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. 2012;13(1):56-70.
doi: 10.3390/ijms13010056. Epub 2011 Dec 22.

The bone-protective effect of genistein in the animal model of bilateral ovariectomy: roles of phytoestrogens and PTH/PTHR1 against post-menopausal osteoporosis

Qing Miao  1 , Jing-Ge Li, Shan Miao, Nan Hu, Jin Zhang, Song Zhang, Yan-Hua Xie, Jian-Bo Wang, Si-Wang Wang
Affiliations

The bone-protective effect of genistein in the animal model of bilateral ovariectomy: roles of phytoestrogens and PTH/PTHR1 against post-menopausal osteoporosis

Qing Miao et al. Int J Mol Sci. 2012.

Abstract

Genistein, a major phytoestrogen of soy, is considered a potential drug for the prevention and treatment of post-menopausal osteoporosis. Mounting evidence suggested a positive correlation between genistein consumption and bone health both in vivo and in vitro. Earlier studies have revealed that genistein acted as a natural estrogen analogue which activated estrogen receptor and exerted anti-osteoporotic effect. However, it remains unclear whether PTH, the most crucial hormone that regulates mineral homeostasis, participates in the process of genistein-mediated bone protection. In the present study, we compared the therapeutic effects between genistein and nilestriol and investigated whether PTH and its specific receptor PTHR1 altered in response to genistein-containing diet in the animal model of ovariectomy. Our results showed that genistein administration significantly improved femoral mechanical properties and alleviates femoral turnover. Genistein at all doses (4.5 mg/kg, 9.0 mg/kg and 18.0 mg/kg per day, respectively) exerted improved bending strength and b-ALP limiting effects than nilestriol in the present study. However, genistein administration did not exert superior effects on bone protection than nilestriol. We also observed circulating PTH restoration in ovariectomized rats receiving genistein at the dose of 18 mg/kg per day. Meanwhile, PTHR1 abnormalities were attenuated in the presence of genistein as confirmed by RT-PCR, Western blot and immunohistochemistry. These findings strongly support the idea that besides serving as an estrogen, genistein could interact with PTH/PTHR1, causing a superior mineral restoring effect than nilestriol on certain circumstance. In conclusion, our study reported for the first time that the anti-osteoporotic effect of genistein is partly PTH/PTHR1-dependent. Genistein might be a potential option in the prevention and treatment of post-menopausal osteoporosis with good tolerance, more clinical benefits and few undesirable side effects.

Keywords: PTH; PTHR1; genistein; osteoporosis; phytoestrogen.

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Figures

Figure 1
Figure 1
Chemical structure of genistein and nilestriol.
Figure 2
Figure 2
Bone mineral density (BMD) measurement of femur (A) and tibia (B). BMD significantly decreased in the animal model of ovariectomy (OVX) compared with the sham group animals. In the presence of nilestriol and genistein, BMD was recovered. Genistein dose-dependently enhanced femur and tibia BMD, and these effects were statistically significant. There were no significant difference of BMD between NIL and GEN groups. * P < 0.05 vs. sham group, ** P < 0.01 vs. OVX group.
Figure 3
Figure 3
The mechanical failure properties of the femora in the sham and ovariectomized rats supplemented with nilestriol and different dose of genistein were conducted using an Instron 8501 material testing system. Femur bending strength markedly decreased after ovariectomy (** P < 0.01 vs. sham group). Treatment with nilestriol or genistein at any dosage significantly limited the failure properties that were induced by ovariectomy (* P < 0.05 vs. OVX group).
Figure 4
Figure 4
Effects of genistein on serum bone-specific alkaline phosphatase (b-ALP) and osteocalcin (OCN) concentrations in ovariectomized rats supplemented with nilestriol and different dose of genistein. (A) b-ALP markedly increased after ovariectomy (** P < 0.01 vs. sham group). Treatment with nilestriol (** P < 0.01 vs. OVX group) or genistein (* P < 0.05 vs. OVX group) at any dosage significantly limited b-ALP concentrations; (B) Serum OCN significantly increased in the animal model of ovariectomy (* P < 0.05 vs. sham group). Administration of nilestriol or genistein at any dose did not restore circulating OCN concentrations.
Figure 5
Figure 5
Effects of genistein treatment on parathyroid hormone receptor 1 (PTHR1) expressions in femur. (A) RT-PCR revealed decreased expression of PTHR1 mRNA in the animal model of ovariectomy. Nilestriol did not alleviate PTHR1 impairment. Genistein treatment recovered PTHR1 mRNA expressions in ovariectomized rats; (B) Western blotting analysis of femoral PTHR1 proteins showed impaired PTHR1 protein content in ovariectomized rats. Administration of nilestriol failed to reverse PTHR1 protein expression while genistein enhanced PTHR1 protein content compared with the OVX group. Genistein dose-dependently elevated both PTHR1 mRNA and protein expressions in ovariectomized rats.
Figure 6
Figure 6
Location and distribution of PTHR1 immunoreactivity in the kidney. (A) sham group; (B) Ovariectomized (OVX) group; (C) OVX+ Nilestriol group (NIL); (D) OVX+ High dose genistein group (GENH) (18 mg/kg), respectively. The PTHR1 positive region was marked with black arrows. Original magnification ×400.
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