Wnt signaling and osteoporosis

Major advances in understanding basic bone biology and the cellular and molecular mechanisms responsible for the development of osteoporosis, over the last 20 years, have dramatically altered the management of this disease. The purpose of this mini-review is to highlight the seminal role of Wnt signaling in bone homeostasis and disease and the emergence of novel osteoporosis therapies by targeting Wnt signaling with drugs.     

牛蒡苷元通过OPG/RANKL信号通路介导对去卵巢大鼠骨量流失的保护作用

目的探讨牛蒡苷元(AGN)对去卵巢大鼠骨强度和骨量的影响,并探索可能的机制。方法本研究中通过双侧去卵巢建立骨质疏松大鼠模型;随后随机分为假手术组(Sham)、去卵巢组(OVX)以及牛蒡苷元组(AGN),每组10只;其中牛蒡苷元组大鼠接受牛蒡苷元[40 mg/(kg.d)]治疗12周;待治疗结束后使用Micro-CT、Masson染色切片、骨代谢指标、骨生物力学检测以及蛋白质印迹观察治疗效果以及可能的机制。结果治疗12周后,与OVX组相比,Micro-CT和Masson染色切片结果显示AGN组的大鼠骨小梁数量和骨密度得到明显改善。AGN组大鼠BMD、TV/BV、Tb.N、Tb.Th和Tb.Sp较OVX组明显改善(P0.05)。治疗12周时,AGN组极限载荷和刚度较OVX组显著增加(P0.05),而AGN组骨代谢指标AKP和TRACP水平显著降低(P0.05),差异有统计学意义(P0.05)。和OVX组比较,AGN组OPG表达水平明显上调,而RANKL表达水平显著下调,差异有统计学意义(P0.05)。表明AGN组的大鼠OPG/RANKL信号通路被激活。结论牛蒡苷元可以通过OPG/RANKL信号通路介导对去卵巢大鼠骨骼的保护作用。     

基于OPG/RANKL/RANK轴观察加味阳和汤及其拆方对去卵巢骨质疏松大鼠的影响

目的观察加味阳和汤及其拆方对OPG、RANKL、RANK含量的影响,探讨其防治绝经后骨质疏松症可能的作用机制及组方配伍的合理性。方法选取48只雌性SD大鼠,加味阳和汤按君臣佐使关系拆方,将大鼠等量随机分为假手术组(SHAM)、模型组(OVX)、君药+臣药组(A组)、君药+臣药+佐药组(B组)、君药+臣药+佐药+使药组(C组)、戊酸雌二醇组(E2V)。除SHAM组外,均采用去卵巢骨质疏松大鼠模型,干预给药后(灌胃90 d),处死动物后取右侧股骨及胫骨通过双能X射线骨密度仪检测骨密度(bone mineral density,BMD)及骨矿含量(bone mineral content,BMC),取左侧股骨行HE染色观察骨显微结构,检测血清中骨代谢指标ALP、Ca~(2+)、P~(3-)、E2及血清OPG、RANKL、RANK含量。结果与SHAM组相比,OVX组大鼠股骨及胫骨BMD、BMC降低(P0.05),骨小梁变细、间隙增大、结构缺失,血清Ca~(2+)、P~(3-)、E2、OPG水平下降(P0.05),血清ALP、RANKL、RANK水平上升(P0.05);与OVX组比较,除A组大鼠股骨及胫骨BMD、BMC、血清Ca~(2+)、P~(3-)、E2、OPG、RANKL及B组P~(3-)水平无显著差异外(P0.05),各给药组大鼠股骨及胫骨BMD、BMC均显著升高(P0.05),骨小梁增多、间隙减小、结构趋向完整,血清Ca~(2+)、P~(3-)、E2、OPG水平上升(P0.05),血清ALP、RANKL、RANK水平下降(P0.05)。结论加味阳和汤及其拆方通过提高去卵巢骨质疏松大鼠BMD、BMC,降低骨代谢,改善骨显微结构从而发挥治疗作用,调节OPG/RANKL/RANK轴是可能的机制。     

OPG/RANK/RANKL系统与骨折和类风湿性关节炎

骨保护素(OPG)、细胞核因子-κB受体活化因子(RANK)和RANK配体(RANKL)是偶联成骨细胞、基质细胞和破骨细胞分化、活化及生物活性的3种主要细胞因子,其形成的局部调节体系在骨代谢中起十分重要的作用。本文简要介绍了OPG/RANK/RANKL系统及该系统在骨质疏松性骨折发生中的作用,RANKL/OPG比值与骨折的关系,OPG和RANKL对骨折愈合的作用,血清OPG或RAN-KL水平与骨折的联系,OPG基因多态性与骨折关系的研究结果。另外还介绍其在类风湿性关节炎发病机制中的作用,OPG/RANK/RANKL与滑膜组织的联系,OPG治疗的相关实验进展。     

Expression levels of the receptor activator of NF-κB ligand and osteoprotegerin and the number of gram-negative bacteria in symptomatic and asymptomatic periapical lesions

ObjectiveThe study aimed to verify the potential correlation between the detected amount of gram-negative bacteria and the radiographic sizes of the lesions in patients with symptomatic and asymptomatic apical periodontitis. Furthermore, to evaluate whether the expression of receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG) and the RANKL/OPG ratio are differentially regulated in both groups.DesignTwenty patients with periapical lesions were divided into two groups: symptomatic (SYM) n = 10 and asymptomatic (ASYM) n = 10. After periapical surgery, the lesions were collected and processed for histological examination, and immunohistochemistry. The percentage of RANKL- and OPG-immunopositive areas relative to the total area of the microscopic field was calculated. For gram staining, the number of gram-negative cells per microscopic field was assessed. The radiographs of each patient were processed and measured. The Student’s t-test and the Pearson correlation coefficient were performed.ResultsThe SYM group showed a significantly higher number of gram-negative cells (p = 0.007) when compared to the ASYM group. A higher number of gram-negative bacteria occurred more frequently in larger periapical lesions and the SYM group (p = 0.03). The expression for RANKL and OPG and the RANKL/OPG ratio were not significantly different between the groups. There was a significant positive correlation between the number of bacteria and OPG levels in the SYM group (p = 0.01).ConclusionThe number of bacteria seems to influence the symptoms and the radiographic size of a periapical lesion. Gram-negative bacteria may play an important role in OPG activity in the SYM group.     

Paclitaxel-Coated Balloon in Infrapopliteal Arteries: 12-Month Results From the BIOLUX P-II Randomized Trial (BIOTRONIK'S-First in Man study of the Passeo-18 LUX drug releasing PTA Balloon Catheter vs. the uncoated Passeo-18 PTA balloon catheter in subjects requiring revascularization of infrapopliteal arteries)

ObjectivesThe aim of BIOLUX P-II (BIOTRONIK'S–First in Man study of the Passeo-18 LUX drug releasing PTA Balloon Catheter vs. the uncoated Passeo-18 PTA balloon catheter in subjects requiring revascularization of infrapopliteal arteries) trial was to compare the safety and efficacy of a novel paclitaxel-coated drug-eluting balloon (DEB) versus an uncoated balloon (percutaneous transluminal angioplasty [PTA]) in de novo or native restenotic lesions of the infrapopliteal arteries in patients with claudication and critical limb ischemia.BackgroundDEB have shown promising results in femoropopliteal lesions, but data for infrapopliteal lesions are scarce.MethodsIn this prospective, multicenter, randomized first-in-man study, 72 patients were randomized 1:1 to either a Passeo-18 Lux DEB (Biotronik AG, Buelach, Switzerland) (n = 36) or Passeo-18 PTA (n = 36). Follow-up assessments were scheduled at 1, 6, and 12 months, with angiographic assessment at 6 months. Adverse events were adjudicated by an independent clinical events committee, and angiographic parameters were assessed by an independent core laboratory.ResultsThe primary safety endpoint (a composite of all-cause mortality, target extremity major amputation, target lesion thrombosis, and target vessel revascularization at 30 days) was 0% in the DEB group versus 8.3% in the PTA group (p = 0.239). The primary performance endpoint (patency loss at 6 months) was 17.1% in the DEB group versus 26.1% in the PTA group (p = 0.298), and major amputations of the target extremity occurred in 3.3% versus 5.6% of the patients at 12 months, respectively.ConclusionsThe Passeo-18 Lux DEB has been proven to be safe and effective in infrapopliteal lesions with comparable outcomes to PTA.     

橄榄苦苷对成骨细胞OPG/RANKL mRNA的影响

目的 通过测定橄榄苦苷对成骨细胞OPG/RANKL mRNA的表达,探讨其治疗骨质疏松症的机制。方法 运用荧光定量PCR技术（RT-PCR）检测不同浓度橄榄苦苷不同时间对成骨细胞OPG/RANKL mRNA 表达量。结果 与阴性对照组比较,RT-PCR 结果显示不同浓度的橄榄苦苷均能促进OPG mRNA的表达,并且抑制成骨细胞RANKL mRNA 的表达。结论 橄榄苦苷可能通过抑制RANKL分泌来降低破骨细胞活性,同时促进成骨细胞分泌OPG,使之与RANKL结合增多,间接作用于破骨细胞,使其活性降低,而达到治疗骨质疏松的目的。     

骨质疏松性骨折与OPG/RANK/RANKL的相关性研究

目的探讨OPG、RANK和RANKL水平的变化在骨质疏松性骨折愈合过程中的意义。方法随机选择在本院住院治疗的骨质疏松性骨折病例228例为病例组,同期因其他外伤入院者106人为对照组。采用ELISA方法检测血清OPG、RANK和RANKL的水平。比较2组OPG、RANK和RANKL的水平及OPG/RANKL比值的变化。结果骨折后病例组OPG水平上升,至伤后1周达到最高(206.64±57.22)pg/m L,显著高于对照组(P0.05),伤后2周仍维持在较高的水平。病例组RANK和RANKL在伤后第3天达最高,分别为(108.45±20.45)pg/m L和(107.45±32.67)pg/m L,均显著高于对照组(P0.05),然后逐步下降。病例组OPG/RANKL比值在伤后呈升高趋势,至伤后2周达到高峰(2.13±0.02),伤后第3天、1周、2周、4周的比值均显著高于伤后第1天(P0.05)。OPG与RANKL呈负相关关系(P0.05)。结论 OPG/RANK/RANKL系统对骨质疏松性骨折术后的愈合有较重要的作用。     

Bone formation following lenalidomide-dexamethasone combination therapy in cases of multiple myeloma refractory to high-dose chemotherapy with bortezomib and autologous peripheral blood stem cell transplantation: report of a case and review of the literature

A 41-year-old man presented with the chief complaint of right hip pain that had persisted for 6 months. F18-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) imaging showed FDG accumulation in the right pubic bone. A bone biopsy specimen from the site revealed findings suggestive of a plasma cell tumor. Bone marrow examination and serum and urine immunofixation tests showed no abnormalities. Based on these findings, the patient was diagnosed as having non-secretory multiple myeloma. FDG accumulation in the right pubic bone diminished following four cycles of weekly bortezomib and concomitant dexamethasone therapy. Tandem autologous peripheral blood stem cell transplantation was performed, followed by monthly bortezomib/dexamethasone maintenance therapy. A further FDG-PET/CT scan 9 months after the start of therapy indicated that FDG accumulation in the right pubic bone had worsened. Consequently, the therapy was switched to twice-weekly bortezomib/dexamethasone as remission re-induction therapy. New FDG uptake in the right hip bone was noted after six cycles of the therapy, and plain X-ray examination revealed osteolytic changes. The patient was then administered eight cycles of combined lenalidomide-dexamethasone therapy, which resulted in a marked decrease of the FDG accumulation in the right pubic bone and disappearance of uptake in the right hip bone. There was radiographic evidence of bone formation at these sites. This is only the second reported case in which treatment with the immunomodulatory drug lenalidomide and concomitant dexamethasone has been found to induce bone formation.     

补骨脂素干预大鼠成骨细胞骨保护素/核因子κB受体激活因子配体mRNA的表达

背景：补骨脂素有促进大鼠成骨细胞增殖与分化的作用,但其作用机制尚不明确。 目的：探讨补骨脂素对大鼠成骨细胞中骨保护素(osteoporogeterin, OPG)和核因子κB受体激活因子配体(receptor activator nuclear factor kappa b ligand, RANKL) mRNA表达的影响。 方法：取第3代生长状况良好的出生24 h内的SD大鼠成骨细胞,补骨脂素组加入1×10-7 mol/L的补骨脂素,雌二醇组加入1×10-7 mol/L的雌二醇,对照组正常培养。给药72 h后提取细胞总RNA,RT-PCR方法分析细胞OPG/RANKL mRNA的表达。 结果与结论：与对照组比较,补骨脂素组和雌二醇组OPG mRNA的表达均明显增加(P < 0.05),而RANKL mRNA的表达明显下降(P < 0.05),但补骨脂素组成骨细胞OPG mRNA的表达较雌二醇组弱(P < 0.05),VOPG/VRANKL比值也较雌二醇组小(P < 0.05)。说明补骨脂素可能通过增加成骨细胞OPG的表达,抑制RANKL的表达来抑制破骨细胞的分化和成熟,从而抑制骨吸收,达到防治骨质疏松症的目的,但作用不如雌二醇明显。