TANG Lin, WEI Min-ke, WEI Jian-xun, LIU Da. Effects of angiotensin Ⅱ receptor inhibitor on lumbar vertebrae bone tissue in ovariectomized osteoporosis mice and its possible mechanism[J]. Journal of Spinal Surgery, 2018, 16(3): 157-162.
Effects of angiotensin Ⅱ receptor inhibitor on lumbar vertebrae bone tissue in ovariectomized osteoporosis mice and its possible mechanism
TANG Lin1, WEI Min-ke1, WEI Jian-xun1, LIU Da2
1. Department of Orthopaedics, People's Hospital of Guangxi Zhuang Autonomous Region, Nanning 530021, Guangxi Zhuang Autonomous Region, China; 2. Department of Orthopaedics, Fourth Affiliated Hospital of China Medical University, Shenyang 110000, Liaoning, China
Abstract:
Objective
To investigate the effects of angiotensin Ⅱ receptor inhibitor on lumbar vertebrae bone tissue in ovariectomized osteoporosis mice and its possible mechanism.
Methods
Totally 60 female mice were randomly and equally divided into sham group, model group and losartan treatment group, and the ovariectomized models were established in model group and losartan treatment group. From the 7th day after the operation, the mice were given 0.5 mL normal saline daily in the sham group and model group, while 0.5 mL losartan water solvent with the dose of 10 mg/(kg·d) was used in the losartan treatment group. At 8 and 12 weeks after the modeling, the serum levels of estradiol, alkaline phosphatase(ALP), osteocalcin (OCN) and procollagen typeⅠcarboxyterminal propeptide(PICP) were measured. The metrology of the lumbar spine in mice were measured using Micro-CT three-dimensional imaging system. The expressions of osteoprotegerin(OPG), receptor activator of NF-κB(RANK) and receptor activator for nuclear factor-κB ligand(RANKL) in the lumbar vertebrae were detected by realtime quantitative PCR.
Results
Compared with the sham group, the serum levels of estradiol at 8 weeks and 12 weeks in the model and losartan treatment groups were decreased; the serum levels of ALP, OCN and PICP at 8 weeks and 12 weeks in the model group were increased; the serum levels of ALP, OCN and PICP at 8 weeks in the losartan treatment group were increased; all with statistical significance(P < 0.05). Compared with the model group, the serum levels of ALP, OCN and PICP at 8 weeks and 12 weeks in the losartan treatment group were decreased, all with statistical significance(P < 0.05). Compared with at 8 weeks, the serum levels of ALP, OCN and PICP at 12 weeks in the model group were increased; the serum levels of ALP, OCN and PICP at 12 weeks in the losartan treatment group were decreased; all with statistical significance(P < 0.05). Compared with the sham group, the bone mineral density(BMD), trabecular plate number(Tb.N), trabecular bone volume fraction(BV/TV), and trabecular plate thickness(Tb.Th) in the model and losartan treatment group were decreased, while the trabecular spacing(Tb.Sp) and structure model index(SMI) were increased, all with statistical significance(P < 0.05). Compared with the model group, the BMD, Tb.N, BV/TV and Tb.Th in the losartan treatment group were increased, while the Tb.Sp and SMI were decreased, all with statistical significance(P < 0.05). Compared with the sham group, the relative expression levels of OPG mRNA and RANK mRNA in the lumbar vertebrae in the model and losartan treatment were decreased, while the relative expression levels of RANKL mRNA and RANKL/OPG ratio were increased, all with statistical significance (P < 0.05). Compared with the model group, the relative expression levels of OPG mRNA and RANK mRNA in the lumbar vertebrae in the losartan treatment group were increased, while the relative expression levels of RANKL mRNA and RANKL/OPG ratio were decreased, all with statistical significance(P < 0.05).
Conclusion
Angiotensin Ⅱ receptor inhibitor may improve osteoporosis state in lumbar spine bone tissues in ovariectomized osteoporosis mice through promoting bone formation, inhibiting bone resorption and reducing the bone loss caused by negative conversion.
Key words:
Lumbar vertebraeOsteoporosisOvaryAngiotensin Ⅱ type 1 receptor blockersMice
表 2 3组小鼠血清雌二醇、ALP、OCN和PICP水平比较
Table 2 Comparison of serum levels of estradiol, ALP, OCN and PICP between 3 groups
n=20,x±s
组别 Group
8周 8 weeks
12周 12 weeks
雌二醇/ (ng·L-1) Estradiol / (ng·L-1)
ALP/ (ng·mL-1)
OCN/ (pg·mL-1)
PICP/ (ng·mL-1)
雌二醇/ (ng·L-1) Estradiol / (ng·L-1)
ALP/ (ng·mL-1)
OCN/ (pg·mL-1)
PICP/ (ng·mL-1)
假手术 Sham
38.32±10.25
35.61±3.47
106.35±4.16
37.15±2.38
37.25±9.75
36.35±3.72
108.41±4.45
38.75±2.19
模型 Model
29.17±5.39*
53.92±5.05*
138.28±3.92*
58.47±2.64*
28.26±5.18*
62.67±4.05*▲
149.37±5.06*▲
69.24±3.04*▲
氯沙坦治疗 Losartan treatment
30.26±5.67*
40.34±4.12*△
118.16±4.83*△
41.33±2.75*△
28.75±5.27*
37.28±3.91△▲
110.35±4.74△▲
39.14±2.52△▲
注:*与假手术组相比,P < 0.05;△与模型组相比,P < 0.05;▲与8周时相比,P < 0.05 Note:* P < 0.05,compared with sham group;△P < 0.05,compared with model group;▲P < 0.05,compared with 8 weeks
表 2 3组小鼠血清雌二醇、ALP、OCN和PICP水平比较
Table 2 Comparison of serum levels of estradiol, ALP, OCN and PICP between 3 groups
Thulkar J, Singh S, Sharma S, et al. Preventable risk factors for osteoporosis in postmenopausal women:systematic review and meta-analysis[J]. J Midlife Health, 2016, 7(3): 108–113.
[3]
Colafella KM, Hilliard LM, Denton KM. Epochs in the depressor/pressor balance of the renin-angiotensin system[J]. Clin Sc(i Lond), 2016, 130(10): 761–771.
DOI:10.1042/CS20150939
Liu JX, Wang L, Zhang Y. Involvement of reninangiotensin system in damage of angiotensin-converting enzyme inhibitor captopril on bone of normal mice[J]. Biol Pharm Bull, 2015, 38(6): 869–875.
DOI:10.1248/bpb.b14-00829
[6]
Shuai B, Yang YP, Shen L, et al. Local reninangiotensin system is associated with bone mineral density of glucocorticoid-induced osteoporosis patients[J]. Osteoporos Int, 2015, 26(3): 1063–1071.
DOI:10.1007/s00198-014-2992-y
[7]
Li H, Li RX, Wan ZM, et al. Counter-effect of constrained dynamic loading on osteoporosis in ovariectomized mice[J]. J Biomech, 2013, 46(7): 1242–1247.
DOI:10.1016/j.jbiomech.2013.02.016
Melo AD, Silveira H, Luciano FB, et al. Intestinal alkaline phosphatase:potential roles in promoting gut health in weanling piglets and its modulation by feed additives-a review[J]. Asian-Australas J Anim Sci, 2016, 29(1): 16–22.
[12]
Liu W, Zhang X. Receptor activator of nuclear factor-κB ligand(RANKL)/RANK/osteoprotegerin system in bone and other tissues(review)[J]. Mol Med Rep, 2015, 11(5): 3212–3218.
DOI:10.3892/mmr.2015.3152
[13]
Nakagami H, Osako MK, Morishita R. Potential effect of angiotensin Ⅱ receptor blockade in adipose tissue and bone[J]. Curr Pharm Des, 2013, 19(17): 3049–3053.
DOI:10.2174/1381612811319170011
Zhang Y, Wang L, Song Y, et al. Renin inhibitor aliskiren exerts beneficial effect on trabecular bone by regulating skeletal renin-angiotensin system and kallikrein-kinin system in ovariectomized mice[J]. Osteoporos Int, 2016, 27(3): 1083–1092.
DOI:10.1007/s00198-015-3348-y
[17]
Xu F, Dong Y, Huang X, et al. Pioglitazone affects the OPG/RANKL/RANK system and increase osteoclastogenesis[J]. Mol Med Rep, 2016, 14(3): 2289–2296.
DOI:10.3892/mmr.2016.5515
[18]
Zhang Y, Zhang Y, Kou J, et al. Role of reactive oxygen species in angiotensin Ⅱ:induced receptor activator of nuclear factor-κB ligand expression in mouse osteoblastic cells[J]. Mol Cell Biochem, 2014, 396(1/2): 249–255.