2型糖尿病合并颈动脉狭窄患者血清FGF23水平与颈动脉斑块稳定性的关联性研究

目的:探讨血清FGF23对2型糖尿病合并颈动脉狭窄(ICAS)患者不稳定斑块稳定性的作用。方法:选取糖尿病患者78例,分为无ICAS(WICAS)组47例和ICAS组31例,ICAS组行颈动脉内膜切除术。比较2组的血清FGF23、骨保护素(OPG)水平、颈动脉狭窄程度、颈动脉斑块稳定性等。另外,对ICAS组血清FGF23水平与颈动脉狭窄、颈动脉斑块的稳定性及其与炎性细胞因子超敏C反应蛋白(hs-CRP)和白细胞介素-6(IL-6)的相关性进行评估。结果:与WICAS组相比,ICAS组的FGF23水平更高,差异有统计学意义(P0.05),且FGF23水平与ICAS组不稳定斑块的稳定性显著相关(P0.001)。结论:2型糖尿病颈动脉狭窄患者血清FGF23水平与患者颈动脉狭窄斑块不稳定性明显相关。     

Pamidronate is an effective treatment for osteoporosis in patients with beta-thalassaemia

Osteoporosis in beta-thalassaemia is multifactorial; increased osteoclast function seems to play an important role in its pathogenesis. The aim of this study was to evaluate the effect of pamidronate on the osteoporosis of thalassaemia. To this effect we studied 26 patients who received this drug in doses of 30 or 60 mg i.v. once a month over 12 months. The effects were monitored by measuring bone mineral density (BMD) in association with markers of osteoclast function [soluble receptor activator of nuclear factor-kappa B ligand (sRANKL), osteoprotegerin (OPG)] and of bone remodelling [N-telopeptide of collagen type-I (NTX), tartrate-resistant acid phosphatase isoform-5b (TRACP-5b), bone-alkaline phosphatase (bALP), and osteocalcin (OC)]. Thirty healthy individuals were also studied, as controls. NTX, TRACP-5b, bALP and OC levels were significantly higher in thalassaemic patients compared with controls; in contrast, OPG levels were significantly lower, while the levels of sRANKL varied within normal limits. Administration of pamidronate was followed by a clear decrease of NTX, TRACP-5b, OPG, and OC, and by a significant increase in the BMD of the lumbar spine, which was similar in patients of both treatment groups. These data suggest that pamidronate, at a monthly dose of 30 mg, is an effective treatment for thalassaemic osteoporosis.     

重组人骨保护素抑制破骨细胞及促进羟磷灰石修复去势大鼠下颌骨缺损的研究

目的 探讨转染人骨保护素（hOPG）基因的大鼠骨髓间充质干细胞（rBMSCs）复合羟磷灰石（HA）支架对去势大鼠下颌骨缺损的修复作用。方法 将重组腺病毒pDC316-hOPG-EGFP转染rBMSCs,蛋白质印迹法和骨磨片试验分别检测hOPG的表达水平和抑制破骨细胞功能;构建骨质疏松大鼠模型,分别将HA支架、未转染rBMSCs复合HA支架、转染rBMSCs复合HA支架植入大鼠下颌骨骨缺损,6周后通过抗酒石酸酸性磷酸酶、苏木精-伊红染色检测骨缺损区破骨细胞及骨修复情况。结果 体外携载有hOPG基因的腺病毒成功转染rBMSCs,转染后的rBMSCs表达具有抑制破骨细胞活性功能的hOPG;表达hOPG的rBMSCs复合HA支架后骨缺损处破骨细胞明显减少,成骨增多。结论 转染hOPG基因的rBMSCs在体内外均具有抑制破骨细胞功能的作用,且转染rBMSCs复合HA支架可促进骨质疏松大鼠的下颌骨缺损修复。     

福建地区汉族人群骨保护素基因rs2073617T/C、rs2073618G/C多态性与急性冠脉综合征的相关性研究

目的 探讨骨保护素(OPG)基因启动子rs2073617T/C(950T/C)和第1外显子rs2073618G/C(1181G/C)位点基因多态性在福建地区汉族人群中的分布及其与急性冠脉综合征(ACS)的相关性.方法 纳入福建地区无血缘关系的汉族人720例作为研究对象,分为ACS组(n=360)和对照组(n=360),采用聚合酶链式反应－限制性片段长度多态性(PCR-RFLP)技术对OPG基因950T/C和1181G/C多态性位点进行基因型分型,同时采用DNA测序对酶切产物进行鉴定.结果 在福建地区汉族人群中,OPG基因950T/C多态性TC、TT、CC 3种基因型在ACS组和对照组中的频率分别为47.8％、26.7％、25.6％和43.3％、33.3％、23.3％;1181G/C多态性GG、GC、CC 3种基因型在ACS组和对照组中的频率分别为51.1％、40.0％、8.9％和60.0％、35.0％、5.0％.ACS组与对照组OPG基因950T/C、1181G/C基因型及等位基因频率分布进行比较均差异无统计学意义(P＞0.05).OPG基因950T/C、1181G/C在ACS组患者单支病变、双支病变及三支以上病变组之间比较差异无统计学意义(P＞0.05).结论 福建地区汉族人群OPG 950T/C、1181G/C位点基因多态性与ACS发生无相关性.     

Soluble Receptor Activator of Nuclear Factor-κB Ligand (sRANKL)/Osteoprotegerin Balance in Ageing and Age-Associated Diseases

Recently, novel members of the TNF/TNF receptor superfamily, receptor activator of nuclear factor- kappa B ligand (RANKL), its receptor RANK, and the decoy receptor osteoprotegerin (OPG), have been identified as paracrine mediators of both the immune system and bone functions. The balance of RANK/RANK-L and OPG is critical for osteoclastogenesis modulation and physiological bone remodeling. In order to evaluate whether RANKL/OPG balance is modified by ageing, we analyzed, by imunoassay, systemic levels of OPG and sRANKL in healthy elderly subjects (age range from 70 to over 90 years) and in patients affected by two age-related diseases, osteoarthritis (OA) and polymyalgia rheumatica (PMR), characterized by bone metabolism alteration and involvement of the immune system. We demonstrated that (a) plasma concentrations of OPG increased significantly with age; (b) conversely, sRANKL significantly declined in the group of subjects aged between 81 and 90 years, being similar to the young controls in the other age groups; (c) in OA and PMR, circulating OPG did not differ from plasma levels found in age-matched control groups, while sRANKL concentration was significantly increased compared to controls. Hence, in ageing, the sRANKL/OPG system appears to be modified, with prominent changes in circulating OPG levels; in OA and PMR, the sRANKL/OPG balance alteration was shown to be mainly due to the increase of plasma sRANKL concentration.     

高脂饮食诱导肥胖小鼠模型中氧化应激、炎症递质对骨代谢的影响及其可能机制

目的：探讨高脂饮食诱导肥胖小鼠模型中氧化应激和炎症递质对骨代谢的影响及其可能机制。方法：选用5周龄C57BL/6雄性小鼠16只,随机平均分为正常饮食组、高脂饮食组,分别用正常饮食和高脂饮食喂养。于实验16周末,测各组动物体质量,处死后取内脏脂肪并测量内脏脂肪/体质量比值;用ELISA法测量血清抗酒石酸酸性磷酸酶5b（TRACP-5b）、血清骨钙素（OC）、白介素-6（IL-6）和肿瘤坏死因子-α（TNF-α）;分别用硫代巴比妥酸（TBA）法和羟胺法检测胫骨骨组织丙二醛（MDA）含量、超氧化物歧化酶（SOD）活性;用骨密度仪检测右侧股骨骨密度（BMD）;分别用免疫组织化学技术和实时荧光定量PCR（RT-qPCR）技术检测骨组织骨保护素（OPG）和核因子-κB受体活化因子配体（RANKL）蛋白及mRNA的表达;HE染色光镜观察左侧股骨组织形态学改变。结果：与正常饮食组相比,高脂饮食组体质量、内脏脂肪/体质量比值、骨组织RANKL mRNA/OPG mRNA比值、血清TRACP-5b、IL-6和TNF-α水平、骨组织RANKL表达及骨组织MDA均明显升高,差异均具统计学意义（P＜0.05）;而血清OC水平、骨组织OPG表达、骨组织SOD及BMD均明显下降,差异均具统计学意义（P＜0.05）。在组织形态学上,发现高脂饮食组股骨干骺端骨小梁分布稀疏,骨小梁变细及断裂,伴骨髓腔中有大量脂肪浸润。各指标的相关分析结果显示：BMD与骨组织SOD呈正相关（r=0.627, P＜0.01）,与内脏脂肪/体质量比值（r=-0.858,P＜0.01）、骨组织MDA均呈负相关（r=-0.538,P＜0.01）;SOD与OPG mRNA呈显著正相关（r=0.637,P＜0.01）,与TNF-α（r=-0.673,P＜0.01）、IL-6（r=-0.874,P＜0.01）、RANKL mRNA（r=-0.760,P＜0.01）及RANKL/OPG比值（r=-0.768,P＜0.01）呈显著负相关;而MDA与TNF-α、IL-6、OPG mRNA、RANKL mRNA以及RANKL/OPG无显著相关性（P＞0.05）。结     

还原型谷胱甘肽对大鼠动脉钙化模型的影响与作用机制

目的：探讨还原型谷胱甘肽（glutathione GSH）在大鼠动脉钙化模型中,对肿瘤坏死因子-α（tumor necrosis factor-α,TNF-α）与骨保护素（osteoprotegerin,OPG）表达的影响及其意义。方法：将雄性SD大鼠30只随机分为正常对照组、钙化组、GSH治疗组,每组10只。钙化组和治疗组分别皮下注射维生素D3注射液50万U/kg·d-1,连续3d,制备大鼠动脉钙化模型,且治疗组在注射维生素D3前3d开始腹腔注射GSH注射液400mg/kg·d-1,直到处死大鼠。结果：治疗组大鼠Von Kossa染色黑染钙盐明显少于钙化组;治疗组TNF-α免疫组化蛋白含量与mRNA表达量明显低于钙化组（P〈0.05）;治疗组OPG免疫组化蛋白含量与mRNA表达量明显高于钙化组（P〈0.05）。结论：GSH在大鼠动脉钙化过程中,可抑制TNF-α的表达,保护大鼠动脉组织,减少OPG的消耗,抑制大鼠动脉钙化的形成。     

Role of denosumab in breast cancer

Recent advances in adjuvant treatment have improved progression-free and overall survival in patients with early stage breast cancer. However, up to one third of women will experience tumour recurrence, with bone being a common metastatic site. Current treatment options for metastases to bone comprise systemic antitumour therapy, irradiation, surgery and biphosphonates. As osteoclast activation is mediated by the receptor activator of NF-κB (RANK)/RANK ligand pathway and inhibited by osteoprotegerin (OPG), it was suggested that inhibition of this system may treat bone metastases. Recombinant Fc-OPG was evaluated in women with osteoporosis and malignant bone disease. The fully human antibody denosumab has demonstrated superior activity in reducing markers of bone turnover; therefore this drug was further developed in clinical settings. In advanced breast cancer, denosumab reduced urinary-N-telopeptide:creatinine ratio with potentially fewer side effects compared with bisphosphonates. Proof of direct antitumor activity is missing. Here we review the development and current status of denosumab in breast cancer. Data were obtained by searching the Medline database and abstracts from the American Society for Clinical Oncology (ASCO) annual meeting, European Cancer organization (ECCO), European Society for Medical Oncology (ESMO) and the San Antonio Breast Cancer Symposium, using search terms including bone metastases, bisphosphonates, breast cancer, denosumab, osteoprotegerin, RANK and skeletal-related events.     

RANKL inhibition: Clinical implications for the management of patients with multiple myeloma and solid tumors with bone metastases

Background: Receptor activator of NF-κB ligand (RANKL) binds to RANK on the surface of osteoclast precursors and enhances their differentiation, survival and fusion, activates mature osteoclasts and inhibits their apoptosis. Osteoprotegerin (OPG) is the decoy receptor of RANKL. Disruption of the RANK/RANKL/OPG axis is implicated in bone metastases. Objective/methods: A review of the role of RANKL signaling in bone development and the rationale for targeting RANKL in treatment of bone metastases and myeloma bone disease. Results/conclusions: In preclinical models of solid tumors and myeloma, RANKL inhibition reduced osteoclast numbers and subsequent bone resorption, prevented development of osteolytic lesions and decreased tumor burden. Preliminary clinical studies with denosumab, an anti-RANKL fully human monoclonal antibody, in patients with solid tumors with bone metastases and myeloma showed that targeting RANKL reduces osteoclastogenesis, bone resorption markers and skeletal-related events, supporting further study of this molecule and others with anti-RANKL activity.