Role of the local bone renin‑angiotensin system in steroid‑induced osteonecrosis in rabbits

Zhang,Yongtao; Wang,Kunzheng; Song,Qichun; Liu,Ruiyu; Ji,Wenchen; Ji,Le; Wang,Chunsheng

doi:10.3892/mmr.2014.1978

Role of the local bone renin‑angiotensin system in steroid‑induced osteonecrosis in rabbits

Authors:
- Yongtao Zhang
- Kunzheng Wang
- Qichun Song
- Ruiyu Liu
- Wenchen Ji
- Le Ji
- Chunsheng Wang
View Affiliations

Affiliations: Department of Orthopaedics, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China, Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
Published online on: February 21, 2014 https://doi.org/10.3892/mmr.2014.1978
Pages: 1128-1134

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The specific pathogenesis of steroid‑induced osteonecrosis (ON) is yet to be elucidated and until recently effective prophylactic therapies have not been available. The local renin‑angiotensin system (RAS) exists in the bone and has an important role in local bone regulation. However, to the best of our knowledge, the interrelation between local bone RAS and steroid‑induced ON is yet to be investigated. In the present study, 45 rabbits were injected with a single intramuscular dose of 20 mg/kg methylprednisolone acetate (MPA) and were sacrificed 1 (group A), 2 (group B) and 3 (group C) weeks subsequent to MPA administration (n=15 per group). Ten rabbits were used as a control group (group N). The presence or absence of ON in the bilateral femoral heads was examined histopathologically. The mRNA and protein expression of components of the RAS, including angiotensin II (Ang II), angiotensin converting enzyme (ACE) and Ang II type 1 (AT1) and Ang II type 2 (AT2) receptors, were detected in the bone. Significant changes in Ang II, ACE, and AT1 and AT2 receptor expression were observed in the bone of the rabbits in the different groups. Moreover, the expression of Ang II and ACE was highest one week subsequent to administration of the glucocorticoid methylprednisolone and the expression of the AT1 and AT2 receptors was highest two weeks following methylprednisolone administration. ON occurs most significantly at three weeks following the administration of MPA in this animal model, thus the changes in Ang II, ACE and AT1 and AT2 receptor expression preceded this. The present study found that ON was strongly associated with the activation of the local bone RAS in rabbits.

View Figures

View References

1	Miyanishi K, Yamamoto T, Irisa T, et al: Bone marrow fat cell enlargement and a rise in intraosseous pressure in steroid-treated rabbits with osteonecrosis. Bone. 30:185–190. 2002. View Article : Google Scholar : PubMed/NCBI
2	Ichiseki T, Ueda Y, Katsuda S, Kitamura K, Kaneuji A and Matsumoto T: Oxidative stress by glutathione depletion induces osteonecrosis in rats. Rheumatology (Oxford). 45:287–290. 2006. View Article : Google Scholar : PubMed/NCBI
3	Calder JD, Buttery L, Revell PA, Pearse M and Polak JM: Apoptosis - a significant cause of bone cell death in osteonecrosis of the femoral head. J Bone Joint Surg Br. 86:1209–1213. 2004. View Article : Google Scholar : PubMed/NCBI
4	Ichiseki T, Matsumoto T, Nishino M, Kaneuji A and Katsuda S: Oxidative stress and vascular permeability in steroid-induced osteonecrosis model. J Orthop Sci. 9:509–515. 2004. View Article : Google Scholar : PubMed/NCBI
5	Kabata T, Kubo T, Matsumoto T, et al: Onset of steroid-induced osteonecrosis in rabbits and its relationship to hyperlipaemia and increased free fatty acids. Rheumatology (Oxford). 44:1233–1237. 2005. View Article : Google Scholar : PubMed/NCBI
6	Paul M, Poyan Mehr AP and Kreutz R: Physiology of local renin-angiotensin systems. Physiol Rev. 86:747–803. 2006. View Article : Google Scholar : PubMed/NCBI
7	Asaba Y, Ito M, Fumoto T, et al: Activation of renin-angiotensin system induces osteoporosis independently of hypertension. J Bone Miner Res. 24:241–250. 2009. View Article : Google Scholar : PubMed/NCBI
8	Garcia P, Schwenzer S, Slotta JE, et al: Inhibition of angiotensin-converting enzyme stimulates fracture healing and periosteal callus formation - role of a local renin-angiotensin system. Br J Pharmacol. 159:1672–1680. 2010. View Article : Google Scholar
9	Schurman SJ, Bergstrom WH, Shoemaker LR and Welch TR: Angiotensin II reduces calcium uptake into bone. Pediatr Nephrol. 19:33–35. 2004. View Article : Google Scholar : PubMed/NCBI
10	Hagiwara H, Hiruma Y, Inoue A, Yamaguchi A and Hirose S: Deceleration by angiotensin II of the differentiation and bone formation of rat calvarial osteoblastic cells. J Endocrinol. 156:543–550. 1998. View Article : Google Scholar : PubMed/NCBI
11	Lynn H, Kwok T, Wong SY, Woo J and Leung PC: Angiotensin converting enzyme inhibitor use is associated with higher bone mineral density in elderly Chinese. Bone. 38:584–588. 2006. View Article : Google Scholar : PubMed/NCBI
12	Marchesi C, Paradis P and Schiffrin EL: Role of the renin-angiotensin system in vascular inflammation. Trends Pharmacol Sci. 29:367–374. 2008. View Article : Google Scholar : PubMed/NCBI
13	Fishel RS, Eisenberg S, Shai SY, Redden RA, Bernstein KE and Berk BC: Glucocorticoids induce angiotensin-converting enzyme expression in vascular smooth muscle. Hypertension. 25:343–349. 1995. View Article : Google Scholar : PubMed/NCBI
14	Barreto-Chaves M, Anéas I and Krieger J: Glucocorticoid regulation of angiotensin-converting enzyme in primary culture of adult cardiac fibroblasts. Am J Physiol Regul Integr Comp Physiol. 280:R25–R32. 2001.PubMed/NCBI
15	Mendelsohn FA, Lloyd CJ, Kachel C and Funder JW: Induction by glucocorticoids of angiotensin-converting enzyme production from bovine endothelial cells in culture and rat lung in vivo. J Clin Invest. 70:684–692. 1982. View Article : Google Scholar
16	Sato A, Suzuki H, Nakazato Y, Shibata H, Inagami T and Saruta T: Increased expression of vascular angiotensin II type 1A receptor gene in glucocorticoid-induced hypertension. J Hypertens. 12:511–516. 1994. View Article : Google Scholar : PubMed/NCBI
17	Iwakiri K, Oda Y, Kaneshiro Y, et al: Effect of simvastatin on steroid-induced osteonecrosis evidenced by the serum lipid level and hepatic cytochrome P4503A in a rabbit model. J Orthop Sci. 13:463–468. 2008. View Article : Google Scholar : PubMed/NCBI
18	Kuribayashi M, Fujioka M, Takahashi KA, et al: Vitamin E prevents steroid-induced osteonecrosis in rabbits. Acta Orthop. 81:154–160. 2010. View Article : Google Scholar
19	Mitani H, Bandoh T, Ishikawa J, Kimura M, Totsuka T and Hayashi S: Inhibitory effects of fluvastatin, a new HMG-CoA reductase inhibitor, on the increase in vascular ACE activity in cholesterol-fed rabbits. Br J Pharmacol. 119:1269–1275. 1996. View Article : Google Scholar : PubMed/NCBI
20	Liu BC, Gao J, Li Q and Xu LM: Albumin caused the increasing production of angiotensin II due to the dysregulation of ACE/ACE2 expression in HK2 cells. Clin Chim Acta. 403:23–30. 2009. View Article : Google Scholar : PubMed/NCBI
21	Izu Y, Mizoguchi F, Kawamata A, et al: Angiotensin II type 2 receptor blockade increases bone mass. J Biol Chem. 284:4857–4864. 2009. View Article : Google Scholar : PubMed/NCBI
22	Haznedaroglu IC and Oztürk MA: Towards the understanding of the local hematopoietic bone marrow renin-angiotensin system. Int J Biochem Cell Biol. 35:867–880. 2003. View Article : Google Scholar : PubMed/NCBI
23	Powell C, Chang C and Gershwin ME: Current concepts on the pathogenesis and natural history of steroid-induced osteonecrosis. Clin Rev Allergy Immunol. 41:102–113. 2011. View Article : Google Scholar : PubMed/NCBI
24	Wang L, Wang N, Li M and Wang KZ: To investigate the role of the nervous system of bone in steroid-induced osteonecrosis in rabbits. Osteoporos Int. 21:2057–2066. 2010. View Article : Google Scholar : PubMed/NCBI
25	Drescher W, Weigert KP, Bunger MH, Ingerslev J, Bünger C and Hansen ES: Femoral head blood flow reduction and hypercoagulability under 24 h megadose steroid treatment in pigs. J Orthop Res. 22:501–508. 2004. View Article : Google Scholar : PubMed/NCBI
26	Sabanai K, Tsutsui M, Sakai A, et al: Genetic disruption of all NO synthase isoforms enhances BMD and bone turnover in mice in vivo: involvement of the renin-angiotensin system. J Bone Miner Res. 23:633–643. 2008. View Article : Google Scholar : PubMed/NCBI
27	Fukuda D and Sata M: Role of bone marrow renin-angiotensin system in the pathogenesis of atherosclerosis. Pharmacol Ther. 118:268–276. 2008. View Article : Google Scholar : PubMed/NCBI
28	Wassmann S and Nickenig G: Pathophysiological regulation of the AT1-receptor and implications for vascular disease. J Hypertens Suppl. 24:S15–S21. 2006. View Article : Google Scholar : PubMed/NCBI
29	Pueyo ME, Gonzalez W, Nicoletti A, Savoie F, Arnal JF and Michel JB: Angiotensin II stimulates endothelial vascular cell adhesion molecule-1 via nuclear factor-kappaB activation induced by intracellular oxidative stress. Arterioscler Thromb Vasc Biol. 20:645–651. 2000. View Article : Google Scholar
30	Harrison DG: Cellular and molecular mechanisms of endothelial cell dysfunction. J Clin Invest. 100:2153–2157. 1997. View Article : Google Scholar : PubMed/NCBI
31	Yao EH, Fukuda N, Matsumoto T, et al: Losartan improves the impaired function of endothelial progenitor cells in hypertension via an antioxidant effect. Hypertens Res. 30:1119–1128. 2007. View Article : Google Scholar : PubMed/NCBI
32	Ohtsu H, Frank GD, Utsunomiya H and Eguchi S: Redox-dependent protein kinase regulation by angiotensin II: mechanistic insights and its pathophysiology. Antioxid Redox Signal. 7:1315–1326. 2005. View Article : Google Scholar : PubMed/NCBI
33	Vaughan DE, Lazos SA and Tong K: Angiotensin II regulates the expression of plasminogen activator inhibitor-1 in cultured endothelial cells. A potential link between the renin-angiotensin system and thrombosis. J Clin Invest. 95:995–1001. 1995. View Article : Google Scholar : PubMed/NCBI
34	Zhao C, Irie N, Takada Y, et al: Bidirectional ephrinB2-EphB4 signaling controls bone homeostasis. Cell Metab. 4:111–121. 2006. View Article : Google Scholar : PubMed/NCBI
35	Shimizu H, Nakagami H, Osako MK, et al: Angiotensin II accelerates osteoporosis by activating osteoclasts. FASEB J. 22:2465–2475. 2008. View Article : Google Scholar : PubMed/NCBI
36	Liu JJ, Li DL, Zhou J, et al: Acetylcholine prevents angiotensin II-induced oxidative stress and apoptosis in H9c2 cells. Apoptosis. 16:94–103. 2011. View Article : Google Scholar : PubMed/NCBI