大豆异黄酮对不同雌马酚代谢表型绝经后妇女骨质疏松症防治效应及机制研究
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摘要
骨质疏松是一种以骨量减少、骨的微观结构退化为特征的中老年常见疾病,主要表现为髋部和/或腰椎骨折,女性尤为严重。在西方人群中,髋部骨折的发生率随着年龄增加呈指数增长。50岁以上的骨折病例中女性与男性比例为3:1。世界范围内,随着老年人口比重的增加,骨质疏松性骨折的发生也显著增加。我国作为发展中国家,人口基数大,老龄人群增加速度快,这就决定了骨质疏松症,尤其是绝经后骨质疏松(postmenopausal osteoporosis, PMOP)已成为我国严重的公众健康问题。因此,深入研究PMOP的防治措施,对提高绝经后妇女的健康及生活质量具有重要的现实意义。
业已证明,绝经后雌激素减少所导致的骨转换增加是PMOP的主要发病原因。激素替代治疗(hormone replacment therapy, HRT)是国际上广泛开展,用以维持体内雌激素水平、改善更年期症状的治疗方案。大量研究证实HRT能预防绝经后妇女的骨质疏松及相应骨折的发生,然而美国妇女健康倡议(Women's Health Initiative,WHI)等大型人群研究发现HRT同时能引起治疗人群罹患乳腺癌、心血管疾病的风险显著增加。美国食品药品监督管理局由此建议不能将HRT用以绝经后妇女骨质疏松预防的一线方案,而应当通过膳食、运动等途径来寻找新的防治方法。
近年来,植物雌激素、尤其是大豆制品来源的大豆异黄酮(soybean isoflavones, SI)备受研究关注,并被期待是HRT的天然替代物。该类化合物具有弱雌激素样作用,同时作为雌激素受体的选择性调节剂能够对雌激素生物效应发挥相应的拮抗或促进效应,从而没有雌激素的副作用。流行病学研究发现,在摄入豆制品较高的亚洲地区绝经后妇女中,其膳食SI摄入水平与骨密度之间呈显著正相关。然而,随后开展的诸多临床研究在评价膳食大豆制品或SI干预对绝经后妇女骨密度的影响效应时,所得结果却不尽相同。目前认为,以往研究之间观察到的SI干预效应的差异主要与不同研究人群间体内SI的代谢水平不同有关。其中,作为SI的代谢终产物之一,雌马酚(equal, Eq)与其它代谢物如苷元金雀异黄素(genistein, GNT)、黄豆黄素(glycitein, GLY)、双氢大豆黄酮苷元(dihydrodaidzein,DHD)等相比具有更强的雌激素受体结合能力和稳定性,但在人群中仅有30%~50%的个体能产生Eq(equol producer, EP+),且不同人种对Eq的代谢能力也不同。以往评价豆制品或SI摄入对骨质疏松防治效果的研究大都在高加索籍妇女中开展,且未考虑不同Eq代谢表型下豆制品摄入对PMOP影响的差异。因此,探讨PMOP发生的危险因素、膳食结构与SI代谢相关因素,深入观察SI干预对不同Eq表型绝经后妇女骨质疏松的防治效应并探讨其相关机制,对于指导女性合理食用大豆及其制品防治PMOP具有重要的现实意义。
基于以上分析,本研究围绕不同Eq代谢表型对大豆制品生物学效应的潜在影响,通过病例-对照研究,按统一标准共纳入PMOP新发病例152名,对照者308名,探讨了绝经后妇女骨质疏松症的危险因素,采用半定量食物频数表调查了各研究人群的膳食结构以及豆制品摄入情况,通过高效液相色谱法检测了各人群尿液中异黄酮的代谢水平并分析Eq代谢表型,使用SPSS13.0软件比较不同人群间膳食豆制品摄入及SI代谢产物水平的差异并分析其与PMOP发生风险的相关性。为了进一步分析Eq代谢表型差异性对大豆异黄酮防治PMOP效应的影响,针对PMOP和非PMOP人群的不同Eq代谢表型又分别设置干预组(20g大豆分离蛋白/d,约含50mgSI)和空白对照组(20g乳清分离蛋白/d,不含SI),干预6个月。分别在试验0、3、6个月检测各组人群的SI代谢水平、骨密度(Bone mineral density, BMD)以及血脂、性激素水平,深入观察大豆分离蛋白干预对不同Eq表型绝经后妇女骨质疏松的防治效应,评价Eq代谢表型差异性对SI防治骨质疏松效应的影响,并就其相关机制进行探讨。此外,体外试验用含20%胎牛血清的α-MEM培养新生Wistar大鼠颅骨分离培养的成骨细胞,同时分别给予10-8 mol/L～10-6mol/L的雌马酚和雌二醇(estradiol, E2)以及对应剂量的雌激素受体拮抗剂ICI182780,用Western blot检测细胞蛋白激酶C(protein kinase C, PKC)的表达,用MTT法检测细胞增殖情况,用对硝基酚磷酸盐法及放免法测定成骨细胞碱性磷酸酶(alkaline phosphatas, ALP)和骨钙素(Boneglaprotein, BGP)的活性,研究雌马酚对体外原代培养成骨细胞增殖和分化作用的影响,旨在从细胞水平探讨雌马酚预防骨质疏松症的作用机制。
主要研究结果:
一、人群研究
1. PMOP常规危险因素调查:髋骨骨折家族史、低身体质量指数和多产次与重庆市绝经后妇女骨质疏松症发生风险呈显著正相关,而经常运动、饮茶以及保持适当的雌激素水平与PMOP发生的风险呈显著负相关。
2.膳食豆制品摄入与PMOP发生的相关性:PMOP组膳食大豆蛋白及总大豆制品的摄入量显著低于非PMOP组(P<0.05),进一步Logistic回归分析发现膳食大豆蛋白及大豆类及其制品的摄入水平与PMOP的发生呈显著的负相关。此外,调查结果还提示膳食中高水平的Ca、Vit A、Vit D以及深色蔬菜、奶类与PMOP的发生呈显著负相关,而动物蛋白、烹饪油摄入量与PMOP的发生呈显著正相关。
3. SI代谢水平与PMOP发生的相关性:PMOP组人群的EP+比例为32.2%,显著低于非PMOP人群的40.3% ( P<0.05)。同时,PMOP组人群尿液中Eq、GNT、GLY、DHD水平均显著低于非PMOP组(P<0.05);进一步Logistic回归分析发现人群尿液中Eq、GNT水平降低与PMOP的发生呈显著的正相关。
4. SPI干预对不同Eq代谢表型绝经后妇女SI代谢水平的影响:对于EP+人群,与对照组相比较,膳食大豆分离蛋白干预均能显著上升PMOP组和非PMOP组的Eq、GLY及GNT水平(P<0.05),其中PMOP组的改善效应更显著。对于EP-人群,膳食干预能显著上升PMOP组和非PMOP组的GNT水平(P<0.05)。
5. SPI干预对不同Eq代谢表型人群骨密度的影响:对于PMOP人群,与对照组相比较,膳食大豆分离蛋白干预均能显著上升EP+、EP-干预组的BMD及T值水平,其中EP+组的改善效应更显著(P<0.01)。对于非PMOP人群,与对照组相比较,膳食干预能显著上升EP+干预组的BMD及T值水平(P<0.05),而EP-干预组的骨密度值有所上升,但无显著性差异(P>0.05)。
6. SPI干预对各组人群血脂及性激素水平的影响:对于PMOP人群,与对照组相比较,膳食大豆分离蛋白干预均能显著上升EP+、EP-干预组的E2水平,并显著降低LDL-C以及TC水平(P<0.05),HDL-C水平略有上升但无显著性意义(P<0.05),对TG水平无明显改变(P>0.05),其中EP+组的血脂改善效应更显著(P<0.01)。对于非PMOP人群,与对照组相比较,膳食干预仅能显著改善EP+干预组的TC、LDL-C及E2水平(P<0.05)。
二、细胞实验
1.雌马酚对OB增殖功能的影响:Eq干预可显著增强OB的MTT吸光度,该效应随干预时间的延长而增加(P<0.05),而随着浓度的改变无明显的变化(P>0.05)。Eq对OB的MTT吸光度影响弱于E2(P<0.05)。Eq和E2对OB增殖作用均可被ER拮抗剂ICI128780所抑制。
2.雌马酚对成骨细胞分化功能的影响:Eq能显著促进成骨细胞的ALP活性和BGP表达,并随浓度升高和时间延长均有上升的趋势。此外,Eq的干预效应明显低于相同干预浓度、相同作用时间的E2(P<0.05),且二者对OBALP活性和BGP表达的作用均可被ICI128780抑制。
3.雌马酚对成骨细胞胶原蛋白含量的影响: Eq能显著提高细胞内羟脯氨酸的含量,并随浓度升高和时间延长均有上升的趋势。Eq对其作用弱于E2,且均可被ICI78280所抑制。
4.雌马酚对成骨细胞PKCα表达的影响:Eq干预可明显提高OB的PKCα表达(P<0.05),并随作用浓度升高而增强的趋势。E2对OB PKCα表达作用明显强于Eq(P<0.05)。各浓度组联合ICI182780作用后,其PKC表达明显受到抑制并具有显著性意义(p<0.05),但略高于空白对照组。
综上所述,本研究从人群病例-对照研究和体外细胞实验两方面,探讨了重庆地区绝经后骨质疏松发病的常规危险因素及其与膳食豆制品摄入、体内SI代谢水平的相关性,并围绕不同Eq代谢表型对大豆制品生物学效应的潜在影响,深入观察大豆分离蛋白干预对不同Eq表型绝经后妇女骨质疏松的防治效应,评价Eq代谢表型差异性对SI防治骨质疏松效应的影响,并就其相关机制进行探讨。人群研究发现髋骨骨折家族史、低身体质量指数和多产次是影响重庆市绝经后妇女骨质疏松症发生的重要危险因素,而经常运动、饮茶以及保持适当的雌激素水平则有助于预防PMOP的发生。膳食调查结果发现大豆蛋白、Ca、Vit A、Vit D以及大豆类、深色蔬菜和奶类能有效预防PMOP的发生,而膳食动物蛋白、烹饪油摄入能显著上升PMOP的风险。SI代谢水平分析显示Eq代谢表型分布可能直接影响到人群PMOP的患病,同时尿液中Eq与GNT水平上升能显著降低PMOP的发生风险。大豆分离蛋白干预试验发现,膳食SI干预能显著改善PMOP组的骨密度及血脂、雌激素水平,其中EP+人群的干预效果更为显著;而对于非PMOP人群,研究发现膳食SI干预仅对EP+人群有显著的改善效果。膳食干预对EP-人群也有一定的改善效果,其效应可能主要是通过提高体内GNT水平来发挥。此外,细胞实验发现Eq干预可显著促进成骨细胞的增殖、分化以及骨基质形成,而该效应可不同程度上被ER拮抗剂ICI182780所抑制,推测Eq作为一种天然雌激素,能激活雌激素受体,并通过雌激素受体途径调控细胞的增殖和分化,该调控作用可能与跨膜蛋白PKCα信号转导有关。本研究进一步证实膳食因素对PMOP的发生起着重要作用,并且不同人群中Eq代谢表型的差异性可能是影响大豆异黄酮发挥骨质疏松防治效应的重要因素,其中EP+人群的干预效应更显著。以上结果提示女性应在日常生活中选择合理的生活方式及生育方式,同时积极调整饮食平衡,保证大豆类及其制品、深色蔬菜和奶类的摄入,并适当控制动物性食品和烹饪油的摄入,以从膳食、行为途径上更好地预防PMOP的发生。
Osteoporosis is a disease of bone that leads to an increased risk of fracture of lumbar vertebra and hip. In osteoporosis, the bone mineral density (BMD) is reduced, bone microarchitecture is disrupted, and the amount and variety of proteins in bone is altered. It is estimated that 1 in 3 women and 1 in 9 men over the age of 50 worldwide have osteoporosis. As China is the developing country with great number of population, especially the aged group increasing fast, osteoporosis and postmenopausal osteoporosis (PMOP) especially are serious public health problem. For this reason, the research on prevention and cure for PMOP is practical importance for improve health and life quality of post-menopause women.
As result approved, a decrease in estrogen levels at menopause leading to a rapid loss of bone mineral density is key cause of PMOP. Treatment with estrogen has been reported to reduce the risk of hip and wrist fractures. Hormone replacement therapy (HRT) is the standard of treatment for maintenance of internal estrogen level and improvement of menopausal syndrome. Though HRT could prevent PMOP and reduce bone fracture, Women's Health Initiative in USA found that HRT also brought risk of breast cancer and cardiovascular diseases to cured persons. FDA in USA recommends that HRT would not be first-line therapy for PMOP and new approach of diet and exercise would be considered to prevent and cure it.
In recent year, phytoestrogen and soybean isoflavones (SI) derived from soybean are focused in research and expected to be alternative remedy of HRT. This group of compound is with weak estrogenic effects, which has estrogen agonist and antagonist actions without side-effect by estrogen treatment. Epidemiologic studies found that, there was positive correlation between amount of SI intake and BMD in Asian post-menopause women with high intake of bean product. However, there were conflicted results of effect on PMOP in research with more clinical research approached. In recent explanation, the difference of intervention by SI was relation with capability of metabolism of SI. For example, Equol (Eq) is the final metabolite resulting from the metabolism of daidzein in the intestine, which has higher estrogenic activity in body comparison of genistein, glycitein, dihydrodaidzein. It is reported that approximately 30–50% of adult humans who are“equol producers”and metabolism capability are different between race. Past estimations of effect of SI on prevetion and cure of PMOP were seldom focused on Chinese post-menopause women and without consideration of daidzein-metabolizing phenotypes (DMPs) by intake bean product. For this reason, it is interesting and practical that the intervention effect of SI and its mechanism on PMOP with consideration of DMPs is carried out to solve the increase of PMOP in china now.
Basing on the above the analysis, our research focused on influence of biological effect of bean products due to DMPs. There were involved with 152 cases of PMOP and 308 cases of control in our Case–control studies conducted in Chongqing. The risk of PMOP was studied with analysis methods of semi-quantitative food frequency questionnaire on dietary pattern and intake of bean product, judgment of DMPs according to detection of urinary excretion of isoflavone status by HPLC. The correlation betweenrisk of PMOP and level of exposure to SI metabolite and intake of bean product was analyzed by SPSS 13.0. For further analysis of intervention effect of SI according to DMPs, the group of soybean protein isolate(SPI 20g/d, containing 50mgSI) with SI and the group of whey protein (20g/d) without SI were carried out for 6 months. The evaluation of prevention and cure on PMOP by protein isolate with relation of DMPs was done with analysis of metabolism of SI, BMD, Serum lipid and sex hormone level of different groups at before, middle and final phase of the experiment. Moreover, the wistar rat-derived osteoblast cultured inα-MEM supplemented with 20% fetal bovine serum were cured with 10-8 mol/L～10-6mol/L equol and estradiol(E2) respectively, proper amount of estrogen receptor antagonist ICI182780 administered too. Proliferation and differentiation of primary culture of osteoblast influenced by equol was studied by detection of Protein kinase C(PKC) by Western blot, cell proliferation by MTT, activity of alkaline phosphatas (ALP) and activity of Boneglaprotein (BGP) , which mainly concerned the mechanism of prevention and cure of PMOP by Eq at cellular level.
Main results
1. Population study
1. 1 Investigation of common risk of PMOP: Which is important risk factores for PMOP in Chongqing are family history of hip fracture, low body quality index and fecundity. But, regular exercise, tea and maintenance of proper estrogen level would be contributive to preventing PMOP.
1.2 The correlation between occurrence of PMOP and dietary intake of bean product: The intake of bean product or SPI in PMOP group was lower than that in non-PMOP (P<0.05) significantly. The negative correlation between occurrence of PMOP and intake of bean product or SPI was found by regression analysis of Logistic model. Moreover, there were also negative correlation between occurrence of PMOP and intake of Ca, Vit A, Vit D, dark green vegetables and milk in diet, but positive correlation between PMOP and intake of animal protein and cooking oil.
1.3 The correlation between metabolism of daidzein and occurrence of PMOP: The rate of equol producer(32.2%) in PMOP group was lower than that(40.3%) in non-PMOP group(P<0.05) significantly, and the same trend was found in the index of Eq、GNT、GLY and DHD between groups. The positive correlation between occurrence of PMOP and urinary excretion of Eq and GNT was found by regression analysis of Logistic model.
1.4 The influence of SPI intervention on the levels of endogenous SI metabolites among different Eq phenotypes: As to the EP+ populations, compared with the control group, SPI intervention can significantly increase the levels of Eq, GLY and GNT (P<0.05). While in EP- populations, SPI intervention only promote the levels of GNT moderately.
1.5 The influence on BMD of post-menopause women with different DMPs by intervention of SPI: Compared with the control group, the BMD and T scores was increased in PMOP group by SPI intervention, no matter with equol produced or not, but the most significant improvement was found in EP+ (P<0.01). The significant increase of BMD and T scores was found in EP+ (P<0.05), but not in EP- (P>0.05) by SPI in non-PMOP group.
1.5 The influence on serum lipid and sex hormone in groups by SPI: In PMOP group, the levels of E2 of EP+ or EP- was increased significantly and the levels of LDL-C and TC was decreased by comparison of that in control group with intervention of SPI, the most significant change of serum lipid found in EP+, but there was no change of TG. The level of HDL-C was increased a little but no significant difference. In non- PMOP group, compared with control group, the amelioration of serum lipid and E2 was only found in EP+
2. Vitro experiment
2.1 The influence on proliferation of osteoblast by equol: The MTT absorbance value was enhanced by Eq intervention, and the improvement related to prolong exposure to Eq, but no relation with concentration of Eq. Moreover, the effect of Eq was significantly weaker than that of E2 (P<0.05) at the same period in the same concentration. All effects of Eq and E2 were inhibited by ICI128780 antagonist.
2.2 The influence of differentiation of osteoblast by equol: The expressions of ALP and BGP of osteoblast were enhanced by Eq intervention, and was positive dose-effect relationship with action time and concentration (P<0.05). Moreover, the effect of Eq was significantly weaker than that of E2 (P<0.05) at the same period in the same concentration. All effects of Eq and E2 were inhibited by ICI128780 antagonist.
2.3 The influence on amount of bone collagen by equol by Eq intervention: The hydroxyproline in cell was increased and was positive dose-effect relationship with action time and concentration (P<0.05). Moreover, the effect of Eq was significantly weaker than that of E2 (P<0.05) at the same period in the same concentration. All effects of Eq and E2 were inhibited by ICI128780 antagonist.
2.4 The influence on expression of PKCαof osteoblast by equol: The expressions of PKCαof osteoblast was enhanced by Eq intervention, and was positive dose-effect relationship with concentration, but lower effective than that by E2.The decrease of expression of PKC was found by combination with ICI182780 at each concentration of Eq, but higher than that in control group (P>0.05).
Conclusions
On the basis of the above, the correlation between PMOP in Chongqing and common risk factors, intake of bean product and metabolite of SI was studied; moreover, the influence on prevention and cure of PMOP by SI in different DMPs was also carried out. In population-based clinical trial, family history of hip fracture, low body quality index and fecundity is important risk factores for PMOP in Chongqing, regular exercise, tea and maintenance of proper estrogen level would be contributive to preventing PMOP. The intake of bean product, SPI, Ca, Vit A, Vit D, dark vegetables and milk would be contributive to preventing and curing PMOP, but animal protein and cooking oil would increase of risk of PMOP. Equol produced or not would determine the occurrence of PMOP; furthermore the risk of PMOP was decreased with increase of urinary excretion of Eq and GNT. By the intervention of SPI, the improvement of BMD, serum lipid and estrogen level was found in PMOP group, especially greater in EP+. In non-PMOP group, the effect of SPI on those indexes was only found in EP+. With the evidence of increasing proliferation and differentiation of osteoblast and bone matrix, but inhibited by ER antagonist, it is supposed that Eq exerts estrogenic activity and high affinity for estrogen receptor, mediate proliferation and differentiation of cell as estrogen does, which would be related to signal transduction of transmembrane protein PKCα. In our experiment, the important effect of diet on occurrence of PMOP was confirmed. The Equol metabolizing phenotypes may determine the effect of SI on prevention and cure of osteoporosis, the greater effect found in equol producer. So, to prevent PMOP, proper dietary and fertility patterns should be decided by women with intake of bean product, milk, vegetable and fruits, but decrease of intake of animal protein and cooking oil.
业已证明,绝经后雌激素减少所导致的骨转换增加是PMOP的主要发病原因。激素替代治疗(hormone replacment therapy, HRT)是国际上广泛开展,用以维持体内雌激素水平、改善更年期症状的治疗方案。大量研究证实HRT能预防绝经后妇女的骨质疏松及相应骨折的发生,然而美国妇女健康倡议(Women's Health Initiative,WHI)等大型人群研究发现HRT同时能引起治疗人群罹患乳腺癌、心血管疾病的风险显著增加。美国食品药品监督管理局由此建议不能将HRT用以绝经后妇女骨质疏松预防的一线方案,而应当通过膳食、运动等途径来寻找新的防治方法。
近年来,植物雌激素、尤其是大豆制品来源的大豆异黄酮(soybean isoflavones, SI)备受研究关注,并被期待是HRT的天然替代物。该类化合物具有弱雌激素样作用,同时作为雌激素受体的选择性调节剂能够对雌激素生物效应发挥相应的拮抗或促进效应,从而没有雌激素的副作用。流行病学研究发现,在摄入豆制品较高的亚洲地区绝经后妇女中,其膳食SI摄入水平与骨密度之间呈显著正相关。然而,随后开展的诸多临床研究在评价膳食大豆制品或SI干预对绝经后妇女骨密度的影响效应时,所得结果却不尽相同。目前认为,以往研究之间观察到的SI干预效应的差异主要与不同研究人群间体内SI的代谢水平不同有关。其中,作为SI的代谢终产物之一,雌马酚(equal, Eq)与其它代谢物如苷元金雀异黄素(genistein, GNT)、黄豆黄素(glycitein, GLY)、双氢大豆黄酮苷元(dihydrodaidzein,DHD)等相比具有更强的雌激素受体结合能力和稳定性,但在人群中仅有30%~50%的个体能产生Eq(equol producer, EP+),且不同人种对Eq的代谢能力也不同。以往评价豆制品或SI摄入对骨质疏松防治效果的研究大都在高加索籍妇女中开展,且未考虑不同Eq代谢表型下豆制品摄入对PMOP影响的差异。因此,探讨PMOP发生的危险因素、膳食结构与SI代谢相关因素,深入观察SI干预对不同Eq表型绝经后妇女骨质疏松的防治效应并探讨其相关机制,对于指导女性合理食用大豆及其制品防治PMOP具有重要的现实意义。
基于以上分析,本研究围绕不同Eq代谢表型对大豆制品生物学效应的潜在影响,通过病例-对照研究,按统一标准共纳入PMOP新发病例152名,对照者308名,探讨了绝经后妇女骨质疏松症的危险因素,采用半定量食物频数表调查了各研究人群的膳食结构以及豆制品摄入情况,通过高效液相色谱法检测了各人群尿液中异黄酮的代谢水平并分析Eq代谢表型,使用SPSS13.0软件比较不同人群间膳食豆制品摄入及SI代谢产物水平的差异并分析其与PMOP发生风险的相关性。为了进一步分析Eq代谢表型差异性对大豆异黄酮防治PMOP效应的影响,针对PMOP和非PMOP人群的不同Eq代谢表型又分别设置干预组(20g大豆分离蛋白
主要研究结果:
一、人群研究
1. PMOP常规危险因素调查:髋骨骨折家族史、低身体质量指数和多产次与重庆市绝经后妇女骨质疏松症发生风险呈显著正相关,而经常运动、饮茶以及保持适当的雌激素水平与PMOP发生的风险呈显著负相关。
2.膳食豆制品摄入与PMOP发生的相关性:PMOP组膳食大豆蛋白及总大豆制品的摄入量显著低于非PMOP组(P<0.05),进一步Logistic回归分析发现膳食大豆蛋白及大豆类及其制品的摄入水平与PMOP的发生呈显著的负相关。此外,调查结果还提示膳食中高水平的Ca、Vit A、Vit D以及深色蔬菜、奶类与PMOP的发生呈显著负相关,而动物蛋白、烹饪油摄入量与PMOP的发生呈显著正相关。
3. SI代谢水平与PMOP发生的相关性:PMOP组人群的EP+比例为32.2%,显著低于非PMOP人群的40.3% ( P<0.05)。同时,PMOP组人群尿液中Eq、GNT、GLY、DHD水平均显著低于非PMOP组(P<0.05);进一步Logistic回归分析发现人群尿液中Eq、GNT水平降低与PMOP的发生呈显著的正相关。
4. SPI干预对不同Eq代谢表型绝经后妇女SI代谢水平的影响:对于EP+人群,与对照组相比较,膳食大豆分离蛋白干预均能显著上升PMOP组和非PMOP组的Eq、GLY及GNT水平(P<0.05),其中PMOP组的改善效应更显著。对于EP-人群,膳食干预能显著上升PMOP组和非PMOP组的GNT水平(P<0.05)。
5. SPI干预对不同Eq代谢表型人群骨密度的影响:对于PMOP人群,与对照组相比较,膳食大豆分离蛋白干预均能显著上升EP+、EP-干预组的BMD及T值水平,其中EP+组的改善效应更显著(P<0.01)。对于非PMOP人群,与对照组相比较,膳食干预能显著上升EP+干预组的BMD及T值水平(P<0.05),而EP-干预组的骨密度值有所上升,但无显著性差异(P>0.05)。
6. SPI干预对各组人群血脂及性激素水平的影响:对于PMOP人群,与对照组相比较,膳食大豆分离蛋白干预均能显著上升EP+、EP-干预组的E2水平,并显著降低LDL-C以及TC水平(P<0.05),HDL-C水平略有上升但无显著性意义(P<0.05),对TG水平无明显改变(P>0.05),其中EP+组的血脂改善效应更显著(P<0.01)。对于非PMOP人群,与对照组相比较,膳食干预仅能显著改善EP+干预组的TC、LDL-C及E2水平(P<0.05)。
二、细胞实验
1.雌马酚对OB增殖功能的影响:Eq干预可显著增强OB的MTT吸光度,该效应随干预时间的延长而增加(P<0.05),而随着浓度的改变无明显的变化(P>0.05)。Eq对OB的MTT吸光度影响弱于E2(P<0.05)。Eq和E2对OB增殖作用均可被ER拮抗剂ICI128780所抑制。
2.雌马酚对成骨细胞分化功能的影响:Eq能显著促进成骨细胞的ALP活性和BGP表达,并随浓度升高和时间延长均有上升的趋势。此外,Eq的干预效应明显低于相同干预浓度、相同作用时间的E2(P<0.05),且二者对OBALP活性和BGP表达的作用均可被ICI128780抑制。
3.雌马酚对成骨细胞胶原蛋白含量的影响: Eq能显著提高细胞内羟脯氨酸的含量,并随浓度升高和时间延长均有上升的趋势。Eq对其作用弱于E2,且均可被ICI78280所抑制。
4.雌马酚对成骨细胞PKCα表达的影响:Eq干预可明显提高OB的PKCα表达(P<0.05),并随作用浓度升高而增强的趋势。E2对OB PKCα表达作用明显强于Eq(P<0.05)。各浓度组联合ICI182780作用后,其PKC表达明显受到抑制并具有显著性意义(p<0.05),但略高于空白对照组。
综上所述,本研究从人群病例-对照研究和体外细胞实验两方面,探讨了重庆地区绝经后骨质疏松发病的常规危险因素及其与膳食豆制品摄入、体内SI代谢水平的相关性,并围绕不同Eq代谢表型对大豆制品生物学效应的潜在影响,深入观察大豆分离蛋白干预对不同Eq表型绝经后妇女骨质疏松的防治效应,评价Eq代谢表型差异性对SI防治骨质疏松效应的影响,并就其相关机制进行探讨。人群研究发现髋骨骨折家族史、低身体质量指数和多产次是影响重庆市绝经后妇女骨质疏松症发生的重要危险因素,而经常运动、饮茶以及保持适当的雌激素水平则有助于预防PMOP的发生。膳食调查结果发现大豆蛋白、Ca、Vit A、Vit D以及大豆类、深色蔬菜和奶类能有效预防PMOP的发生,而膳食动物蛋白、烹饪油摄入能显著上升PMOP的风险。SI代谢水平分析显示Eq代谢表型分布可能直接影响到人群PMOP的患病,同时尿液中Eq与GNT水平上升能显著降低PMOP的发生风险。大豆分离蛋白干预试验发现,膳食SI干预能显著改善PMOP组的骨密度及血脂、雌激素水平,其中EP+人群的干预效果更为显著;而对于非PMOP人群,研究发现膳食SI干预仅对EP+人群有显著的改善效果。膳食干预对EP-人群也有一定的改善效果,其效应可能主要是通过提高体内GNT水平来发挥。此外,细胞实验发现Eq干预可显著促进成骨细胞的增殖、分化以及骨基质形成,而该效应可不同程度上被ER拮抗剂ICI182780所抑制,推测Eq作为一种天然雌激素,能激活雌激素受体,并通过雌激素受体途径调控细胞的增殖和分化,该调控作用可能与跨膜蛋白PKCα信号转导有关。本研究进一步证实膳食因素对PMOP的发生起着重要作用,并且不同人群中Eq代谢表型的差异性可能是影响大豆异黄酮发挥骨质疏松防治效应的重要因素,其中EP+人群的干预效应更显著。以上结果提示女性应在日常生活中选择合理的生活方式及生育方式,同时积极调整饮食平衡,保证大豆类及其制品、深色蔬菜和奶类的摄入,并适当控制动物性食品和烹饪油的摄入,以从膳食、行为途径上更好地预防PMOP的发生。
Osteoporosis is a disease of bone that leads to an increased risk of fracture of lumbar vertebra and hip. In osteoporosis, the bone mineral density (BMD) is reduced, bone microarchitecture is disrupted, and the amount and variety of proteins in bone is altered. It is estimated that 1 in 3 women and 1 in 9 men over the age of 50 worldwide have osteoporosis. As China is the developing country with great number of population, especially the aged group increasing fast, osteoporosis and postmenopausal osteoporosis (PMOP) especially are serious public health problem. For this reason, the research on prevention and cure for PMOP is practical importance for improve health and life quality of post-menopause women.
As result approved, a decrease in estrogen levels at menopause leading to a rapid loss of bone mineral density is key cause of PMOP. Treatment with estrogen has been reported to reduce the risk of hip and wrist fractures. Hormone replacement therapy (HRT) is the standard of treatment for maintenance of internal estrogen level and improvement of menopausal syndrome. Though HRT could prevent PMOP and reduce bone fracture, Women's Health Initiative in USA found that HRT also brought risk of breast cancer and cardiovascular diseases to cured persons. FDA in USA recommends that HRT would not be first-line therapy for PMOP and new approach of diet and exercise would be considered to prevent and cure it.
In recent year, phytoestrogen and soybean isoflavones (SI) derived from soybean are focused in research and expected to be alternative remedy of HRT. This group of compound is with weak estrogenic effects, which has estrogen agonist and antagonist actions without side-effect by estrogen treatment. Epidemiologic studies found that, there was positive correlation between amount of SI intake and BMD in Asian post-menopause women with high intake of bean product. However, there were conflicted results of effect on PMOP in research with more clinical research approached. In recent explanation, the difference of intervention by SI was relation with capability of metabolism of SI. For example, Equol (Eq) is the final metabolite resulting from the metabolism of daidzein in the intestine, which has higher estrogenic activity in body comparison of genistein, glycitein, dihydrodaidzein. It is reported that approximately 30–50% of adult humans who are“equol producers”and metabolism capability are different between race. Past estimations of effect of SI on prevetion and cure of PMOP were seldom focused on Chinese post-menopause women and without consideration of daidzein-metabolizing phenotypes (DMPs) by intake bean product. For this reason, it is interesting and practical that the intervention effect of SI and its mechanism on PMOP with consideration of DMPs is carried out to solve the increase of PMOP in china now.
Basing on the above the analysis, our research focused on influence of biological effect of bean products due to DMPs. There were involved with 152 cases of PMOP and 308 cases of control in our Case–control studies conducted in Chongqing. The risk of PMOP was studied with analysis methods of semi-quantitative food frequency questionnaire on dietary pattern and intake of bean product, judgment of DMPs according to detection of urinary excretion of isoflavone status by HPLC. The correlation betweenrisk of PMOP and level of exposure to SI metabolite and intake of bean product was analyzed by SPSS 13.0. For further analysis of intervention effect of SI according to DMPs, the group of soybean protein isolate(SPI 20g/d, containing 50mgSI) with SI and the group of whey protein (20g/d) without SI were carried out for 6 months. The evaluation of prevention and cure on PMOP by protein isolate with relation of DMPs was done with analysis of metabolism of SI, BMD, Serum lipid and sex hormone level of different groups at before, middle and final phase of the experiment. Moreover, the wistar rat-derived osteoblast cultured inα-MEM supplemented with 20% fetal bovine serum were cured with 10-8 mol/L～10-6mol/L equol and estradiol(E2) respectively, proper amount of estrogen receptor antagonist ICI182780 administered too. Proliferation and differentiation of primary culture of osteoblast influenced by equol was studied by detection of Protein kinase C(PKC) by Western blot, cell proliferation by MTT, activity of alkaline phosphatas (ALP) and activity of Boneglaprotein (BGP) , which mainly concerned the mechanism of prevention and cure of PMOP by Eq at cellular level.
Main results
1. Population study
1. 1 Investigation of common risk of PMOP: Which is important risk factores for PMOP in Chongqing are family history of hip fracture, low body quality index and fecundity. But, regular exercise, tea and maintenance of proper estrogen level would be contributive to preventing PMOP.
1.2 The correlation between occurrence of PMOP and dietary intake of bean product: The intake of bean product or SPI in PMOP group was lower than that in non-PMOP (P<0.05) significantly. The negative correlation between occurrence of PMOP and intake of bean product or SPI was found by regression analysis of Logistic model. Moreover, there were also negative correlation between occurrence of PMOP and intake of Ca, Vit A, Vit D, dark green vegetables and milk in diet, but positive correlation between PMOP and intake of animal protein and cooking oil.
1.3 The correlation between metabolism of daidzein and occurrence of PMOP: The rate of equol producer(32.2%) in PMOP group was lower than that(40.3%) in non-PMOP group(P<0.05) significantly, and the same trend was found in the index of Eq、GNT、GLY and DHD between groups. The positive correlation between occurrence of PMOP and urinary excretion of Eq and GNT was found by regression analysis of Logistic model.
1.4 The influence of SPI intervention on the levels of endogenous SI metabolites among different Eq phenotypes: As to the EP+ populations, compared with the control group, SPI intervention can significantly increase the levels of Eq, GLY and GNT (P<0.05). While in EP- populations, SPI intervention only promote the levels of GNT moderately.
1.5 The influence on BMD of post-menopause women with different DMPs by intervention of SPI: Compared with the control group, the BMD and T scores was increased in PMOP group by SPI intervention, no matter with equol produced or not, but the most significant improvement was found in EP+ (P<0.01). The significant increase of BMD and T scores was found in EP+ (P<0.05), but not in EP- (P>0.05) by SPI in non-PMOP group.
1.5 The influence on serum lipid and sex hormone in groups by SPI: In PMOP group, the levels of E2 of EP+ or EP- was increased significantly and the levels of LDL-C and TC was decreased by comparison of that in control group with intervention of SPI, the most significant change of serum lipid found in EP+, but there was no change of TG. The level of HDL-C was increased a little but no significant difference. In non- PMOP group, compared with control group, the amelioration of serum lipid and E2 was only found in EP+
2. Vitro experiment
2.1 The influence on proliferation of osteoblast by equol: The MTT absorbance value was enhanced by Eq intervention, and the improvement related to prolong exposure to Eq, but no relation with concentration of Eq. Moreover, the effect of Eq was significantly weaker than that of E2 (P<0.05) at the same period in the same concentration. All effects of Eq and E2 were inhibited by ICI128780 antagonist.
2.2 The influence of differentiation of osteoblast by equol: The expressions of ALP and BGP of osteoblast were enhanced by Eq intervention, and was positive dose-effect relationship with action time and concentration (P<0.05). Moreover, the effect of Eq was significantly weaker than that of E2 (P<0.05) at the same period in the same concentration. All effects of Eq and E2 were inhibited by ICI128780 antagonist.
2.3 The influence on amount of bone collagen by equol by Eq intervention: The hydroxyproline in cell was increased and was positive dose-effect relationship with action time and concentration (P<0.05). Moreover, the effect of Eq was significantly weaker than that of E2 (P<0.05) at the same period in the same concentration. All effects of Eq and E2 were inhibited by ICI128780 antagonist.
2.4 The influence on expression of PKCαof osteoblast by equol: The expressions of PKCαof osteoblast was enhanced by Eq intervention, and was positive dose-effect relationship with concentration, but lower effective than that by E2.The decrease of expression of PKC was found by combination with ICI182780 at each concentration of Eq, but higher than that in control group (P>0.05).
Conclusions
On the basis of the above, the correlation between PMOP in Chongqing and common risk factors, intake of bean product and metabolite of SI was studied; moreover, the influence on prevention and cure of PMOP by SI in different DMPs was also carried out. In population-based clinical trial, family history of hip fracture, low body quality index and fecundity is important risk factores for PMOP in Chongqing, regular exercise, tea and maintenance of proper estrogen level would be contributive to preventing PMOP. The intake of bean product, SPI, Ca, Vit A, Vit D, dark vegetables and milk would be contributive to preventing and curing PMOP, but animal protein and cooking oil would increase of risk of PMOP. Equol produced or not would determine the occurrence of PMOP; furthermore the risk of PMOP was decreased with increase of urinary excretion of Eq and GNT. By the intervention of SPI, the improvement of BMD, serum lipid and estrogen level was found in PMOP group, especially greater in EP+. In non-PMOP group, the effect of SPI on those indexes was only found in EP+. With the evidence of increasing proliferation and differentiation of osteoblast and bone matrix, but inhibited by ER antagonist, it is supposed that Eq exerts estrogenic activity and high affinity for estrogen receptor, mediate proliferation and differentiation of cell as estrogen does, which would be related to signal transduction of transmembrane protein PKCα. In our experiment, the important effect of diet on occurrence of PMOP was confirmed. The Equol metabolizing phenotypes may determine the effect of SI on prevention and cure of osteoporosis, the greater effect found in equol producer. So, to prevent PMOP, proper dietary and fertility patterns should be decided by women with intake of bean product, milk, vegetable and fruits, but decrease of intake of animal protein and cooking oil.
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