Association of CA Repeat Polymorphism in Estrogen Receptor β Gene with Postmenopausal Osteoporosis in Chinese

Postmenopausal osteoporosis （PMO） is considered a polygenic disease. The estrogen receptor β （ESR2） gene is a candidate mediating the genetic influence on bone mass and the risk of osteoporosis. The aim of this study is to investigate the association of a cytosine-adenine （CA） repeat polymorphism in the fifth intron of the ESR2 gene with PMO in Chinese Han population. The CA repeat polymorphism was genotyped in a case-control study, involving 78 femoral neck PMO patients vs. 122 controls and 108 lumbar spine （L2-4） PMO patients vs. 92 controls. The （CA）n〈22 and （CA）n≥22 alleles were designated short （S） and long （L）, respectively. ESR2 genotype was categorically defined as SS （2 S alleles）, SL （having the mixed S and L alleles）, and LL （2 L alleles）. At both the femoral neck and the L2-4 region, LL genotype and L allele frequencies of the PMO group were significantly higher than those of the control group （P〈0.01）. The subjects with the SL, the LL, and the combined SL and LL genotype had a significant increased risk of PMO when compared with those with the SS genotype （P〈0.05）. After adjustments for age, years since menopause, menopausal age, and body mass index, logistic regression analysis showed that the subjects with the combined SL and LL genotype had increased risk of PMO when compared with those with the SS genotype both at the femoral neck （adjusted OR 4.923, 95% CI 1.986-12.203 , P=0.001） and the L2-4 （adjusted OR 2.267, 95% CI 1.121-4.598, P=0.023）. This extensive association study has identified the ESR2 CA repeat polymorphism to be independently associated with PMO at the femoral neck and the L2-4 in Chinese Han population. The data also suggested that the presence of the L allele may dominantly increase the risk of PMO at the two regions.

Effect of long-term aerobic exercise on estrogen level and bone composition in female osteoporosis patients

Objective: To investigate the effect of long-term aerobic exercise on estrogen level and bone composition in female patients with osteoporosis. Methods: A total of 120 women with osteoporosis were selected from January 2017 to July 2018. They were randomly divided into three groups, the experimental group, the conventional treatment group and the pure exercise group, each of 40 cases. The routine group was treated with calcium supplement and vitamin D3. The experimental group was treated with aerobic exercise plus routine therapy. The simple exercise group was treated with aerobic exercise. The estrogen level and bone mineral density of the three groups were compared before and after treatment. Results: There was no significant difference in estradiol levels among the three groups before treatment, and there was significant difference in estradiol levels between the three groups at 3 and 6 months after treatment. The bone mineral density of the experimental group, the routine group and the simple exercise group at 3 months and 6 months after treatment was higher than that before treatment, the difference was statistically significant. The levels of estradiol in the experimental group, the routine group and the simple exercise group at 3 and 6 months after treatment were higher than those before treatment, and the differences among the three groups were statistically significant. Conclusion: Long-term exercise can effectively improve the estrogen level and bone mineral density of female patients with osteoporosis, and has obvious effect on preventing osteoporosis.

Low-molecular-weight estrogenic phytoprotein suppresses osteoporosis development through positive modulation of skeletal estrogen receptors

Age-related osteoporosis is a metabolic skeletal disorder caused by estrogen deficiency in postmenopausal women.Prolonged use of anti-osteoporotic drugs such as bisphosphonates and FDA-approved anti-resorptive selective estrogen receptor modulators(SERMs)has been associated with various clinical drawbacks.We recently discovered a low-molecular-weight biocompatible and osteoanabolic phytoprotein,called HKUOT-S2 protein(32 kDa),from Dioscorea opposita Thunb that can accelerate bone defect healing.Here,we demonstrated that the HKUOT-S2 protein treatment can enhance osteoblasts-induced ossification and suppress osteoporosis development by upregulating skeletal estrogen receptors(ERs)ERα,ERβ,and GPR30 expressions in vivo.Also,HKUOT-S2 protein estrogenic activities promoted hMSCs-osteoblasts differentiation and functions by increasing osteogenic markers,ALP,and RUNX2 expressions,ALP activity,and osteoblast biomineralization in vitro.Fulvestrant treatment impaired the HKUOT-S2 protein-induced ERs expressions,osteoblasts differentiation,and functions.Finally,we demonstrated that the HKUOT-S2 protein could bind to ERs to exert osteogenic and osteoanabolic properties.Our results showed that the biocompatible HKUOT-S2 protein can exert estrogenic and osteoanabolic properties by positively modulating skeletal estrogen receptor signaling to promote ossification and suppress osteoporosis.Currently,there is no or limited data if any,on osteoanabolic SERMs.The HKUOT-S2 protein can be applied as a new osteoanabolic SERM for osteoporosis treatment.

Osteoporosis and obesity: Role of Wnt pathway in human and murine models

Studies concerning the pathophysiological connection between obesity and osteoporosis are currently an intriguing area of research.Although the onset of these two diseases can occur in a different way,recent studies have shown that obesity and osteoporosis share common genetic and environmental factors.Despite being a risk factor for health,obesity has traditionally been considered positive to bone because of beneficial effect of mechanical loading,exerted by high body mass,on bone formation.However,contrasting studies have not achieved a clear consensus,suggesting instead that excessive fat mass derived from obesity condition may not protect against osteoporosis or,even worse,could be rather detrimental to bone.On the other hand,it is hitherto better established that,since adipocytes and osteoblasts are derived from a common mesenchymal stem cell precursor,molecules that lead to osteoblastogenesis inhibit adipogenesis and vice versa.Here we will discuss the role of the key molecules regulating adipocytes and osteoblasts differentiation,which are peroxisome proliferators activated receptor-γand Wnts,respectively.In particular,wewill focus on the role of both canonical and non-canonical Wnt signalling,involved in mesenchymal cell fate regulation.Moreover,at present there are no experimental data that relate any influence of the Wnt inhibitor Sclerostin to adipogenesis,although it is well known its role on bone metabolism.In addition,the most common pathological condition in which there is a simultaneous increase of adiposity and decrease of bone mass is menopause.Given that postmenopausal women have high Sclerostin level inversely associated with circulating estradiol level and since the sex hormone replacement therapy has proved to be effective in attenuating bone loss and reversing menopause-related obesity,we hypothesize that Sclerostin contribution in adipogenesis could be an active focus of research in the coming years.

Osteoporosis in celiac disease and in endocrine and reproductive disorders

As the increase in lifespan brings to light diseases that were previously not clinically detectable,osteoporosis has become an issue of worldwide significance. The disease is marked by a loss of bone mass; the bones become less dense,fragile and more prone to fracturing. Because it is regulated by endocrine and environmental factors,osteoporosis presents a multifactorial etiopathogenesis,with the genetic component accounting for 70% of an individual variation in bone mass density (BMD),the principal determinant,with age,of fracture risk. Pathological conditions such as celiac disease (CD) exacerbate the process of bone loss,so that the occurrence of osteoporosis in celiac subjects is of particular note: indeed,the screening of osteoporosis patients for this disease is advisable,since it may be the only sign of undiagnosed CD. An increase in interleukin IL-1β,of the IL-1 system,in the relatives of celiac patients confirms the genetic predisposition to osteoporosis and its presence is evidence of an association between the two conditions. The direct effect on the bones of CD is secondary to poor absorption of calcium and vitamin D. In women osteoporosis is indirectly associated with early menopause and amenorrhea,and it may follow prolonged breast-feeding and frequent pregnancies,while in men it is associated with hypogonadism and GH deficit. These endocrine and non-endocrine factors exert their effects on bones by modulating the RANK/RANK-L/OPG system. An appropriate lifestyle from adolescence onwards,together with early diagnosis of and treatment for CD and primary and secondary endocrine pathologies are important for the prevention of damage to the bones.

Review Venous Thromboembolism Risk with Anti-Osteoporosis Drugs

Osteoporosis is the most common skeletal diseases, predisposing the patient to an increased risk of fractures. It is an important health issue linked to increased morbidity and mortality. Prevention and treatment strategies are now well defined and are always updating. Indeed, the therapeutic decision is based on the individual risk of fracture, efficiency and degree of therapeutic tolerance. However, some side effects, although rare can be attributed to drugs used. The benefit and risks of prescription drugs can be optimized by choosing the right time and the right treatment. The purpose of this article is the study of thromboembolic risk of various drugs recommended in osteoporosis. Furthermore we discuss preventive measures, and the different approaches after the first event.

Increased Midkine and Estrogen Receptor-β Expression in Human Non-Small Cell Lung Cancer

Objective： Midkine （MK）, a new member of the heparin-binding growth factor family, has been found recently to have a high expression level in many tumor specimens including lung carcinoma. Estrogens may be involved in lung carcinogenesis, and estrogen receptors, mainly estrogen receptor-β （ER-β）, are present and functional in normal lung and tumor cell lines and tissues. In addition, estrogens and growth factors may promote the progression of human non-small cell lung cancer （NSCLC）. Previously, we have immunohistochemically demonstrated that MK and ER-β proteins were overexpressed in NSCLC and their expression levels were both significantly negatively correlated with the pathological classification. The purpose of this study was to further verify their expression and its correlation with NSCLC. Methods： Taking NSCLC tissues and their corresponding paraneoplastic and normal lung as research objects, we further examined the expression of MK and ER-β by meas of RT-PCR, in situ hybridization and Western blot analyses at the levels of messenger RNA （mRNA） and protein, respectively. Results： The increased MK and ER-β mRNA expression was found in NSCLC by RT-PCR and in situ hybridization analyses. Furthermore, Western blot analysis also displayed increased expression of MK and ER-β proteins in NSCLC. Finally, their correlation analysis at the levels of mRNA and protein expression in NSCLC demonstrated that MK protein level was significantly correlated to estrogen receptor-β （P〈0.01, rs=0.535）; in spite of their correlation at the mRNA level, there was no remarkable difference between MK and ER-β （P〉0.05, rs=0.178）. Conclusion： All these results in the present study confirmed that MK and ER-β were overexpressed in human NSCLC.

Long-Term Nikotine Administration Impairs Blood Parameters and Femoral Bone Tissue Structure in an Osteoporosis Model of Rats

Osteoporosis is a systemic bone disease that results in the loss of bone mass and impared bone structure. Animal models for osteoporosis are generated by ovariectomy. Adult female Sprague-Dawley rats were divided into control, bilateral ovariectomy and bilateral ovariectomy and subcutaneous nicotine administered (received nicotine sulphate, 2 mg/kg) groups, daily for 28 days. At the end of the period, rats were sacrified under anesthesia blood samples were taken and femoral tissues were dissected. Estrogen, calcium and alkaline phosphatase levels were measured. Tissue samples were prepared for histopathogical examination. Sections were stained with Hematoxylin and Eosin and examined under light microcope. Biochemical parameters were decreased depending on the overiectomy, also decrement was notable with nicotine intake. In the ovariectomy group;increased inflammatory cells with degenerative changes around the femoral compact bone and dilatation of osteon structures in bone trabeculae and apoptotic changes in osteocyte cells in bone lacuna were apparent. In the ovariectomy with nicotine administration group, excessive dilatation of the havers lamellae in the compact bone region, increased osteoclastic activity, picnosis and apoptotic nucleus of the osteoclastic cells located in the lacuna, and increased collagen fibers in the matrix were observed. We suggest that ovariectomy and nicotine administration together effect estrogen and calcium metabolism negatively, stimulate alterations in the structural properties of bone matrix, also affect osteocyte development and bone lamellar structure that may accelerate osteoporosis development.

Effects of Different Extracts of Kanggushu(抗骨疏) on Osteoporosis in Model Rats and the Underlying Mechanisms

Objective： To investigate the preventive effects and possible underlying mechanism of different extracts of Kanggushu （抗骨疏） on osteoporosis in ovariectomized rats. Methods： One hundred and sixty- five female SD rats were divided into 11 groups： control, sham, model, Xianling Gubao Capsule （仙灵骨葆胶囊）, nilestriol, Kanggushu aqueous extract high-, medium-, and low-dose and suet extract high-, medium-, and low-dose groups. The osteoporosis model was made by ovariectomizing the rats. The latter 8 groups were administered intragastricly with Xianling Gubao Capsule, nilestriol, Kanggushu aqueous extract and suet extract for 12 weeks, respectively, while the other 3 groups were administered orally saline. The whole body bone mineral density, bone mineral content, organ coefficient of uterus, serum estradiol and alkaline phosphatase contents, blood calcium, phosphorus, interleukin 6 and bone Gla-protein levels after treatment were monitored. Additionally, three-point bending test of femur, HE staining, and scanning electron microscope were performed to explore the pharmacodynamics and underlying mechanisms. Results： In comparison with ovariectomized rats of model group, Kanggushu aqueous extract high-dose resulted in an increased bone mineral density, bone mineral content and organ coefficient of uterus, improved estradiol level, and improved maximum load and structural stiffness （P〈0.05 or P〈0.01）. Two-dimensional and thrae-dimensional trabecular structure was also observed under HE staining and scanning electron microscopy, and the number and thickness of trabecular bone in Kanggushu aqueous extract high-dose group was significantly increased compared to the model group, while the lipid droplets in bone marrow cavity were significantly less. However, there were no significant differences in blood calcium, total serum alkaline phosphatase and bone Gla protein among different treatment groups. Overall, the osteoprotective effects of Kanggushu aqueous extract were comparable to those of nilestriol and were significantly more effective than those of Xianling Gubao Capsule. Conclusion： The preventive effects of Kanggushu aqueous extract might be partly due to the increased estradiol level, accelerated restoration of bone trabecular reticulate structure, and accordingly increased bone mineral density in osteoporosis rats.

主要组织相容性复合物Ⅱ类分子与绝经后骨质疏松症的相关性

绝经后骨质疏松症(postmenopausal osteoporosis,PMOP)是由绝经期雌激素缺乏引起的骨代谢紊乱相关的全身性骨骼疾病。主要组织相容性复合体Ⅱ类分子(major histocompatibility complex ClassⅡmolecules,MHC-Ⅱ)是蛋白质呈递途径的核心,其功能受雌激素调节,可通过参与由T和B淋巴细胞介导的适应性免疫反应,促进T细胞衍生各种炎症因子,最终促进破骨细胞介导的骨骼的骨形成和骨吸收。笔者就雌激素、MHC-Ⅱ、淋巴细胞及其在破骨细胞分化过程及功能活性中的潜在机制进行综述,进而更好地理解MHC-Ⅱ在绝经后骨质疏松症中的可能作用。

雌激素受体α在绝经后骨质疏松中的研究进展及作用机制

绝经后骨质疏松(postmenopausal osteoporosis, PMOP)是亟需解决的公共健康问题。患者雌激素减少,雌激素受体(estrogen receptor α,ERα)表达水平下降,成骨细胞功能下降,破骨细胞活性增强,骨代谢偶联失衡。ERα在PMOP的发生发展中具有重要作用,笔者从PubMed、Web of Science和中国知网检索近10年(2013-2023年)骨质疏松研究领域的文献,总结归纳ERα在骨髓间充质干细胞、成骨细胞祖细胞、成骨细胞前体细胞、成熟成骨细胞、破骨细胞和骨细胞中的作用,并以能显著改善PMOP的黄酮类成分淫羊藿苷为例阐述基于ERα的抗PMOP相关机制。

雌激素受体在骨疏康治疗绝经后骨质疏松症中的作用与机制

背景:骨疏康作为治疗绝经后骨质疏松症肾虚血瘀证的中成药,其具体作用机制需深入研究。目的:研究骨疏康对去卵巢大鼠血清雌激素、骨微结构和雌激素受体的影响。方法:首先进行网络药理学分析,分别获取骨疏康有效成分、作用靶点和绝经后骨质疏松症的靶点,利用Cytoscape构建骨疏康有效成分-靶点网络,利用STRING数据库和Cytoscape进行蛋白互作分析(PPI)及核心靶点的筛选,利用DAVID数据库对交集靶点进行基因本体论(GO)和京都基因与基因组百科全书(KEGG)富集分析。然后建立去卵巢SD大鼠动物模型,骨疏康灌胃3个月,ELISA检测血清雌激素水平,microCT检测骨微结构,Western blot检测骨组织雌激素受体ERα和ERβ蛋白表达。结果与结论:①网络药理学分析显示,骨疏康中共有132个有效成分,150个作用靶点,与1155个绝经后骨质疏松症靶点取交集,获得87个骨疏康治疗绝经后骨质疏松症的作用靶点。②构建骨疏康有效成分-靶点网络图发现处于核心位置的有效成分有槲皮素、山柰酚、木犀草素、柚皮素和异鼠李素,处于核心位置的靶点有NCOA2,ESR2,AR,F2,ESR1,PTGS1。③PPI分析及筛选后最终获得的靶点有MAPK8,ESR1,JUN,R3C1,RELA和FOS,其中ESR1为两次分析获得的共同核心靶点。④随后的KEGG富集分析显示雌激素、TNF、凋亡等信号通路,因此动物实验重点关注骨疏康对雌激素信号通路中不同亚型的雌激素受体的影响。⑤动物实结果显示,骨疏康组骨微结构明显改善,血清雌激素无明显变化,但骨组织中ERα和ERβ蛋白量明显升高,说明骨疏康治疗绝经后骨质疏松症可能与其雌激素样作用和提高雌激素受体蛋白的表达有关。

Androgens and estrogens in skeletal sexual dimorphism

Bone is an endocrine tissue expressing androgen and estrogen receptors as well as steroid metabolizing enzymes. The bioactivity of circulating sex steroids is modulated by sex hormone-binding globulin and local conversion in bone tissue, for example, from testosterone （T） to estradiol （E2） by aromatase, or to dihydrotestosterone by 5（x-reductase enzymes. Our understanding of the structural basis for gender differences in bone strength has advanced considerably over recent years due to increasing use of （high resolution） peripheral computed tomography. These microarchitectural insights form the basis to understand sex steroid influences on male peak bone mass and turnover in cortical vs trabecular bone. Recent studies using Cre/LoxP technology have further refined our mechanistic insights from global knockout mice into the direct contributions of sex steroids and their respective nuclear receptors in osteoblasts, osteoclasts, osteocytes, and other cells to male osteoporosis. At the same time, these studies have reinforced the notion that androgen and estrogen deficiency have both direct and pleiotropic effects via interaction with, for example, insulin-like growth factor 1, inflammation, oxidative stress, central nervous system control of bone metabolism, adaptation to mechanical loading, etc., This review will summarize recent advances on these issues in the field of sex steroid actions in male bone homeostasis.

绝经后女性体质量指数与内侧单髁置换后疗效的关系

背景:单髁置换后随访中,部分患者出现膝关节疼痛活动受限,其中绝经后肥胖女性最为多见;体质量指数作为衡量身体肥胖程度的重要指标,是否与单髁置换后疗效有关,肥胖是否会影响术后膝关节功能,值得进一步研究。目的:评价绝经后肥胖女性患者行内侧单髁置换后的临床疗效,明确体质量指数对单髁置换后患者生活质量的影响。方法:纳入新疆医科大学第四临床医学院2017年1月至2019年1月因内侧膝关节疼痛并初次行内侧单髁置换的女性绝经患者;根据标准共纳入270例,按照术前体质量指数分为4组:正常组42例(体质量指数18.5-22.9 kg/m^(2)),超重组58例(体质量指数23.0-24.9 kg/m2),肥胖组122例(体质量指数25.0-29.9 kg/m^(2)),重度肥胖组48例(体质量指数≥30 kg/m^(2))。分别比较各组术前、术后及末次随访美国特种外科医院膝关节评分、安大略省西部和麦克马斯特大学骨关节炎指数评分、膝关节活动度、目测类比评分及髋膝踝角;随访并记录患者术后假体使用时间、失效或翻修原因,计算并比较各组假体的有效使用率,采用生存曲线对假体有效使用率进行统计学分析。结果与结论:(1)各组患者间术后随访时间、膝关节活动度、目测类比评分、髋膝踝角比较差异无显著性意义(P>0.05);(2)术后末次随访各组间美国特种外科医院膝关节评分、安大略省西部和麦克马斯特大学骨关节炎指数评分均较术前显著改善(P<0.05),且各组间比较差异有显著性意义(P<0.05),对于美国特种外科医院膝关节评分重度肥胖组改善效果最差;(3)各组术后即刻与末次随访髋膝踝角对比发现,除正常组外(P>0.05),其余各组2个时间点之间差异均有显著性意义(P<0.05);(4)正常、超重、肥胖及重度肥胖组假体有效使用率依次为100%,95%,94%和94%,组间比较差异无显著性意义(χ^(2)=2.532,P=0.469);(5)提示绝经后肥胖女性患者体质量指数值对内侧单髁假体有效使用率无显著影响;肥胖是影响患者术后膝关节功能评分及假体有效使用率的重要因素,单髁置换前后应适当控制体质量,同时女性体质量指数≥30 kg/m^(2)不是单髁置换的最佳适应证,建议行单髁置换的女性患者应将体质量指数控制在30 kg/m^(2)以下。

The Effect of Estrogen on the Restoration of Bone Mass and Bone Quality in Ovariectomized Rats

To evaluate the effect of estrogen on its ability to restore the bone mass and bone quality in ovariectomized rats by examining the changes of bone morphology and histomorphometry, 3- month-old rats were divided randomly into 4 groups: normal control, ovariectomized (OVX), sham- operated (Sham-O) and OVX plus estrogen (OVX+E2). Treatment initiated from the day 8 weeks after operation and continued for 12 weeks. Bone morphology and histomorphometry were examined afterwards. Results showed that comparing to control group, the trabecular bone in OVX appeared thinner and reduced in the amount. The connectivity between trabecula was decreased and the struc- ture disordered. The free-end of trabecula was increased. The cavity of bone marrow enlarged. After treatment with estrogen, above changes improved remarkably by different degree, although did not reach the normal face. The bone histomorphometry results damonstrated that estrogen treatment in- creased bone mass and the amount of trabecula by 129% and 132% respectively (P<0. 05). The activity of bone resorption decreased significantly and the rate of bone formation increased to 203%. These results suggest that treatment of ovariectomized rats with estrogen can not only increase bone mass, also improve the bone structure and enhance the property of bone mechanics.

Effect of Compound Recipe Gengniankang (更年康) on Senile Sexual Hormone and Expression of Estrogen Receptor in Bone of Climacteric Female Rats

Objective： To compare the therapeutic effect of Compound Recipe Gengniankang （更年康, GNK） with that of hormone replacement treatment （HRT） on climacteric female rats with osteoporosis, and to investigate the roles of estrogen and estrogen receptors in the mechanism of osteoporosis. Methods： Climacteric female rats with osteoporosis were chosen and divided into three groups （GNK group, HRT group and control group）. Apoptosis of ovarian granulose cells was measured by terminal-deoxynucleotidyl transferae mediated nick end labeling （TUNEL） assay. Serum level of estrdiol （E2）, follicle stimulating hormone （FSH）, luteinizing hormone （LH） were determined by the method of radioimmunoassay （RIA）. Reverse transcriptase polymerase chain reaction （RT-PCT） technology was used to evaluate the expression of estrogen receptor （ER） in bone. Bone mineral density （BMD） was measured by double energy X-ray absorption （DEXA）. Results： In the climacteric rats, BMD, serum E2, ER mRNA expression in bone decreased remarkably, and serum FSH, LH and apoptosis of ovarian granulose cells increased obviously. After treating with GNK, all the indexes were reversed except serum E2. The increase of E2 was not significant. Conclusion： GNK is effective on climacteric osteoporosis female rats. Its role is performed not by increasing serum E2 but by enhancing ER in the bone and inhibiting apoptosis of ovarian granulose cells. GNK can deter further exhaustion of ovarian function.

长链非编码RNA通过p38MAPK信号通路直接或间接影响骨质疏松症

背景:近年来大量的研究发现长链非编码RNA参与骨质疏松症的发生和发展。p38MAPK信号通路参与骨髓间充质干细胞、成骨细胞以及破骨细胞的分化等过程而参与骨质疏松症的发展,而长链非编码RNA可通过影响p38MAPK信号通路,直接或间接参与骨质疏松症的发生及发展过程。目的:综述长链非编码RNA通过p38MAPK信号通路,直接或间接影响骨质疏松症的进展,为长链非编码RNA在骨质疏松症中预防和治疗提供一个新思路。方法:检索PubMed、中国知网和万方数据库的相关文献,以“长链非编码RNA,骨质疏松,间充质干细胞,成骨细胞,破骨细胞,p38信号通路”为中文检索词,以“long non-coding RNA,osteoporosis,mesenchymal stem cells,osteoblasts,osteoclast,p38 signaling pathway”为英文检索词,排除陈旧、重复以及可信度低的观点,将检索到的文献进行归纳、总结和分析,选取76篇具有代表性的文章。结果与结论:(1)长链非编码RNA通过多种途径参与骨质疏松症的防治,包括促进骨髓间充质干细胞的成骨分化、促进成骨细胞分化和成骨细胞分泌活性、抑制破骨细胞增殖和对骨的吸收作用,以及调节成骨相关细胞通路的激活或抑制,激活p38MAPK信号通路延缓骨质疏松症进展,抑制该信号通路抑制破骨细胞的吸收作用,从而影响骨质疏松的发生和发展。(2)相应长链非编码RNA的过表达或低表达会通过p38MAPK信号通路来影响成骨细胞和破骨细胞的增殖或分化,调节骨重塑过程,进而影响骨质疏松症的发生和发展。大量的基础研究结果显示,长链非编码RNA和p38MAPK信号通路或许可以成为骨质疏松症治疗中的潜在应用和临床转化价值;且相应的长链非编码RNA过表达或低表达慢病毒、转染质粒,相应的p38MAPK信号通路抑制剂等在体外细胞实验及动物模型中都被证实有靶向调控作用。(3)因此,通过靶向调控长链非编码RNA和p38MAPK信号通路来调节骨髓间充质干细胞的分化和功能,或通过长链非编码RNA和p38MAPK信号通路来抑制破骨细胞的增殖分化,或许能提供一种创新的治疗策略,可以延缓骨质疏松症的进展。

骨质疏松症治疗药物应用对眼部疾病影响的研究进展

骨质疏松症(OP)是一种以骨量减少、骨组织微结构损坏致骨脆性增加、易发生骨折为特征的全身性疾病,目前主要依靠药物治疗。由于OP和一些眼部疾病的发生均与衰老导致的一系列病理机制有关,并且OP治疗药物也具有抗非感染性炎症、抗氧化、抗凋亡、影响性激素水平等作用,与一些眼科疾病的发生机制存在一定的关联,从而对眼部疾病的发生和进展产生影响。OP治疗药物主要包括维生素D及其衍生物、雌激素、双膦酸盐、地舒单抗,这些药物的应用可能增加年龄相关性黄斑变性、干眼、眼部炎症的患病风险,也有可能对一些眼部疾病如干眼、白内障、青光眼、脉络膜新生血管等起到预防作用。故临床上使用OP治疗药物时,应定期观察相关眼病的变化。本文对OP治疗药物应用对眼部疾病的影响研究进行综述。

Expression of voltage.gated sodium channel Nav1.5 in non.metastatic colon cancer and its associations with estrogen receptor(ER)-βexpression and clinical outcomes

Background: Voltage-gated sodium channel 1.5(Nav1.5) potentially promotes the migratory and invasive behaviors of colon cancer cells. Hitherto, the prognostic significance of Nav1.5 expression remains undetermined. The present study aimed to explore the associations of Nav1.5 expression with clinical outcomes and estrogen receptor-β(ER-β)expression in non-metastatic colon cancer patients receiving radical resection.Methods: A total of 269 consecutive patients with pathologically confirmed stages Ⅰ-Ⅲ colon cancer who underwent radical resection were selected. Nav1.5 and ER-β expression was detected by using immunohistochemistry(IHC)on tissue microarray constructed from paraffin-embedded specimens. IHC score was determined according to the percentage and intensity of positively stained cells. Statistical analysis was performed with the X-tile method, k coefficient, Chi square test or Fisher's exact test, logistic regression, log-rank test, and Cox proportional hazards models.Results: We found that Nav1.5 was commonly expressed in tumor tissues with higher mean IHC score as compared with matched tumor-adjacent normal tissues(5.1 ± 3.5 vs. 3.5 ± 2.7, P < 0.001).The high expression of Nav1.5 in colon cancer tissues was associated with high preoperative carcinoembryonic antigen level [odds ratio(OR) = 2.980;95% confidential interval(CI)1.163-7.632; P = 0.023] and high ER-β expression(OR = 2.808; 95% CI 1.243-6.343;p = 0.00 3). Log-rank test results showed that high Nav1.5 expression contributed to a low 5-year disease-free survival(DFS) rate in colon cancer patients(77.2% vs. 92.1%, P = 0.048), especially in patients with high ER-β expression tumor(76.2% vs. 91.3%, P = 0.032). Analysis with Cox proportional hazards model demonstrated that high Nav1.5 expression[hazard ratio(HR) = 2.738; 95% CI 1.100-6.819;P = 0.030] and lymph node metastasis(HR = 2.633; 95% CI 1.632-4.248; P < 0.001) were prognostic factors for unfavorable DFS in colon cancer patients.Conclusions: High expression of Nav1.5 was associated with high expression of ER-β and indicated unfavorable oncologic prognosis in patients with non-metastatic colon cancer.

phytoestrogens/insoluble fibers and colonic estrogen receptor β: randomized, double-blind, placebo-controlled study

AIM:To assess the safety and effect of the supplementation of a patented blend of dietary phytoestrogens and insoluble fibers on estrogen receptor (ER)-β and biological parameters in sporadic colonic adenomas. METHODS:A randomized, double-blind placebo-controlled trial was performed. Patients scheduled to undergo surveillance colonoscopy for previous sporadic colonic adenomas were identified, and 60 eligible patients were randomized to placebo or active dietary intervention (ADI) twice a day, for 60 d before surveillance colonoscopy. ADI was a mixture of 175 mg milk thistle extract, 20 mg secoisolariciresinol and 750 mg oat fiber extract. ER-β and ER-α expression, apoptosis and proliferation (Ki-67 LI) were assessed in colon samples. RESULTS:No adverse event related to ADI was recorded. ADI administration showed a significant increases in ER-β protein (0.822 ± 0.08 vs 0.768 ± 0.10, P = 0.04) and a general trend to an increase in ER-β LI (39.222 ± 2.69vs 37.708 ± 5.31,P = 0.06), ER-β/ER-α LI ratio (6.564 ± 10.04 vs 2.437 ± 1.53, P = 0.06), terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (35.592 ± 14.97 vs 31.541 ± 11.54, P = 0.07) and Ki-67 (53.923 ± 20.91 vs 44.833 ± 10.38, P = 0.07) approximating statistical significance. A significant increase of ER-β protein (0.805 ± 0.13 vs 0.773 ± 0.13,P = 0.04), mRNA (2.278 ± 1.19vs 1.105 ± 1.07, P < 0.02) and LI (47.533 ± 15.47 vs 34.875 ± 16.67,P < 0.05) and a decrease of ER-α protein (0.423 ± 0.06vs 0.532 ± 0.11,P < 0.02) as well as a trend to increase of ER-β/ER-α protein in ADI vs placebo group were observed in patients without polyps (1.734 ± 0.20 vs 1.571 ± 0.42, P = 0.07). CONCLUSION:The role of ER-β on the control of apoptosis, and its amenability to dietary intervention, are supported in our study.