A study of osteoprotective effect of l-arginine, l-norvaline and rosuvastatin on a model of hypoestrogen-induced osteoporosis in rats

Abstract

Effect on the microcirculatory bed of the bony tissue is one of promising approaches to treatment of osteoporosis.

Aim. To study anti-osteoporotic properties of endothelioprotectors: L-arginine, L-norvaline and rosuvastatin.

Materials and Methods. Osteoprotective properties of L-arginine, L-norvaline and rosuvastatin, and also of a reference drug– strontium ranelate – were studied on 152 female rats of Wistar line using a model of hypoestrogen-induced osteoporosis. Anti-osteoporotic and endothelioprotective effect of the drugs were evaluated by laser dopplerflowmetry (LDF) of the proximal metaphysis of the femoral bone, morphometry of trabeculae of bone, and also by calculation of the coefficient of endothelial dysfunction.

Results. LDF showed that maximal increase in microcirculation of the proximal metaphysis of the femoral bone, in comparison with animals with untreated osteoporosis (61.52±3.74 perfusion units, PU) was achieved with L-norvaline (115.25±5.36 PU, p<0.001) and rosuvastatin (106.57±5.22 PU, p<0.001), less expressed effect was demonstrated by L-arginine (98.10±4.48 PU, p<0.001) and a reference drug – strontium ranelate (86.49±4.99 PU). A similar tendency was observed in morphometry of trabeculae of bone: in the group with untreated osteoporosis the diameter of trabeculae was 61.68±1.24 µm, in the group with use fL-norvaline – 91.86±1.8 µm (p<0.001), in the group with use of L-arginine – 86.64±1.39 µm (p<0.001) and in the group with use of strontium ranelate – 89.08±1.09 µm.

Conclusion. L-arginine and L-norvaline and also rosuvastatin possess the property of improving a morphofunctional condition of bone tissue and may be recommended for further preclinical study.

Keywords

osteoporosis / endothelial dysfunction / L-arginine / L-norvaline / rosuvastatin / strontium ranelate / rats

References

[1] Noble le F, Noble le J. Bone biology: Vessels of rejuvenation. Nature. 2014;507(7492):313-4. doi: 10.1038/nature13210

[2] Noble le F., Noble le J. Bone biology: Vessels of rejuvenation // Nature. 2014. Vol. 507 (7492). P. 313-314. doi:10.1038/nature13210

[3] Huang H, Ma L, Kyrkanides S. Effects of vascular endothelial growth factor on osteoblasts and osteoclasts. American Journal of Orthodontics and Dento-facial Orthopedics. 2016;149(3):366-73. doi:10.1016/ j.ajodo.2015.09.021

[4] Huang H., Ma L., Kyrkanides S. Effects of vascular endothelial growth factor on osteoblasts and osteoclasts // American Journal of Orthodontics and Dentofacial Orthopedics. 2016. Vol. 149, №3. P. 366-373. doi:10.1016/j.ajodo.2015.09.021

[5] Prisby RD, Dominguez JM II, Muller-Delp J, et al. Aging and Estrogen Status: A Possible Endothelium-Dependent Vascular Coupling Mechanism in Bone Remodeling. PLoS One. 2012;7(11):e48564. doi:10.1371/journal.pone.0048564

[6] Prisby R.D., Dominguez J.M. II, Muller-Delp J., et al. Aging and Estrogen Status: A Possible Endothelium-Dependent Vascular Coupling Mechanism in Bone Remodeling // PLoS One. 2012. Vol. 7, №11. P.e48564. doi:10.1371/journal.pone.0048564

[7] Xu R, Yallowitz A, Qin A, et al. Targeting skeletal endothelium to ameliorate bone loss. Nature Medicine. 2018;24(6):823-33. doi:10.1038/s41591-018-0020-z

[8] Xu R., Yallowitz A., Qin A., et al. Targeting skeletal endothelium to ameliorate bone loss // Nature Medicine. 2018. Vol. 24, №6. P. 823-833. doi: 10.1038/s41591-018-0020-z

[9] Rajkumar DSR, Gudyrev OS, Faitelson AV, et al. Study of the influence of L-norvaline, rosuvastatin and their combination on the level of microcirculation in bone tissue in experimental osteoporosis and fractures on its background. Research result: pharmacology and clinical pharmacology. 2016; 2(1):20-4. doi:10.18413/2313-8971-2016-2-1-20-24

[10] Rajkumar D.S.R., Gudyrev O.S., Faitelson A.V., et al. Study of the influence of L-norvaline, rosuvastatin and their combination on the level of microcirculation in bone tissue in experimental osteoporosis and fractures on its background // Research Result: Pharmacology and Clinical Pharmacology. 2016. Vol. 2, №1. P. 20-24. doi:10.18413/ 2313-8971-2016-2-1-20-24

[11] Popolo A, Adesso S, Pinto A, et al. L-Arginine and its metabolites in kidney and cardiovascular disease. Amino Acids. 2014;46(10):2271-86. doi:10.1007/ s00726-014-1825-9

[12] Popolo A., Adesso S., Pinto A., et al. L-Arginine and its metabolites in kidney and cardiovascular disease // Amino Acids. 2014. Vol. 46, №10. P. 2271-2286. doi:10.1007/s00726-014-1825-9

[13] Ivlitskaya IL, Korokin MV, Loktionov AL. Pharmacological efficiency of statins and L-norvalin at an endotoxin-induced endothelial dysfunction. Research result: pharmacology and clinical pharmacology. 2016;2(2):25-35. doi:10.18413/2313-8971-2016-2-2-25-35

[14] Ivlitskaya I.L., Korokin M.V., Loktionov A.L. Pharmacological efficiency of statins and L-norvalin at an endotoxin-induced endothelial dysfunction // Research Result: Pharmacology and Clinical Pharmacology. 2016. Vol. 2, №2. P. 25-35. doi:10.18413/2313-8971-2016-2-2-25-35

[15] Denisyuk TA, Lazareva GA, Provotorov VYa, et al. Endothelium and cardioprotective effects of HMG-Co-A-Reductase in combination with L-arginine in endothelial dysfunction modeling. Research Result: Pharmacology and Clinical Pharmacology. 2016;2(1):4-8. doi:10.18413/2313-8971-2016-2-1-4-8

[16] Denisyuk T.A., Lazareva G.A., Provotorov V.Ya., et al. Endothelium and cardioprotective effects of HMG-Co-A-Reductase in combination with L-arginine in endothelial dysfunction modeling // Research Result: Pharmacology and Clinical Pharmacology. 2016. Vol. 2, №1. P. 4-8. doi:10.18413/ 2313-8971-2016-2-1-4-8

[17] Cho KJ, Hill MM, Chigurupati S, et al. Therapeutic levels of the hydroxmethylglutaryl-coenzyme A reductase inhibitor lovastatin activate Ras signaling via phospholipase D2. Molecular and Cellular Biology. 2011;31(6):1110-20. doi: 10.1128/MCB.00989-10

[18] Cho K.J., Hill M.M., Chigurupati S., et al. Therapeutic levels of the hydroxmethylglutaryl-coenzyme A reductase inhibitor lovastatin activate Ras signa-ling via phospholipase D2 // Molecular and Cellular Biology. 2011. Vol. 31, №6. P. 1110-1120. doi:10.1128/MCB.00989-10

[19] Goldstein JL, Brown MS. Regulation of the mevalonate pathway. Nature. 1990;343(6257):425-30. doi:10.1038/343425a0

[20] Goldstein J.L., Brown M.S. Regulation of the mevalonate pathway // Nature. 1990. Vol. 343 (6257). P. 425-430. doi:10.1038/343425a0

[21] Van Aelst L, D’Souza-Schorey C. Rho GTPases and signaling networks. Genes & Development. 1997;11(18):2295-322. doi:10.1101/gad.11.18.2295

[22] Van Aelst L., D’Souza-Schorey C. Rho GTPases and signaling networks // Genes & Development. 1997. Vol. 11, №18. P. 2295-2322. doi:10.1101/ gad.11.18.2295

[23] Laufs U, Liao JK. Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase. Journal of Biological Chemistry. 1998;273(37):24266-71. doi:10.1074/jbc.273.37.24266

[24] Laufs U., Liao J.K. Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase // Journal of Biological Chemistry. 1998. Vol. 273, №37. P. 24266-24271. doi:10.1074/ jbc.273.37.24266

[25] Laufs U, La Fata V, Plutzky J, et al. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation.1998;97(12):1129-35. doi:10.1161/01.cir.97.12.1129

[26] Laufs U., La Fata V., Plutzky J., et al. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors // Circulation. 1998. Vol. 97, №12. P. 1129-1135. doi:10.1161/01.cir.97.12.1129

[27] Oesterle A, Laufs U, Liao JK. Pleiotropic Effects of Statins on the Cardiovascular System. Circulation Research. 2017;120(1):229-43. doi:10.1161/CIR-CRESAHA.116.308537

[28] Oesterle A., Laufs U., Liao J.K. Pleiotropic Effects of Statins on the Cardiovascular System // Circulation Research. 2017. Vol. 120, №1. P. 229-243. doi:10.1161/CIRCRESAHA.116.308537

[29] Steyers CM III, Miller FJ. Endothelial dysfunction in chronic inflammatory diseases. International Journal of Molecular Sciences. 2014;15(7):11324-49. doi:10.3390/ijms150711324

[30] Steyers C.M. III, Miller F.J. Endothelial dysfunction in chronic inflammatory diseases // International Journal of Molecular Sciences. 2014. Vol. 15, №7. P. 11324-11349. doi:10.3390/ijms150711324

RIGHTS & PERMISSIONS

Gudyrev O.S., Faitelson A.V., Sobolev M.S., Pokrovskiy M.V., Pokrovskaya T.G., Korokin M.V., Povetka E.E., Miller E.S., Soldatov V.O.