骨保护素及其配体对破骨细胞功能的调控作用

骨保护素及其配体的发现是近年来骨代谢基础研究方面的重要进展，它从分子水平阐明了破骨细胞的分化和激活过程以及骨髓基质微环境在其中所起的重要作用，作为破骨细胞的终末调控因子，骨保护素及其配体也是其它细胞因子调控骨代谢的关键作用环节，具有很高的临床应用价值。本文对此做一简要综述。     

骨保护蛋白配体与骨吸收

骨终生都在进行改建 (Ｒｅｍｏｄｅｌｉｎｇ) ,通过持续不断的骨形成和骨吸收来维持其形态与功能。这一生理过程涉及到成骨细胞 (ＯＢ)和破骨细胞 (ＯＣ)。ＯＣ来自于造血的祖细胞(ｐｒｏｇｅｎｉｔｏｒ)或造血性单核 /巨噬细胞前体 (ｐｒｅｃｕｒｓｏｒ)。这种前体细胞在骨髓微环境和成骨细胞系分泌的细胞因子的作用下 ,在骨吸收的位点分化为成熟的ＯＣ[1～ 3] 。然而从ＯＣ前体分化为成熟的ＯＣ的确切机制目前还不清楚 ,直至最近骨保护蛋白配件 (Ｏｓｔｅｏｐｒｏｔｅｇｅｒｉｎｌｉｇａｎｄ ,ＯＰＧＬ)的发现 ,才使人们对这一问题的认识…     

细胞因子、激素调节骨保护素和骨保护素配体基因表达及破骨细胞功能的研究进展

破骨细胞(Osteoclast OC)是骨吸收细胞，已知其功能与分化的调节是由成骨细胞(Osteoblast OB)完成的。发现了其调节的新的分子学机理。破骨细胞的分化依赖于成骨／基质细胞，在研究破骨细胞的过程中发现了一种由成骨／基质细胞产生的因子一骨保护素(Osteoporotegerin OPG)及骨保护素配体(Re-     

骨保护蛋白及配体与破骨细胞

破骨细胞对骨量的维持起重要作用,它的发育、成熟信号是由成骨细胞传递的。当受到骨吸收因子作用时,成骨细胞表达骨保护蛋白配体分子,与破骨前体细胞膜上的核因子κB受体激活子结合,使之分化、成熟为破骨细胞。而成骨细胞旁分泌的骨保护蛋白分子,则作为伪受体与核因子κB受体激活子竞争结合骨保护蛋白配体,从而抑制破骨细胞的生成。骨保护蛋白配体-核因子κB受体激活子-骨保护蛋白组成了破骨细胞分化的信号传导通路,对它的认识有助于临床治疗代谢性骨病。     

护骨素及配体在卵巢切除大鼠骨组织的蛋白表达和细胞定位

目的对卵巢切除和假切大鼠骨组织中护骨素（OPG）和配体（RANKL）的表达进行比较，观察不同分化阶段成骨细胞的OPG和RANKL表达变化，深入地探讨成骨细胞对破骨细胞发生的调控作用。方法9月龄雌性大鼠分为卵巢切除组和假切组，相同条件喂养3月后处死，取材制作骨病理切片，用免疫组织化学方法测定大鼠股骨OPG和RANKL的蛋白表达，用图像分析软件对蛋白表达情况半定量分析，对各组数据和组织形态进行分析比较。结果OPG和RANKL蛋白在骨组织表达相对稳定。RANKL主要表达在增殖活跃的成骨细胞和幼稚的骨细胞，OPG主要表达在成熟骨细胞和静息骨衬里细胞。与假切组相比，卵巢切除组骨组织内RANKL表达升高（P〈0．01），OPG表达降低（P〈0．05）。结论卵巢切除后骨组织中RANKL/OPG升高，破骨细胞活性增强，骨转换加快。不同发育阶段的成骨细胞对破骨细胞有不同的调节作用，幼稚阶段表现出对破骨细胞的诱导作用，而成熟阶段则表现为抑制作用。     

瘦素、骨保护素与骨代谢

骨组织时刻处于骨重建的动态变化之中，即不间断的骨形成、骨吸收贯穿生命的始终。骨重建的范围非常广泛，几乎每１０年成人骨骼完全再生一次。对于健康青年人，骨形成量与骨吸收量保持动态平衡。随着年龄增长，骨吸收日益占据优势，由此可导致骨质疏松等衰老性疾病的发生。骨重建的过程有赖于两大类细胞的活性：其一是成骨细胞，负责生成新骨（骨形成）；其二是破骨细胞，负责破坏旧骨（骨吸收）。骨代谢研究中的主要问题就是研究成骨细胞和破骨细胞分化和活性的调控机制，以期实现骨重建的动态平衡，达到预防和治疗各种代谢性骨病的目的。…     

骨保护素/骨保护素配体在大鼠创伤性股骨头坏死中的表达及意义

[目的]探讨大鼠创伤性股骨头坏死模型中OPG/OPGL蛋白表达及意义。[方法]6个月龄SD大鼠32只,雌雄不限。分组:实验组按术后1、2、4、6周4个时间点将动物随机分成4组,每组8只。对照组采用自身非实验侧股骨头做正常对照。采用圆韧带离断方法制备大鼠创伤性股骨头坏死动物模型;分别于术后1,2,4,6周处死动物。光镜下观察股骨头坏死病理形态学改变;采用CM IAS真彩色医学图像分析系统检测骨髓腔内脂肪组织与造血组织比值并计数骨组织内空骨陷窝百分率;免疫组化技术检测OPG/OPGL蛋白在股骨头坏死组织中的表达。[结果]成功的复制出大鼠股骨头坏死进展期模型,呈现出典型股骨头坏死不同时期病理改变;股骨头坏死不同时期实验组空骨陷窝百分率高于对照组(P0.05);实验组骨髓腔内脂肪组织与造血组织的面积比值高于对照组(P0.05);免疫组化检测结果显示实验组OPG蛋白在股骨头坏死不同时期表达的光密度值(OD值)均明显低于对照组(P0.05);OPGL蛋白表达高于对照组(P0.05)。[结论](1)本实验成功复制了大鼠股骨头坏死模型并在一定程度上反映了股骨头坏死的病理变化过程;(2)股骨头坏死局部OPG、OPGL表达水平与病变严重程度密切相关,OPG表达随病程的延长逐渐降低;而OPGL表达水平则相反。提示OPG的过度表达可抑制破骨细胞功能,减少骨吸收;反之则促进骨吸收。如能提高坏死局部OPG浓度可以抑制骨丢失,将有助于股骨头修复,可能为股骨头坏死的早期治疗提供新方法。     

间歇性负压培养对人BMSCs骨保护素和骨保护素配体mRNA表达水平的影响

目的 探讨间歇性负压对体外培养的人BMSCs骨保护素(osteoprotegerin,OPG)mRNA和骨保护素配体(osteoprotegerin ligand,OPGL)mRNA表达水平的影响. 方法 2008年1月由2例髋关节骨性关节炎行人工关节置换患者自愿捐赠骨髓,分离并体外培养人BMSCs,取第3代细胞.实验组进行负压诱导,设置压力为50 kPa,30 min/次,2次/d,间歇性负压干预2周;对照组于普通CO2培养箱中常规培养.倒置相差显微镜下观察细胞形态,并通过实时定量PCR检测OPG mRNA和OPGL mRNA表达水平. 结果 实验组细胞增殖速度略低于对照组,细胞逐渐由梭形向多角形转变,有数个突起,数目和形态不定,10～14d细胞融合成单层,2周后逐渐形成多个散在致密岛状结构;对照组细胞大部分为梭形.间歇性负压培养2周后,与对照组比较,实验组细胞OPG mRNA表达水平显著提高,OPGL mRNA表达水平显著降低,OPGL mRNA与OPG mRNA比率显著下降,差异均有统计学意义(P＜0.01). 结论 间歇性负压促进入BMSCsOPG表达,同时抑制其OPGL表达.     

骨保护素和骨保护素配体在假体周围骨溶解中作用的实验研究

目的通过动物实验模拟聚乙烯颗粒诱导假体周围骨溶解,观察骨溶解的组织学反应和界膜内肿瘤坏死因子-α(TNF-α)、骨保护素(OPG)和骨保护素配体(OPGL)的变化,了解上述物质在磨损颗粒诱导假体周围骨溶解中的作用机理。方法实验选用SPF级雄性SD大鼠24只,经双侧膝关节向股骨远端植入钛合金棒,术后2、4、6、8、10周分别向左侧膝关节注入聚乙烯颗粒,右侧注射生理盐水作为对照,术后12周处死动物取材,观察界膜的组织学改变、TNF-α的浓度和OPG、OPGL的mRNA含量变化。所得数据选用配剥t检验进行统计学分析。结果注射颗粒侧钛合金棒周围有明显界膜形成,界膜中的TNF-α也有明显增高。RT-PCR半定量分析发现,注射颗粒侧界膜组织中OPG mRNA水平低于对照侧,而OPGL mRNA水平则高于对照侧(P＜0．05)。结论聚乙烯颗粒可引起钛合金棒周围多种细胞参与的异物肉芽肿反应,成骨细胞/骨髓基质细胞OPGL的合成增加而OPG的合成减少,此过程可能与TNF-α的升高有关。     

血液透析患者血管钙化、骨密度与骨保护素及其配体的相互关系

目的 研究维持性血液透析（MHD）患者血管钙化、骨密度与血清骨保护素（OPG）及其配体sRANKL的相互关系。 方法 采用酶联免疫吸附法测定血清OPG、sRANKL水平；X线平片检测腹主动脉、股动脉及桡动脉部位血管钙化，计算血管钙化积分；双能X线骨密度仪测定腰椎及股骨骨密度。对各参数的相互关系进行统计分析。 结果 （1）39例MHD患者中25例（64.1%）在不同部位有不同程度的血管钙化，其中轻度钙化16例（41.0%），中重度钙化9例（23.1%）。中重度钙化者血清OPG水平、OPG/sRANKL比值显著高于轻度钙化者[（342.50±171.53） ng/L比（206.21±137.88） ng/L，t = -2.253，P = 0.025；454.65±455.63比135.31±136.81，t = 59，P = 0.035]，而sRANKL水平差异无统计学意义[（0.10±0.08） pmol/L比(0.12±0.08) pmol/L，t = 0.534，P > 0.05]。多元线性回归分析显示 OPG/sRANKL是血管钙化评分的独立影响因素。（2）与骨量正常者比较，骨量异常者血清OPG水平升高[（249.05±137.66） ng/L比（226.67±170.12） ng/L]，sRANKL水平降低[（0.11±0.08） pmol/L比（0.12±0.02） pmol/L]，OPG/sRANKL比值升高（202.31±219.24比148.08±210.10），但差异均无统计学意义。多元线性回归分析显示OPG/sRANKL是腰椎T值的独立影响因素。（3）多元线性回归分析显示血管钙化评分是腰椎和股骨T值的独立影响因素。 结论 MHD患者血管钙化程度是腰椎及股骨骨密度的独立影响因素， OPG/sRANKL可能在血管钙化和骨密度的关系中起了纽带作用。     

骨保护素在腹主动脉瘤中的表达及作用

目的：探讨骨保护素（OPG）的表达在腹主动脉瘤（AAA）形成中的作用。方法：收集20例AAA组织和6例正常腹主动脉组织,用补片法构建兔AAA动物模型（18只AAA模型动物分别于造模后7,21,35 d取材,以6只假手术兔为对照）。用免疫组化法检测OPG在人AAA组织与正常腹主动脉组织中的表达;Western blot和RT-PCR法检测上述组织以及动物模型AAA组织中OPG、基质金属蛋白酶9（MMP-9）蛋白及mRNA的表达;末端转移酶标记（TUNEL）法观察动物模型AAA组织中膜血管平滑肌细胞（VSMC）的凋亡情况。结果：免疫组化显示,人AAA组织中OPG蛋白表达量较正常腹主动脉组织增加,且随AAA直径的增大而增加,在破裂性AAA组织中表达量最高。Western blot和RT-PCR结果显示,OPG与MMP-9蛋白及mRNA的表达在人AAA组织及动物模型AAA组织组均较各自的对照组明显升高（P<0.05）,且两者的蛋白与mRNA表达水平均随瘤体直径的增加或造模时间的延长而逐渐增加。TUNEL染色显示模型组VSMC凋亡细胞较对照组明显增加,且随造模时间延长有增加趋势（P<0.05）。结论：OPG表达水平与AAA的发生发展密切相关,机制可能与其促进MMP的表达和诱导VSMC凋亡有关。

     

Osteoprotegerin and receptor activator of nuclear factor-kappaB ligand system in the early post-operative period of liver transplantation

Abstract: Background: The precise mechanism that leads to accelerated bone resorption in the early post‐transplant period remains unclear. Recent data suggest that osteoprotegerin (OPG) and its ligand receptor activator of nuclear factor‐κB ligand (RANKL) constitute a novel cytokine system that can influence the function of both bone and immune cells. The aim of our study was to assess OPG and RANKL concentrations in the early post‐operative period of liver transplantation. Methods: Serum OPG and RANKL levels were measured in 30 patients who underwent liver transplantation at 1, 7 and 14 d post‐operatively. These values were compared with 22 age‐ and sex‐matched healthy controls. Plasma sodium, creatinine, aspartate‐aminotransferase, alanine‐amino transferase, γ‐glutamyl transferase, alkaline phosphatase, bilirubin, albumin, prothrombin time, tacrolimus and cyclosporine levels were measured in each patient. Results: We found a significant increase in OPG levels in the early post‐operative period compared with the control group: day 1 (10.42 pmol/L, range 3.80–17.50 vs. 3.91 pmol/L, range 1.20–6.60; p = 0.0001), day 7 (6.90 pmol/L, range 3.00–15.30 vs. 3.91 pmol/L, range 1.20–6.60; p = 0.0001) and day 14 (5.76 pmol/L, range 2.60–10.70 vs. 3.91 pmol/L, range 1.20–6.60; p = 0.001). Similarly, serum RANKL levels were significantly higher than in the control group in this period, day 1 (0.123 pmol/L, range 0.010–0.420 vs. 0.054 pmol/L, range 0.010–0.300; p = 0.02), day 7 (0.236 pmol/L, range 0.010–0.720 vs. 0.054 pmol/L, range 0.010–0.300; p = 0.0004) and day 14 (0.137 pmol/L, range 0.010–0.520 vs. 0.054 pmol/L, range 0.010–0.300; p = 0.007). No correlation was found between OPG levels and RANKL, ischemic times, liver function tests, albumin, sodium or creatinine concentrations and tacrolimus or cyclosporine levels. Conclusions: A significant amount of OPG and RANKL is released in the early post‐transplant period of liver transplantation. This might be explained by an activation of the immune system caused by the allograft. Therefore, the RANKL/OPG system may be involved in the pathophysiological evolution of transplantation osteoporosis.     

Osteoprotegerin and its Ligand: A New Paradigm for Regulation of Osteoclastogenesis and Bone Resorption

In just 3 years, striking new advances have been made in understanding the molecular mechanisms that govern the crosstalk between osteoblasts/stromal cells and hematopoietic osteoclast precursor cells that leads to osteoclastogenesis. Led first by the discovery of osteoprotegerin (OPG), a naturally occurring protein with potent osteoclastogenesis inhibitory activity, rapid progress was made to the isolation of RANKL, a transmembrane ligand expressed on osteoblasts/stromal cells that binds to RANK, a transmembrane receptor on hematopoietic osteoclast precursor cells. The interaction of RANK and RANKL initiates a signaling and gene expression cascade that results in differentiation and maturation of osteoclast precursor cells to active osteoclasts capable of resorbing bone. OPG acts as a decoy receptor, binding to RANKL and blocking its interaction with RANK, inhibiting osteoclast development. Many of the calciotropic hormones and cytokines, including 1,25(OH)₂D₃, PTH, PGE₂ and IL-11, appear to act through a dual capacity to inhibit production of OPG and stimulate production of RANKL. Estrogen, on the other hand, appears to inhibit production of RANKL and RANKL-stimulated osteoclastogenesis. Recently, the results of the first clinical trial with OPG supported its potential as a therapeutic agent for diseases such as osteoporosis. The new understanding provided by the RANK/RANKL/OPG paradigm for both differentiation of osteoclasts and their activation has had tremendous impact on the field and opened new avenues for development of possible treatments of diseases characterized by excessive bone resorption.     

Osteoprotegerin mitigates tail suspension-induced osteopenia

Osteoprotegerin (OPG) is a recently discovered protein related to the tumor necrosis factor receptor family. It has been shown to inhibit ovariectomy (ovx)-induced resorption in rats and increase bone mineral density in young mice. Tail suspension is a procedure that inhibits bone formation in maturing rodents. This study was designed to quantify OPG's effect on cortical bone formation. Fifty-four mice were assigned to one of five groups (n = 10-11/group). A baseline control group was killed on day 0 of the 10 day study. The remaining groups were: vivarium housed (nonsuspended) control mice receiving 0.3 mg/kg per day OPG; vivarium control mice receiving daily placebo injections; tail-suspended mice receiving 0. 3 mg/kg per day OPG; and tail-suspended mice receiving placebo injections. Tetracycline was administered on days 0 and 8. OPG treatment of tail-suspended mice produced mechanical properties similar to those of placebo-treated, vivarium-housed mice: structural stiffness (8.5%, 20.7%) and elastic (13.9%, 10.1%) and maximum (4.7%, 8.1%) force were increased compared with placebo controls (vivarium, suspended groups). Percent mineral composition was highly significantly greater (p < 0.001 for all comparisons) for OPG-treated mice in the femur, tibia, and humerus, relative to placebo treatment. Matrix mass was also significantly increased in the femur, although not to the same degree as mineral mass. OPG decreased the amount of femoral endocortical resorption compared with the placebo-treated groups for both vivarium (27%) and suspended (24%) mice. Administration of OPG significantly decreased endocortical formation of the tibia. Periosteal bone formation rates were not altered by OPG. OPG-mitigated tail suspension induced osteopenia not by returning bone formation to normal levels, but by inhibiting resorption and increasing percent mineral composition.     

Osteoprotegerin and its correlations with new markers of bone formation and bone resorption in kidney transplant recipients

Osteoprotegerin (OPG), a natural decoy receptor for osteoclast differentiation factor, is produced by osteoblasts in response to PTH. OPG and its ligand RANKL constitute a complex mediator system involved in the regulation of bone resorption, probably playing an important role in the homeostasis of bone turnover. At present, little is known about the effects of OPG on uremic bone. Successful kidney transplantation reverses many abnormalities of bone metabolism; however, the improvement is often incomplete. The aim of the study was to assess OPG and RANKL concentrations in long-term kidney allograft recipients and their correlations with biochemical markers of bone resorption and formation. The present studies on 48 kidney transplant recipients and 25 healthy volunteers included concentrations of parathormone, osteocalcin, bone-specific alkaline phosphatase, serum CrossLaps, calcidiol, calcitriol, ICTP, PICP, tartrate-resistant acid phosphatase, beta2 microglobulin, IGF-1, IFGBP-1, IGFBP-3, OPG, and RANKL using commercially available kits for measurements. Among kidney transplant recipients OPG and RANKL did not differ between transplant patients and healthy volunteers, whereas other markers of bone formation and resorption were significantly higher in the former group. OPD was related to age, time on dialysis prior transplantation, urea, platelet count, CSA dose, azathioprine dose, 25(OH)D(3), TRAP, IGF-1, IGFBP-3, whereas RANKL was related to leukocyte count, CSA concentration and dose, urine DPD, and beta2 microglobulin content. In healthy volunteers OPG correlated only with CrossLaps, whereas RANKL correlated only with osteocalcin and TRAP. Correlations between OPG, IGF system components, and some markers of bone metabolism may indicate the role of OPG/RANKL system in the pathogenesis of bone metabolism disturbances following renal transplantation.     

Osteoprotegerin and uremic osteoporosis in chronic hemodialysis patients

International Urology and Nephrology - Osteoprotegerin (OPG) is a powerful inhibitor of osteoclast activity, and it plays an important role in bone metabolism. In hemodialysis (HD) patients, the...     

Osteoprotegerin and Bone Mineral Density in Hemodiafiltration Patients

A newly identified cytokine, osteoprotegerin (OPG) appears to be involved in the regulation of bone remodeling. In vitro studies suggest that OPG, a soluble member of the TNF receptor family of proteins, inhibits osteoclastogenesis by interrupting the intercellular signaling between osteoblastic stromal cells and osteoclast progenitors. As patients with chronic renal failure (CRF) often have renal osteodystrophy (ROD), we investigated the role of osteoprotegerin (OPG) in ROD, and investigated whether there was any relationship between serum OPG, intact parathyroid (PTH) (iPTH), vitamin D, and trabecular bone. Serum OPG combined with iPTH might be a useful tool in the noninvasive diagnosis of ROD, at least in cases in which the range of PTH values compromises reliable diagnosis. Thirty-six patients on maintenance hemodiafiltration (HDF) and a control group of 36 age and sex matched healthy subjects with no known metabolic bone disease were studied. The following assays were made on serum: iPTH, osteocalcin (BGP), bone alkaline phosphatase, 25(OH)-cholecalciferol, calcium, phosphate, OPG, IGF-1, estradiol, and free testosterone. Serum Ca^{+ +}, P, B-ALP, BGP, IGF-1, iPTH, and OPG levels were significantly higher in HDF patients than in controls, while DXA measurements and quantitative ultrasound (QUS) parameters were significantly lower. On grouping patients according to their mean OPG levels, we observed significantly lower serum IGF-1, vitamin D3 concentrations, and lumbar spine and hip bone mineral density in the high OPG groups. No correlation was found between OPG and bone turnover markers, whereas a negative correlation was found between serum OPG and IGF-1 levels (r= ? 0.64, p = 0.032). Serum iPTH concentrations were positively correlated with bone alkaline phosphatase (B-ALP) (r = 0.69, p = 0.038) and BGP (r = 0.92, p < 0.001). The findings made suggest that an increase in OPG levels may be a compensatory response to elevated bone loss. The low bone mineral density (BMD) levels found in the high OPG group might have been due to the significant decrease in serum IGF-1 and vitamin D3 observed. In conclusion, the findings made in the present study demonstrate that increased OPG in hemodiafiltration patients is only partly due to decreased renal clearance. As it may partly reflect a compensatory response to increased bone loss, this parameter might be helpful in the identification of patients with a marked reduction in trabecular BMD.     

Osteoprotegerin and bone mineral density in hemodiafiltration patients

A newly identified cytokine, osteoprotegerin (OPG) appears to be involved in the regulation of bone remodeling. In vitro studies suggest that OPG, a soluble member of the TNF receptor family of proteins, inhibits osteoclastogenesis by interrupting the intercellular signaling between osteoblastic stromal cells and osteoclast progenitors. As patients with chronic renal failure (CRF) often have renal osteodystrophy (ROD), we investigated the role of osteoprotegerin (OPG) in ROD, and investigated whether there was any relationship between serum OPG, intact parathyroid (PTH) (iPTH), vitamin D, and trabecular bone. Serum OPG combined with iPTH might be a useful tool in the noninvasive diagnosis of ROD, at least in cases in which the range of PTH values compromises reliable diagnosis. Thirty-six patients on maintenance hemodiafiltration (HDF) and a control group of 36 age and sex matched healthy subjects with no known metabolic bone disease were studied. The following assays were made on serum: iPTH, osteocalcin (BGP), bone alkaline phosphatase, 25(OH)-cholecalciferol, calcium, phosphate, OPG, IGF-1, estradiol, and free testosterone. Serum Ca++, P, B-ALP, BGP, IGF-1, iPTH, and OPG levels were significantly higher in HDF patients than in controls, while DXA measurements and quantitative ultrasound (QUS) parameters were significantly lower. On grouping patients according to their mean OPG levels, we observed significantly lower serum IGF-1, vitamin D3 concentrations, and lumbar spine and hip bone mineral density in the high OPG groups. No correlation was found between OPG and bone turnover markers, whereas a negative correlation was found between serum OPG and IGF-1 levels (r=-0.64, p=0.032). Serum iPTH concentrations were positively correlated with bone alkaline phosphatase (B-ALP) (r=0.69, p=0.038) and BGP (r=0.92, p<0.001). The findings made suggest that an increase in OPG levels may be a compensatory response to elevated bone loss. The low bone mineral density (BMD) levels found in the high OPG group might have been due to the significant decrease in serum IGF-1 and vitamin D3 observed. In conclusion, the findings made in the present study demonstrate that increased OPG in hemodiafiltration patients is only partly due to decreased renal clearance. As it may partly reflect a compensatory response to increased bone loss, this parameter might be helpful in the identification of patients with a marked reduction in trabecular BMD.     

Correlates of Osteoprotegerin Levels in Women and Men

Osteoprotegerin (OPG) is a potent antiresorptive molecule that binds the final effector for osteoclastogenesis, receptor activator of NF-kB ligand (RANK-L). OPG production is regulated by a number of cytokines and hormones, including sex steroids, but there are few data on age and gender effects on circulating serum OPG levels, as well as possible relationships between OPG levels and bone turnover markers or bone mineral density (BMD). Thus, we measured serum OPG levels in an age-stratified, random sample of men (n= 346 age range, 23–90 years) and women (n= 304; age range 21–93 years) and related them to sex steroid levels, bone turnover markers and BMD. Serum OPG levels increased with age in both men (R= 0.39, p<0.001) and women (R= 0.18, p<0.01). Premenopausal women had higher OPG levels than men under age 50 years (171 ± 6 pg/ml vs 134 ± 6 pg/ml, respectively, p<0.001), whereas serum OPG levels were no different in postmenopausal women compared with men = 50 years (195 ± 7 pg/ml vs 188 ± 7 pg/ml, respectively, p= 0.179). OPG levels correlated inversely with serum bioavailable testosterone levels in men = 50 years (R=–0.27, p<0.001), but no associations were present with either estrogen or testosterone levels in the women. In the men, there was a trend for OPG levels to be associated positively with bone resorption markers and inversely with BMD. Collectively, the gender difference in OPG levels suggests that sex steroids may regulate OPG production in vivo, as has been found in vitro. Moreover, OPG production may also rise with increases in bone turnover, probably as a homeostatic mechanism to limit bone loss. Further studies directly testing these hypotheses should provide additional insights into the potential role of OPG in bone loss related to aging and sex steroid deficiency. Received: 14 August 2001 / Accepted: 20 November 2001