骨质疏松治疗中抗骨吸收药物的作用机制

骨质疏松(Osteoporosis,OP)是一种骨量减少、骨组织显微结构破坏、骨强度减低、骨脆性增加而易骨折的全身性疾病,主要发生于老年人群.发病原因大多由于成骨细胞(Osteo-blast,OB)和破骨细胞(Osteoclast,OC)的再生和凋亡发生紊乱.近几年,随着世界范围内老龄人口的增加,OP发病率的不断增高,相应的治疗药物也随之上升,主要分为3大类:抗骨吸收药物,促骨吸收药物,对骨细胞起双向作用药物.     

选择性雌激素受体调节剂-盐酸雷洛昔芬的研究进展

本文对雷洛昔芬构效关系、组织选择效应、不良反应等临床资料进行综述。虽然雌激素仍是大多数绝经后妇女进行激素治疗的备选药物,但对于其中某些骨质疏松者,在权衡利弊后,雷洛昔芬可作为替代药物。     

骨保护素与骨质疏松

肿瘤坏死因子家族新成员骨保护素(OPG)通过与细胞核因子κB受体活化因子(RANK)配体(RANKL)结合,抑制RANKL/RANK对破骨细胞信号转导的活化,发挥抗骨质疏松作用。OPG基因多态性与骨质疏松也存在相关性。OPG受多种激素、细胞因子和转录因子的调控,骨OPG/RANKL比率的改变在各型骨质疏松的发病中起重要作用。目前OPG已成为新的骨转换指标,但其在血清中的浓度变化和临床意义尚存在争论。由于在动物实验中利用OPG基因和蛋白治疗骨质疏松已取得一定进展,故OPG有望成为新一代的抗骨质疏松药物。     

骨质疏松的研究进展及雌激素抗骨质疏松的新机制

骨质疏松 (ＯＰＳ)是中老年人常患的一类疾病 ,随着年龄增长 ,体内骨吸收增加 ,而骨形成减少 ,导致骨量减少 ,骨密度降低 ,骨脆性增加 ,由其引发的疼痛及骨折严重影响中老年人的生活质量。近年来随着研究的不断深入 ,对骨质疏松的发病机制有了更深刻的认识 ,研究发现骨保护素 (ＯＰＧ)和细胞凋亡 (ａｐｏｐｔｏｓｉｓ)在骨质疏松的发生发展中起重要的作用。绝经后骨质疏松 (ＰＭＯ)是骨质疏松中最常见的一种类型 ,雌激素(Ｅｓｔｒｏｇｅｎ)作为治疗绝经后骨质疏松最有效的药物 ,得到了临床广泛的应用。以前的研究证实 ,雌激素可通过细胞受体…     

选择性雌激素受体调节剂在临床应用上的前景

绝经期妇女易患骨质疏松，而激素替代治疗又会产生一些不良反应。目前出现的新一类药物——选择性雌激素受体调节剂在骨质疏松治疗上既发挥了雌激素样骨保护作用，又能避免一些不良反应的出现。它在骨骼、心血管系统表现出雌激素样作用的同时，在子宫及乳腺组织中与不同的雌激素受体亚型结合，表现出雌激素拮抗效应，从而减少不良反应的发生。但是它也会增加静脉血栓发生率，无法降低由于雌激素缺乏所致的潮热、骨盆组织脱垂等现象的出现。由于它表现的雌激素协同和拮抗双重效应，目前在临床上有着广阔的应用前景。     

骨保护素与骨质疏松

肿瘤坏死因子家族新成员骨保护素(OPG)通过与细胞核因子kB受体活化因子(RANK)配体(RANKL)结合，抑制RANKL／RANK对破骨细胞信号转导的活化，发挥抗骨质疏松作用。OPG基因多态性与骨质疏松也存在相关性。OPG受多种激素、细胞因子和转录因子的调控，骨OPG／RANKL比率的改变在各型骨质疏松的发病中起重要作用。目前OPG已成为新的骨转换指标，但其在血清中的浓度变化和临床意义尚存在争论。由于在动物实验中利用OPG基因和蛋白治疗骨质疏松已取得一定进展，故OPG有望成为新一代的抗骨质疏松药物。     

雌激素抗骨质疏松的研究进展

雌激素是治疗绝经后骨质疏松症的一线药物,对其抗骨质疏松的作用已进行了相当多的研究,最近发现雌激素对骨的作用与直接上调骨保护素(OPG)有关。OPG是近年来发现的最有效抑制破骨细胞,继而抑制骨吸收的肿瘤坏死因子受体超家族新成员。由于雌激素长期应用的副作用,植物雌激素正成为研究开发的热点。     

骨保护素的研究进展

骨保护素（Ｏｓｔｅｏｐｔｅｇｅｒｉｎ,ＯＰＧ）及其配体（ＯＰＧＬ）的发现是近年来骨代谢研究领域的又一项重要发现。ＯＰＧ是一种可溶性肿瘤坏死因子受体,主要通过与ＯＰＧＬ结合而起作用。ＯＰＧ不仅抑制破骨细胞（ＯＣ）生成,而且还抑制ＯＣ的骨吸收功能。对于骨质疏松、免疫性骨关节损害、恶性肿瘤并发体液性高钙血症等疾病,ＯＰＧ可能具有有效的治疗作用。     

选择性雌激素受体调节剂雷洛昔芬阻止去卵巢大鼠骨丢失的机制

目的　了解选择性雌激素受体调节剂雷洛昔芬 (RLX)阻止去卵巢大鼠骨丢失的机制。对骨质疏松症模型大鼠进行雌激素及选择性雌激素受体调节剂类药物RLX治疗 ,观察其对去卵巢大鼠骨组织光镜、电镜及骨密度 (BMD)等各种指标的影响。　方法　用 3月龄雌性SD大鼠 32只 ,随机分为卵巢未切除组、卵巢切除组、雌激素治疗组、RLX治疗组 ,5个月后处死 ,检测股骨、腰椎及全身BMD、子宫重量、骨形态。　结果　卵巢切除组经RLX治疗 3个月后腰椎、股骨、全身BMD增加35 %、4 0 %、2 1% ,分别为 (0 2 5 6± 0 0 2 2 ) g/cm2 、(0 2 93± 0 0 15 ) g/cm2 和 (0 36 8± 0 0 2 5 ) g/cm2 ;RLX组大鼠骨小梁表面的破骨细胞数比卵巢切除组减少 ;与卵巢切除组相比 ,雌激素治疗组的子宫重量增加了 5 5 % ,而RLX组则对子宫无明显刺激作用。　结论　RLX及雌激素都具有防治骨质疏松的作用 ,RLX能阻止去卵巢所造成的骨丢失。     

骨质疏松相关基因在骨质疏松中的作用

骨质疏松（osteoporosis OP)是以骨质量的丢失以及骨组织的退变为特征的骨代谢疾病。近年来，骨质疏松相关基因如：维生素D受体（VDR）基因型，雌激素受体（ER）基因型，I型胶原A1（COLIAI）基因型，骨钙素基因，白细胞介素基因等在骨质疏松的形成和转归方面的作用日益成为人们关注的焦点。 雌激素可以增加破骨细胞的产物－转移生长因子β1（TGF-β1）在骨中富含，对病人带有的T等位基因发挥作用。中国妇女的BMD与VDR基因型有关。白细胞介素1（IL－1）是促进皮骨细胞的骨吸收作用因子，它随雌激素的减少而增加；在成骨细胞中近似于对雌激素的受体后效应，还可以促进破骨细胞凋亡，这种多效性维持着骨的稳态（homeostasis）。     

雷洛昔芬对血管内皮素-1基因mRNA表达的影响及与雌激素受体的关系

目的　观察选择性雌激素受体调节剂雷洛昔芬 (Raloxifene)对血管内皮细胞内皮素 1基因mRNA表达的影响 ,并探讨Raloxifene的作用是否通过雌激素受体机制介导。　方法　采用Raloxifene处理培养的牛颈动脉内皮细胞 2 4h ,然后提取细胞总RNA ,取 2 0ug进行Northernblotting分析 ,观察Raloxifene对血管内皮细胞内皮素 1基因mRNA表达的影响 ,同时采用雌激素受体阻断剂ICI182 780处理细胞 ,观察内皮素 1基因表达的变化。　结果　与未经Raloxifene处理的细胞相比 ,Raloxifene处理后的血管内皮细胞内皮素 1基因mRNA表达明显降低〔分别为 (0 16± 0 0 5 ) ,(0 39± 0 0 7) ,P <0 0 5〕若同时应用ICI182 780处理 ,内皮素 1mRNA表达增强 (0 6 9± 0 0 8,P <0 0 5 ) ,Raloxifene的作用被阻断。　结论　选择性雌激素受体调节剂Raloxifene通过雌激素受体机制抑制血管内皮细胞内皮素 1基因表达。     

雷洛昔芬对去卵巢大鼠血脂的影响

目的探讨选择性雌激素受体调节剂雷洛昔芬对去卵巢大鼠血脂的影响。方法将40只3月龄雌性SD大鼠随机分为5组,去卵巢组、假手术组、雌激素组、小剂量雷洛昔芬组(小剂量组)和大剂量雷洛昔芬组(大剂量组),每组8只。治疗3个月后,测量各组治疗前后体重、血压和血脂的变化。结果去卵巢组TC和LDL-C显著高于其他4组(P<0.01),雌激素组与假手术组比较无统计学差异(P>0.05),与小剂量组比较,大剂量组能更进一步降低TC和LDL-C(P<0.05)。去卵巢组TG与假手术组比较稍有升高,但无统计学差异,雌激素组TG高于假手术组和大、小剂量组(P<0.05)。去卵巢组HDL-C明显低于其他4组(P<0.01),雌激素组HDL-C与假手术组比较无统计学差异(P>0.05),与小剂量组比较,大剂量组能更进一步升高HDL-C(P<0.05)。结论雷洛昔芬可改善去卵巢大鼠的脂代谢状况,有助于降低绝经后的心血管危险。     

Activity of three selective estrogen receptor modulators on hormone-dependent responses in the mouse uterus and mammary gland

Selective estrogen receptor modulators (SERMs) have the unique potential to provide estrogenic effects in the skeletal and cardiovascular system, while minimizing/eliminating side effects on reproductive organs. However, despite the unifying characteristic of mixed estrogen receptor (ER) agonist/antagonist activity, compounds within this class are not interchangeable. In order to define and compare the effects of SERMs on different hormone-responsive tissues, we evaluated effects of bazedoxifene acetate (BZA), lasofoxifene (LAS) and raloxifene (RAL) in the mammary gland and uterus of the ovariectomized mouse. Endpoints measured included those regulated by estradiol alone (uterine wet weight, uterine G protein-coupled receptor 105 (GPR105) mRNA expression and mammary gland indoleamine-pyrrole 2,3 dioxygenase (INDO) mRNA expression) as well as others that required the combination of estradiol and progesterone (uterine serine protease inhibitor Kazal type 3 (Spink3) mRNA expression, mammary gland morphology and mammary gland defensin beta1 (Defbeta1) mRNA expression). The three SERMs tested had variable agonist and antagonist activity on these endpoints. In the uterus, the SERMs were mixed agonists/antagonists on estradiol-induced wet weight increase, whereas all three SERMs were estrogen receptor antagonists on GPR105 mRNA expression. However, in the presence of progesterone, BZA and RAL were agonists on Spink3 expression, while LAS was primarily an antagonist. In the mammary gland, BZA and RAL were predominantly agonists on the endpoint of mammary morphology and all three SERMs were clear agonists on Defbeta1 mRNA expression, an E+P-dependent marker. Finally, LAS and RAL had mixed agonist/antagonist activity on INDO mRNA expression, while BZA had only antagonist activity. These results demonstrate that compounds with small structural differences can elicit distinct biological responses, and that in general, SERMs tended to behave more as antagonists on endpoints requiring estrogen alone and agonists on endpoints requiring the combination of estrogen and progesterone.     

增龄及去卵巢对C57BL/6J小鼠护骨素表达的影响

目的观察增龄和去卵巢状态下小鼠血清护骨素(OPG)水平和骨组织中OPG表达的变化。方法4组C57BL/6J小鼠,每组15只：成年雄鼠组(6月龄),老年雄鼠组(20月龄)；假手术雌鼠组和去卵巢雌鼠组鼠在9月龄时分别行假手术和卵巢切除术,手术6个月后处死小鼠。双能X线检测小鼠骨量变化,实时RT-PCR观察OPG mRNA表达水平,ELISA测定血清中OPG的蛋白水平。结果老年组小鼠和去卵巢组小鼠骨密度明显下降。老年组雄性小鼠血清中OPG水平和成年组[(729±180)ng/Lvs (565±131)ng/L]比较明显上升(P＜0.01)。和假手术组比较(644±140)ng/L,去卵巢组小鼠OPG水平(908±338)ng/L也升高(P＜0.05)。老年组雄鼠骨中OPG mRNA的表达拷贝数为成年组的43.75%(P＜0.05)。与假手术比较,去卵巢组雌鼠骨中OPG mRNA的表达拷贝数下降了75%(P＜0.01)。结论增龄以及去卵巢状态下．小鼠血清中OPG以及骨中OPG mRNA表达水平均有明显变化。     

SERMs for the treatment and prevention of breast cancer

Tamoxifen and raloxifene are both selective estrogen receptor modulators (SERMs). The medicines can block estrogen mediated breast cancer growth and development but will also maintain bone density in postmenopausal women and lower circulating cholesterol. Tamoxifen has remained the antihormonal therapy of choice for the treatment of ER positive breast cancer for the last 30 years. However, although adjuvant tamoxifen produces profound increases in disease-free and overall survival in patients with ER positive breast cancer, concerns about drug resistance, blood clots and endometrial cancer have resulted in a change to the use of aromatase inhibitors for the treatment of postmenopausal women. Nevertheless, tamoxifen remains the antihormonal treatment of choice for premenopausal women with ER positive breast cancer and for risk reduction in premenopausal women who are at high risk for developing breast cancer. The risk of endometrial cancer and thromboembolic disorders during tamoxifen therapy is not elevated in premenopausal women. It is important to note that aromatase inhibitors or raloxifene should not be used in premenopausal women. Raloxifene is used to prevent osteoporosis in postmenopausal women and, unlike tamoxifen, does not increase the risk of endometrial cancer. However, raloxifene does reduce breast cancer risk by 50–70% in both low risk and high risk postmenopausal women. Comparisons of raloxifene with tamoxifen show equal efficacy as a chemopreventive for breast cancer but there is a reduction in thromboembolic disorders, fewer endometrial cancers, hysterectomies, cataracts and cataract surgeries in women taking raloxifene. Overall, SERMs continue to fulfill their promise as appropriate medicines that target specific populations for the treatment and prevention of breast cancer.     

Serum osteoprotegerin levels in school-aged children with asthma

BackgroundVarious inflammatory biomarkers have been used in asthma cases for evaluating inflammation, however it has been determined that the majority of these biomarkers are insufficient for putting forth the course and severity of the disease. Osteoprotegerin is a glycoprotein mediator in the lung and macrophages. As far as we know, there are no studies about the role played by osteoprotegerin in child patients with asthma.ObjectiveIt was planned to examine the relationship between osteoprotegerin levels in childhood asthma and respiratory functions and airway inflammation and to assess its use as a biomarker.MethodsThe study included patients aged 6–16 years who were diagnosed with asthma at the pediatric allergy outpatient clinic of Bagcilar Training and Research Hospital in Turkey. The correlation analyses for the osteoprotegerin levels of asthma patients and their respiratory functions were examined.ResultsThe age average of asthma cases was 10.61 ± 3.04 years and 51.2 % were female. No statistically significant difference was observed between the osteoprotegerin levels of the groups (p > 0.05). A negative and statistically significant correlation was observed between the FEV1 and FVC values and osteoprotegerin levels (p = 0.015, p = 0.003).ConclusionsThis was the first study to examine the relationship between osteoprotegerin levels and airway inflammation in children with asthma. We believe that there is a need for wider scale studies in which clinical symptoms and more parameters are evaluated for defining the role played by osteoprotegerin level in children with asthma and for determining its usability as a biomarker.     

Estrogen induces apoptosis in estrogen deprivation-resistant breast cancer through stress responses as identified by global gene expression across time

In laboratory studies, acquired resistance to long-term antihormonal therapy in breast cancer evolves through two phases over 5 y. Phase I develops within 1 y, and tumor growth occurs with either 17β-estradiol (E(2)) or tamoxifen. Phase II resistance develops after 5 y of therapy, and tamoxifen still stimulates growth; however, E(2) paradoxically induces apoptosis. This finding is the basis for the clinical use of estrogen to treat advanced antihormone-resistant breast cancer. We interrogated E(2)-induced apoptosis by analysis of gene expression across time (2-96 h) in MCF-7 cell variants that were estrogen-dependent (WS8) or resistant to estrogen deprivation and refractory (2A) or sensitive (5C) to E(2)-induced apoptosis. We developed a method termed differential area under the curve analysis that identified genes uniquely regulated by E(2) in 5C cells compared with both WS8 and 2A cells and hence, were associated with E(2)-induced apoptosis. Estrogen signaling, endoplasmic reticulum stress (ERS), and inflammatory response genes were overrepresented among the 5C-specific genes. The identified ERS genes indicated that E(2) inhibited protein folding, translation, and fatty acid synthesis. Meanwhile, the ERS-associated apoptotic genes Bcl-2 interacting mediator of cell death (BIM; BCL2L11) and caspase-4 (CASP4), among others, were induced. Evaluation of a caspase peptide inhibitor panel showed that the CASP4 inhibitor z-LEVD-fmk was the most active at blocking E(2)-induced apoptosis. Furthermore, z-LEVD-fmk completely prevented poly (ADP-ribose) polymerase (PARP) cleavage, E(2)-inhibited growth, and apoptotic morphology. The up-regulated proinflammatory genes included IL, IFN, and arachidonic acid-related genes. Functional testing showed that arachidonic acid and E(2) interacted to superadditively induce apoptosis. Therefore, these data indicate that E(2) induced apoptosis through ERS and inflammatory responses in advanced antihormone-resistant breast cancer.     

Who will benefit from treatment with selective estrogen receptor modulators (SERMs)?

Clinical trials have demonstrated that the selective estrogen receptor modulator raloxifene can reduce the risk of vertebral fracture, but have not unequivocally demonstrated an effect on non-vertebral fracture. Consequently it is recommended that raloxifene be used mainly in postmenopausal women with milder osteoporosis as a preventive measure or for treatment in those with predominantly spinal osteoporosis. Since the effects of raloxifene on bone mineral density and bone turnover may reverse soon after cessation, it is recommended that raloxifene be used as long-term therapy for 5-10 years. Because of its quicker offset, use of raloxifene may have advantages over potent bisphosphonates if use of anabolic agents are contemplated in an individual patient.     

C950T and C1181G osteoprotegerin gene polymorphisms in myeloma bone disease

Objectives

Bone disease is one of the hallmarks of multiple myeloma (MM). The role of osteoprotegerin (OPG) in the RANK/RANKL/OPG signaling system is well defined in the myeloma bone disease. Polymorphisms of the TNFRSF11B gene encoding OPG have been studied in various bone diseases. However, relationship between the levels of OPG and development of bone lesions regardless of RANKL is yet unknown. In this study, the effects of OPG gene polymorphism on the development of bone lesions in MM were investigated.

Methods

C950T and C1181G polymorphisms of the OPG gene were studied in 52 MM patients (36 with bone lesions and 16 without bone lesions) and in another 20 control subjects using DNA sequencing.

Results

1181 G and 950 T alleles were overrepresented in MM patients having bone lesions. 950 TT/1181 GG haplotype frequency and TT/GG combined haplotype were also higher in MM patients having bone lesions compared to MM patients without bone lesions or to control.

Discussion

This is the first study searching for the relationship between OPG gene variants C950T (promoter), C1181G (exon 1), and myeloma bone disease. It was concluded that the presence of polymorphic 1181 G/950 T alleles and 950 TT/1181 GG genotypes may play a role in the development of bone disease.     

骨保护素与动脉粥样硬化的研究进展

骨保护素是属于肿瘤坏死因子超家族成员之一的一种可溶性糖蛋白,近来研究表明骨保护素不仅参与骨代谢,同时与体内能量和糖脂代谢关系密切,且其与动脉粥样硬化及糖脂代谢异常相关的心血管病变、微血管病变联系紧密。骨保护素可能通过调节糖脂代谢和内皮功能、抑制血管钙化、抑制炎症、抑制凋亡等机制参与动脉粥样硬化发生发展过程。