Advances in Clinical and Experimental Medicine

2016, vol. 25, nr 2, March-April, p. 213–218

doi: 10.17219/acem/41860

Publication type: original article

Language: English

Download citation:

  • BIBTEX (JabRef, Mendeley)
  • RIS (Papers, Reference Manager, RefWorks, Zotero)

Creative Commons BY-NC-ND 3.0 Open Access

The Negative Impact of Selective Activation of Retinoic Acid Receptors on Bone Metabolism and Bone Mechanical Properties in Rats

Beata Nowak1,A,B,C,D,F, Agnieszka Matuszewska1,A,B, Jarosław Filipiak2,B,C, Anna Nikodem2,B,C, Anna Merwid-Ląd1,B,E, Małgorzata Pieśniewska1,B, Joanna Kwiatkowska1,B, Bartosz Grotthus1,E, Adam Szeląg1,E,F

1 Department of Pharmacology, Wroclaw Medical University, Poland

2 Division of Biomedical Engineering and Experimental Mechanics, Wroclaw University of Technology, Poland

Abstract

Background. Drug-induced osteoporosis is a significant health problem, as many drugs have deleterious effects on bone metabolism. Data from several studies concerning the influence of retinol on bone homeostasis are inconsistent.
Objectives. The purpose of this study was to investigate the influence of tazarotene, a selective agonist of the retinoic acid receptor (RAR), on bone metabolism and bone mechanical properties in rats.
Material and Methods. Sixteen male Wistar rats were assigned either to the group receiving tazarotene or to the control group. Serum biochemical markers of bone turnover (osteocalcin: OC, tartrate resistant acid phosphatase 5: TRACP5b, and osteoprotegerin: OPG) and the mechanical properties of bones were analyzed.
Results. The mean Young’s modulus was 24% higher (p < 0.05) in the control group than in the group receiving tazarotene. The stiffness of femur bones was 25% lower (p < 0.05) in rats receiving tazarotene. Flexural yield stress was slightly (2%) decreased in the tazarotene group, but the difference was not statistically significant. In the tazarotene group significantly lower serum concentration of bone turnover markers were obeserved (TRACP5b: 0.86 ± 0.30 ng/mL vs. 2.17 ± 0.67 ng/mL, OC: 7.77 ± 2.28 ng/mL vs. 13.04 ± 3.54 ng/mL and OPG: 0.09 ± 0.04 ng/mL vs. 0.27 ± 0.10) than in the control group.
Conclusion. Tazarotene worsened bone mechanical properties and inhibited bone turnover in rats. These results suggest that tazarotene has a negative impact on bone metabolism and that it exerts osteoporotic activity.

Key words

retinoic acid receptors, osteoporosis, bone turnover, bone mechanical properties, tazarotene

References (37)

  1. Panday K, Gona A, Humphrey MB. Medication-induced osteoporosis: Screening and treatment strategies. Ther Adv Musculoskelet Dis 2014, 6, 185–202.
  2. Lohnes D, Mark M, Mendelsohn C, Dollé P, Dierich A, Gorry P, Gansmuller A, Chambon P: Function of the retinoic acid receptors (RARs) during development (I). Craniofacial and skeletal abnormalities in RAR double mutants. Development 1994, 120, 2723–2748.
  3. Lee K, Skromne I: Retinoic acid regulates size, pattern and alignment of tissues at the head-trunk transition. Development 2014, 141, 4375–4384.
  4. Koyama E, Golden EB, Kirsch T, Adams SL, Chandraratna RA, Michaille JJ, Pacifici M: Retinoid signaling is required for chondrocyte maturation and endochondral bone formation during limb skeletogenesis. Dev Biol 1999, 208, 375–391.
  5. Ahmadieh H, Arabi A: Vitamins and bone health: Beyond calcium and vitamin D. Nutr Rev 2011, 69, 584–598.
  6. Binkley N, Krueger D: Hypervitaminosis A and bone. Nutr Rev 2000, 58, 138–44.
  7. Michaëlsson K, Lithell H, Vessby B, Melhus H: Serum retinol levels and the risk of fracture. N Engl J Med 2003, 348, 287–294.
  8. Barker ME, McCloskey E, Saha S, Gossiel F, Charlesworth D, Powers HJ, Blumsohn A: Serum retinoids and beta-carotene as predictors of hip and other fractures in elderly women. J Bone Miner Res 2005, 20, 913–920.
  9. Ambrosini GL, Alfonso H, Reid A, Mackerras D, Bremner AP, Beilby J, Olsen NJ, Musk AW, de Klerk NH: Plasma retinol and total carotenes and fracture risk after long-term supplementation with high doses of retinol. Nutrition 2014, 30, 551–556.
  10. Ambrosini GL, Bremner AP, Reid A, Mackerras D, Alfonso H, Olsen NJ, Musk AW, de Klerk NH: No dose-dependent increase in fracture risk after long-term exposure to high doses of retinol or beta-carotene. Osteoporos Int 2013, 24, 1285–1293.
  11. Lawson JP, McGuire J: The spectrum of skeletal changes associated with long-term administration of 13-cisretinoic acid. Skeletal Radiol 1987, 16, 91–97.
  12. McGuire J, Lawson JP: Skeletal changes associated with chronic isotretinoin and etretinate administration. Dermatologica 1987, 175, Suppl 1, 169–181.
  13. Margolis DJ, Attie M, Leyden JJ: Effects of isotretinoin on bone mineralization during routine therapy with isotretinoin for acne vulgaris. Arch Dermatol 1996, 132, 769–774.
  14. Śliwiński L, Janiec W, Pytlik M, Folwarczna J, Kaczmarczyk-Sedlak I, Pytlik W, Cegieła U, Nowińska B: Effect of administration of alendronate sodium and retinol on the mechanical properties of the femur in ovariectomized rats. Pol J Pharmacol 2004, 56, 817–824.
  15. Hough S, Avioli LV, Muir H, Gelderblom D, Jenkins G, Kurasi H, Slatopolsky E, Bergfeld MA, Teitelbaum SL: Effects of hypervitaminosis A on the bone and mineral metabolism of the rat. Endocrinology 1988, 122, 2933–2939.
  16. Hotchkiss CE, Latendresse J, Ferguson SA: Oral treatment with retinoic acid decreases bone mass in rats. Comp Med 2006, 56, 502–511.
  17. Rhinn M, Dollé P: Retinoic acid signalling during development. Development 2012, 139, 843–858.
  18. Long MD, Sucheston-Campbell LE, Campbell MJ: Vitamin D receptor and RXR in the post-genomic era. J Cell Physiol 2015, 230, 758–766.
  19. Rohde CM, Manatt M, Clagett-Dame M, DeLuca HF: Vitamin A antagonizes the action of vitamin D in rats. J Nutr 1999, 129, 2246–2250.
  20. Rohde CM, DeLuca H: Bone resorption activity of all-trans retinoic acid is independent of vitamin D in rats. J Nutr 2003, 133, 777–783.
  21. Hisada K, Hata K, Ichida F, Matsubara T, Orimo H, Nakano T, Yatani H, Nishimura R, Yoneda T: Retinoic acid regulates commitment of undifferentiated mesenchymal stem cells into osteoblasts and adipocytes. J Bone Miner Metab 2013, 31, 53–63.
  22. Hu L, Lind T, Sundqvist A, Jacobson A, Melhus H: Retinoic acid increases proliferation of human osteoclast progenitors and inhibits RANKL-stimulated osteoclast differentiation by suppressing RANK. PLoS One 2010, 5, e13305.
  23. Conaway HH, Pirhayati A, Persson E, Pettersson U, Svensson O, Lindholm C, Henning P, Tuckermann J, Lerner UH: Retinoids stimulate periosteal bone resorption by enhancing the protein RANKL, a response inhibited by monomeric glucocorticoid receptor. J Biol Chem 2011, 286, 31425–31436.
  24. Ohishi K, Nishikawa S, Nagata T, Yamauchi N, Shinohara H, Kido J, Ishida H: Physiological concentrations of retinoic acid suppress the osteoblastic differentiation of fetal rat calvaria cells in vitro. Eur J Endocrinol 1995, 133, 335–341.
  25. De Luca F, Uyeda JA, Mericq V, Mancilla EE, Yanovski JA, Barnes KM, Zile MH, Baron J: Retinoic acid is a potent regulator of growth plate chondrogenesis. Endocrinology 2000, 141, 346–353.
  26. Harada H, Miki R, Masushige S, Kato S: Gene expression of retinoic acid receptors, retinoid-X receptors, and cellular retinol-binding protein I in bone and its regulation by vitamin A. Endocrinology 1995, 136, 5329–5335.
  27. Delmas PD: Different effects of antiresorptive therapies on vertebral and nonvertebral fractures in postmenopausal osteoporosis. Bone 2002, 30, 14–17.
  28. Peng ZQ, Väänänen HK, Zhang HX, Tuukkanen J: Long-term effects of ovariectomy on the mechanical properties and chemical composition of rat bone. Bone 1997, 20, 207–212.
  29. Younes M, Hachfi H, Ouertani D, Jguirim M, Hassine Neffati F, Zrour S, Bejia I, Touzi M, Najjar MF, Bergaoui N: Utility of biochemical markers of bone turnover in diagnosis of osteoporosis and fracture risk prediction. Tunis Med 2014, 92, 304–310.
  30. Hofbauer LC, Kühne CA, Viereck V: The OPG/RANKL/RANK system in metabolic bone diseases. J Musculoskelet Neuronal Interact 2004, 4, 268–275.
  31. Canalis E: Clinical review 83: Mechanisms of glucocorticoid action in bone: implications to glucocorticoid-induced osteoporosis. J Clin Endocrinol Metab 1996, 81, 3441–3447.
  32. Cai L, Yan X, Chen X, Meng Q, Zhou J: Chronic all-trans retinoic acid administration induced hyperactivity of HPA axis and behavioral changes in young rats. Eur Neuropsychopharmacol 2010, 20, 839–847.
  33. Minkin C: Bone acid phosphatase: tartrate-resistant acid phosphatase as a marker of osteoclast function. Calcif Tissue Int 1982, 34, 285–290.
  34. Kanbur NO, Derman O, Sen TA, Kinik E: Osteocalcin. A biochemical marker of bone turnover during puberty. Int J Adolesc Med Health 2002, 14, 235–244.
  35. Mokuda S, Sawada N, Matoba K, Yamada A, Onishi M, Okuda Y, Jouyama K, Murata Y, Takasugi K: Serum undercarboxylated osteocalcin level increases with 48 weeks of teriparatide treatment in pre-treated elderly rheumatoid arthritis patients who use anti-resorptive drugs. J Endocrinol Invest 2012, 35, 796–799.
  36. Wang A, Ding X, Sheng S, Yao Z: Retinoic acid inhibits osteogenic differentiation of rat bone marrow stromal cells. Biochem Biophys Res Commun 2008, 375, 435–439.
  37. Conaway HH, Persson E, Halén M, Granholm S, Svensson O, Pettersson U, Lie A, Lerner UH: Retinoids inhibit differentiation of hematopoietic osteoclast progenitors. FASEB J 2009, 23, 3526–3538.