Interleukin-4 Cellular Gene Therapy and Osteoprotegerin Decrease Inflammation-Associated Bone Resorption in Collagen-Induced Arthritis

To evaluate the respective action of IL-4, an anti-inflammatory cytokine, and OPG, an inhibitor of bone resorption, on the inflammatory process and the associated bone resorption in collagen-induced arthritis (CIA). After CIA induction, DBA/1 mice were treated with OPG or with IL-4 DBA/1 transfected fibroblasts or both OPG + IL-4. CIA significantly improved in IL-4 groups. OPG had no effect on arthritis clinical scores but histologic scores were reduced in OPG, IL-4, and OPG + IL-4 groups vs. nontreated CIA mice. OPG increased significantly BMD and decreased by 45% D-pyridinolin levels. Moreover association of IL-4 and OPG exerted an additive effect of BMD and resorption marker (-68%). Production of IFN-gamma in the supernatants of spleen cells was reduced in IL-4 treated mice. OPG had a moderate effect on IFN-gamma, but potentiated the inhibitory effect of IL-4. OPG and IL-4 prevent bone loss in CIA-mice model and could have additive effects on IFN-gamma secretion.     

25-羟维生素D及骨保护素与慢性心力衰竭的相关性研究

目的 检测慢性心力衰竭患者25-羟维生素D 25（OH）D及骨保护素（OPG）水平,分析两者与慢性心力衰竭的相关性。方法 148例慢性心力衰竭患者依据心功能不同分为心功能Ⅱ、Ⅲ及Ⅳ级组,选取同期入院但无心力衰竭的患者42例为对照组,检测所有研究对象肝肾功能、血脂、血糖、碱性磷酸酶（ALP）、25（OH）D、OPG等,心脏超声检查左室舒张末期容积（LVDD）及左室射血分数（LVEF）,分析25（OH）D及OPG与其他指标的相关性。结果 心力衰竭患者25（OH）D水平降低,ALP及OPG水平较对照组升高,心功能Ⅳ级患者25（OH）D水平最低,与心功能Ⅱ级及对照组比较,心功能Ⅲ、Ⅳ级患者OPG水平升高,LVDD增大,LVEF降低,差异有统计学意义（P?<0.05）。相关性分析发现25（OH）D与NT-proBNP呈负相关;OPG与LVEF呈负相关,与NT-proBNP及ALP呈正相关（P?<0.05）。结论 慢性心力衰竭患者OPG高表达,25（OH）D低表达,两者与心力衰竭有一定相关性。     

Osteoprotegerin reduces the loss of periarticular bone mass in primary and secondary spongiosa but does not influence inflammation in rat antigen-induced arthritis

Objective: To assess the effect of osteoprotegerin (OPG) on joint swelling, synovial inflammation and cartilage destruction, periarticular and axial bone volume, and bone turnover in rat antigen-induced arthritis (AIA). Design: Rats were treated with OPG (3 mg/kg/day) at regular intervals from day 1 to day 20 of AIA. Disease activity was evaluated by measurement of joint swelling as well as, joint inflammation and destruction by histology. Bone volume and cellular turnover parameters of secondary spongiosa of the right tibia head and the third lumbar vertebra were evaluated by histomorphometry. Periarticular bone volume of the primary spongiosa at the right tibia head was measured by linear scanning. The findings were compared with those of PBS-treated AIA and healthy animals. Result: OPG treatment did not reduce joint swelling or histological signs of inflammation. Cartilage destruction was reduced. However, this effect did not reach statistical significance . In the secondary spongiosa OPG treatment reduced the loss of periarticular bone volume. However, the latter did not reach the level of healthy controls. OPG treatment significantly reduced parameters of bone formation and bone resorption. In the primary spongiosa, OPG-treatment led to a higher amount of mineralized tissue and a greater number of trabeculae compared to PBS-treated animals with AIA or healthy controls. In the axial skeleton, OPG treatment reduced bone formation and bone resorption parameters compared to healthy animals. This treatment had no influence on bone volume. Conclusions: In periarticular bone of AIA rats, OPG treatment reduced the loss of bone volume and decreased the bone turnover, thus preventing periarticular bone destruction. OPG treatment had no influence on inflammatory process or on cartilage destruction. Received 2 June 2005; returned for revision 26 July 2005; returned for final revision 9 August 2005; accepted by M. Parnham 24 September 2005 Presented in part at the 66. Annual Meeting of the American College of Rheumatology, New Orleans, U.S.A., October 2002, and at the 25. Annual Meeting of the American Society of Bone and Mineral Research, Minneapolis, USA, September 2003 Supported by grants from the Thuringian Ministry of Science, Research and Art (B307-01025, B378-01017), the Interdisciplinary Center for Clinical Research (IZKF) Jena, and the Deutsche Forschungsgemeinschaft (Br 1372/5-1) Osteoprotegerin was generously provided by Amgen (Thousand Oaks, CA, USA). Drs. Neumann and Oelzner contributed equally to this work.     

Associations between osteoprotegerin and femoral neck BMD in hemodialysis patients

Numerous humoral factors are involved in the development of renal osteodystrophy, causing perturbations in bone mineral density (BMD) in patients with end-stage renal disease (ESRD). The RANKL/OPG cytokine system appears to mediate the effects of many of these factors on bone turnover, contributing to the pathogenesis of renal bone disease. The aim of this study was to evaluate the clinical and biochemical correlations of BMD measurements in patients on chronic hemodialysis. Fifty-four hemodialysis patients underwent measurement of BMD at the proximal femur and the lumbar spine (L2–L4). Intact parathyroid hormone (PTH), osteoprotegerin (OPG), sRANKL, and main bone biochemical markers were also measured in serum samples of all patients. BMD of the femoral neck was negatively correlated with OPG levels (r = 0.333, P = 0.014). OPG levels were significantly different among normal, osteopenic, and osteoporotic tertiles defined according to BMD of the femoral neck. The highest OPG levels were measured in the lowest T-score (osteoporotic) tertile and were higher than in the osteopenic and normal tertiles (P < 0.05). A threshold level for OPG at 21.5 pmol/l enabled the detection of osteoporotic patients with 76.5% sensitivity and 62.2% specificity. BMD values of trabecular bone-rich sites of the skeleton such as lumbar spine (L2–L4), trochanter, and Ward’ s triangle were inversely correlated with total ALP levels (P < 0.05). Hemodialysis patients with low BMD of the femoral neck demonstrated higher OPG levels than patients with normal BMD. Those with lumbar spine (L2–L4), trochanteric, and Ward's triangle BMDs below the normal range presented higher total ALP levels. These results suggest that OPG and total ALP may be clinically useful markers in the detection of significant femoral neck and trabecular bone mineral deficit in hemodialysis patients, warranting further investigations.     

淫羊藿对激素性股骨头坏死骨组织OPG/RANKL mRNA表达的影响

目的观察糖皮质激素对大鼠股骨头骨组织中骨保护素(OPG)/核因子kappa B受体活化因子配基(RANKL)mRNA表达的影响及淫羊藿的拮抗作用,探讨淫羊藿预防激素性股骨头坏死的作用效果及其作用机制。方法健康SD大鼠48只,雌雄各半,随机分为激素组、淫羊藿组和对照组,每组16只。激素组和淫羊藿组每只给予肌肉注射醋酸泼尼松龙12.5mg/kg,2次/周,淫羊藿组同时给予淫羊藿提取液1 ml/100 g(相当于0.1 g/ml生药)灌胃,而激素组用生理盐水代替淫羊藿灌胃,1次/d;对照组用生理盐水代替激素和淫羊藿以同样方式肌注和灌胃。4周后取左侧股骨头骨组织石蜡包埋,HE染色,鉴定股骨头坏死情况;取右侧股骨头骨组织提取总RNA,采用实时定量聚合酶链反应技术检测OPG和RANKLmRNA表达水平,计算出OPG/RANKL比值。结果激素组、淫羊藿组、对照组大鼠出现股骨头坏死表现比例分别为71.43%(10/14)、26.67%(4/15)、0(0/16);激素组、淫羊藿组、对照组OPG mRNA表达分别为1.13±0.32、1.47±0.42和1.51±0.43;RANKL mRNA表达分别为2.70±1.24、1.82±0.46和1.55±0.42。激素组OPG和OPG/RANKL比值低于淫羊藿和对照组,而RANKL表达高于淫羊藿组和对照组,差异有统计学意义(P<0.05)。淫羊藿组与对照组比较,差异无统计学意义。结论淫羊藿预防激素性股骨头坏死可能与其拮抗皮质激素导致的OPG/RANKL mRNA表达异常有关。     

IL-4与骨保护素联合抑制聚乙烯磨损颗粒诱导的溶骨效应

目的运用小鼠植骨气囊模型,研究白介素-4(IL-4)与骨保护素(OPG)联合减少骨破坏吸收防治人工关节松动的效应。方法在小鼠背部注入空气形成气囊,取同源小鼠的颅骨植入气囊内。将已制成的气囊模型小鼠分成3组:对照组(气囊注入聚乙烯颗粒及生理盐水);IL-4组(气囊内注入聚乙烯颗粒及IL-4);联合组(气囊内注入聚乙烯颗粒、IL-4及OPG),3周后取囊壁和植入颅骨组织进行HE染色检测炎症反应情况及炎症细胞渗出量;取组织匀浆液应用ELISA方法检测炎性细胞因子(IL-1、TNF)浓度;抗酒石酸酸性磷酸酶染色观察破骨细胞的分化成熟情况;应用扫描电镜检测骨片吸收情况。结果(1)HE染色检测炎症细胞渗出量IL-4组、联合组明显少于对照组(P<0.05)。(2)ELISA法检测炎性细胞因子(IL-1、TNF)浓度IL-4组与联合组均明显少于对照组(P<0.05)。(3)抗酒石酸酸性磷酸酶染色阳性区域与视野面积的百分比IL-4组与联合组明显少于对照组,且联合组较IL-4组染色面积也有显著减少(P<0.05)。(4)应用扫描电镜检测骨片吸收陷窝面积与视野面积的百分比IL-4组与联合组明显少于对照组;且联合组较IL-4组的骨片吸收面积有显著减少。讨论证实IL-4不仅能明显减轻炎症情况,并且能明显减少破骨细胞的激活、骨破坏吸收情况,抑制聚乙烯磨损颗粒所致的骨吸收效应。IL-4与OPG联合应用于小鼠植骨气囊模型中,其抑制骨吸收效应更加明显。     

骨保护素在兔下颌牵张后新骨组织中的表达

目的 研究骨保护素（osteoprotegerin,OPG）在不同时期下颌骨牵张成骨过程中表达水平的变化,探讨其可能发挥的作用.方法在30只成年大耳白兔的一侧下颌骨前部行骨切开术,用牵引器延长一侧下颌骨4mm,分别于牵张完成后的第1,3,7,14,28天处死一组动物,取牵引区新生骨痂行组织学及OPG免疫组化染色.结果下颌牵引延长后牵引间隙均有新骨形成,免疫组化染色OPG主要定位于成骨细胞的胞浆中.其中以牵引结束的第1,7天的表达最强,以后逐渐下降,第28天仅有微弱表达.结论OPG可能在牵引成骨过程中特别是调控组织细胞应力信号传递的早期发挥重要作用.