Lysoglycerophospholipids in chronic inflammatory disorders: The PLA2/LPC and ATX/LPA axes

Lysophosphatidylcholine (LPC) and lysophosphatidic acid (LPA), the most prominent lysoglycerophospholipids, are emerging as a novel class of inflammatory lipids, joining thromboxanes, leukotrienes and prostaglandins with which they share metabolic pathways and regulatory mechanisms. Enzymes that participate in LPC and LPA metabolism, such as the phospholipase A₂ superfamily (PLA₂) and autotaxin (ATX, ENPP2), play central roles in regulating LPC and LPA levels and consequently their actions. LPC/LPA biosynthetic pathways will be briefly presented and LPC/LPA signaling properties and their possible functions in the regulation of the immune system and chronic inflammation will be reviewed. Furthermore, implications of exacerbated LPC and/or LPA signaling in the context of chronic inflammatory diseases, namely rheumatoid arthritis, multiple sclerosis, pulmonary fibrosis and hepatitis, will be discussed. This article is part of a Special Issue entitled Advances in Lysophospholipid Research.     

小分子药物BNTA通过上调Insig1缓解高胆固醇引起的骨关节炎

骨关节炎(osteoarthritis,OA)是运动系统常见的退行性疾病,具有高发病率和高致残率。骨关节炎的发病机制目前尚不明确,既往研究认为骨关节炎发病主要与创伤因素相关,而近期研究表明,以胆固醇代谢异常为主的代谢性因素同样与骨关节炎密切相关,骨关节炎的治疗以早期对症治疗和晚期手术治疗为主,尚无针对病因的特效药物。既往研究中发现,有一种具有软骨保护作用的小分子药物BNTA,其在创伤引起的骨关节炎中具有较好的疗效,但其对高胆固醇引起的骨关节炎的作用尚不明确。本研究为探究BNTA对高胆固醇引起的骨关节炎的治疗作用及其机制,采用高胆固醇饮食构建了大鼠骨关节炎模型,取膝关节石蜡切片进行组织学评估,使用油红O染色评估大鼠软骨细胞内的脂质积聚情况,使用RT-qPCR、免疫荧光和免疫组化评估软骨细胞合成代谢、分解代谢及胆固醇代谢相关基因和蛋白质的表达。结果显示,BNTA可缓解高胆固醇大鼠骨关节炎模型中的病理表现,改善OARSI评分。在大鼠软骨细胞中,BNTA可促进合成代谢相关基因col2、sox9、acan的表达,抑制分解代谢相关基因mmp13、adamts5的表达,可改善高胆固醇引起的大鼠软骨细胞脂质积聚。在大鼠软骨细胞和高胆固醇大鼠骨关节炎模型中BNTA均可上调Insig1表达。本研究证实,高胆固醇可在体内和体外实验中加重骨关节炎,可引起大鼠软骨细胞脂质积聚增加。在体内和体外实验中BNTA均能缓解高胆固醇引起的骨关节炎表型,改善软骨细胞内的异常脂质积聚,其作用可能为通过上调Insig1抑制细胞内的胆固醇生物合成,从而缓解脂质异常积聚。     

氨甲环酸联合利伐沙班对单侧全膝关节置换术后患者出血量、凝血功能以及膝关节功能的影响

目的:探讨氨甲环酸联合利伐沙班对单侧全膝关节置换术后患者出血量、凝血功能及膝关节功能的影响。方法:选取2015年1月-2016年1月在解放军425医院骨科初次行单侧全膝关节置换术的患者66例为研究对象,按照随机数字表法分为治疗组与对照组,每组各33例。治疗组患者在止血带释放前向关节腔内注射氨甲环酸,对照组患者则给予氯化钠注射液进行静脉滴注,在术后6-12h内两组患者均口服利伐沙班。记录并对比两组患者总失血量、隐性出血量、输血率、输血量,对比两组患者手术前后凝血功能指标、膝关节功能评分、膝关节活动度、疼痛视觉模拟评分(VAS),并观察两组患者并发症发生情况。结果:与对照组对比,治疗组患者的总失血量、隐性出血量、输血量及输血率均明显降低(P0.05);治疗组与对照组患者术前与术后3 d的活化部分凝血酶时间(APTT)、凝血酶原时间(PT)、纤维蛋白原(FG)水平比较均无显著差异(P0.05);术前两组患者的美国膝关节协会评分(AKSS)及膝关节活动度比较无显著差异(P0.05),术后7 d,治疗组与对照组患者的AKSS评分及膝关节活动度均较术前升高(P0.05),且治疗组患者的AKSS评分及膝关节活动度高于同时期对照组(P0.05);术前两组VAS评分比较无显著差异(P0.05),术后1 d,两组患者的VAS评分比较及与同组术前比较均无显著差异(P0.05),术后7 d,两组患者的VAS评分明显较术前及术后1 d降低(P0.05),但两组之间比较无显著差异(P0.05)。两组患者并发症总发生率对比无显著差异(P0.05)。结论:氨甲环酸联合利伐沙班可有效降低行单侧全膝关节置换术患者的出血量,加快关节功能的恢复,且不影响患者的凝血功能,值得临床推广。     

Cellular senescence and longevity of osteophyte‐derived mesenchymal stem cells compared to patient‐matched bone marrow stromal cells

This study aimed to determine the cellular aging of osteophyte‐derived mesenchymal cells (oMSCs) in comparison to patient‐matched bone marrow stromal cells (bMSCs). Extensive expansion of the cell cultures was performed and early and late passage cells (passages 4 and 9, respectively) were used to study signs of cellular aging, telomere length, telomerase activity, and cell‐cycle‐related gene expression. Our results showed that cellular aging was more prominent in bMSCs than in oMSCs, and that oMSCs had longer telomere length in late passages compared with bMSCs, although there was no significant difference in telomere lengths in the early passages in either cell type. Telomerase activity was detectable only in early passage oMSCs and not in bMSCs. In osteophyte tissues telomerase‐positive cells were found to be located perivascularly and were Stro‐1 positive. Fifteen cell‐cycle regulator genes were investigated and only three genes (APC, CCND2, and BMP2) were differentially expressed between bMSC and oMSC. Our results indicate that oMSCs retain a level of telomerase activity in vitro, which may account for the relatively greater longevity of these cells, compared with bMSCs, by preventing replicative senescence. J. Cell. Biochem. 108: 839–850, 2009. © 2009 Wiley‐Liss, Inc.     

How do rocker-soled shoes influence the knee adduction moment in people with knee osteoarthritis? An analysis of biomechanical mechanisms

The primary objective was to examine mechanisms behind previously observed changes in the knee adduction moment (KAM) with rocker-soled shoes, in participants sub-grouped according to whether they experienced an immediate decrease, or increase, in peak KAM. In subgroups where frontal plane knee ground reaction force (GRF) lever-arm emerged as a significant predictor, a secondary aim was to examine biomechanical factors that contributed to change in this parameter. Thirty individuals with symptomatic, radiographic knee osteoarthritis (OA) underwent 3D gait analysis in unstable rocker-soled shoes and non-rocker-soled shoes. Multiple regression analyses, within each subgroup, examined relationships between changes in frontal plane knee-GRF lever arm and frontal plane resultant GRF magnitude and changes in peak KAM and KAM impulse between shoe conditions. In the subgroup that decreased peak KAM with rocker-soled shoes (n = 23), change in knee-GRF lever arm and frontal plane GRF magnitude at peak KAM together were significant predictors of change in peak KAM; however, only change in mean knee-GRF lever arm significantly predicted change in KAM impulse. Decreased medial GRF magnitude, increased lateral trunk lean towards the stance limb and reduced varus/increased valgus hip-knee-ankle angle were associated with a lower knee-GRF lever arm in this group, with rocker-soled shoes. In contrast, none of the independent variables predicted changes in KAM in the subgroup who increased peak KAM with rocker-soled shoes (n = 7).     

A comparison of cartilage stress-relaxation models in unconfined compression: QLV and stretched exponential in combination with fluid flow

Cartilage exhibits nonlinear viscoelastic behaviour. Various models have been proposed to explain cartilage stress relaxation, but it is unclear whether explicit modelling of fluid flow in unconfined compression is needed. This study compared Fung's quasi-linear viscoelastic (QLV) model with a stretched-exponential model of cartilage stress relaxation and examined each of these models both alone and in combination with a fluid-flow model in unconfined compression. Cartilage explants were harvested from bovine calf patellofemoral joints and equilibrated in tissue culture for 5 days before stress-relaxation testing in unconfined compression at 5% nominal strain. The stretched exponential models fit as well as the QLV models. Furthermore, the average stretched exponential relaxation time determined by this model lies within the range of experimentally measured relaxation times for extracted proteoglycan aggregates, consistent with the hypothesis that the stretched exponential model represents polymeric mechanisms of cartilage viscoelasticity.     

Muscle fatigue and metabolic responses following three different antagonist pre-load resistance exercises

PurposePreload of antagonist muscles can be achieved by reciprocal actions (RAs) or by opposing muscle actions. However, evidence concerning neuromuscular and fatigue responses are scarce.ObjectiveTo compare the effects of different knee flexor (KF) preload methods on knee extension (KE) vastus medialis muscle fatigue, based on EMG-spectral index (FI), load range (LR), total work (TW), blood lactate (LAC) and biceps femoris co-activation (BFc) during resistance exercise.MethodsTwenty-four healthy men (23.5 ± 3.6 yrs) performed three antagonist pre-load isokinetic exercises (4 sets, 10 repetitions, 60° s^?1, 1 min rest between sets): RA (KF contraction immediately followed by KE); Superset (SS; one KF set immediately followed by one KE set); Multiple Set (MS; four KF sets followed by four KE sets).ResultsTotal work was significantly greater in RA. There was no significant decrease in LR between sets in RA. The BFc did not differ between protocols (p = 0.063). However, RA presented greater biceps femoriscoactivation. The FI was greater during SS compared to RA and MS (p < 0.05). The SS had greater LAC when compared to MS and RA (p = 0.005 and p = 0.007, respectively).ConclusionIt is suggested that the RA protocol is more neuromuscular and metabolic efficient during the performance of knee extension resistance exercise.     

Validation of method for analysing mechanics of unloader brace for medial knee osteoarthritis

Unloader braces are one non-invasive treatment of knee osteoarthritis, which primarily function by applying an external abduction moment to the joint to reduce loads in the medial compartment of the knee. We developed a novel method using brace deflection to estimate the mechanical effect of valgus braces and validated this model using strain gauge instrumentation.Three subjects performed static and walking trials, in which the moment applied by an instrumented brace was calculated using the deflection and strain methods. The deflection method predicted average brace moments of 8.7 Nm across static trials; mean error between the deflection model predictions and the gold-standard strain gauge measurements was 0.32 Nm. Mean brace moment predictions throughout gait ranged from 7.1 to 8.7 Nm using the deflection model. Maximum differences (MAE) over the gait cycle in mean and peak brace moments between methods were 1.50 Nm (0.96) and 0.60 Nm (0.42).Our proposed method enables quantification of brace abduction moments without the use of custom instrumentation. While the deflection-based method is similar to that implemented by Schmalz et al. (2010), the proposed method isolates abduction deflection from the 3 DOF angular changes that occur within the brace. Though the model should be viewed with more caution during swing (MAE = 1.16 Nm), it was shown that the accuracy is influenced by the uncertainty in angle measurement due to cluster spacing. In conclusion, the results demonstrate that the deflection-based method developed can predict comparable brace moments to those of the previously established strain method.     

Differences in proprioception,muscle force control and comfort between conventional and new-generation knee and ankle orthoses

The aim of this study was to compare muscle force control and proprioception between conventional and new-generation experimental orthoses. Sixteen healthy subjects participated in a single-blind controlled trial in which two different types of orthosis were applied to the dominant knee or ankle, while the following variables were evaluated: muscle force control (accuracy), joint position sense, kinesthesia, static balance as well as subjective outcomes. The use of experimental orthoses resulted in better force accuracy during isometric knee extensions compared to conventional orthoses (P = 0.005). Moreover, the use of experimental orthoses resulted in better force accuracy during concentric (P = 0.010) and eccentric (P = 0.014) ankle plantar flexions and better knee joint kinesthesia in the flexed position (P = 0.004) compared to conventional orthoses. Subjective comfort (P < 0.001) and preference scores were higher with experimental orthoses compared to conventional ones. In conclusion, orthosis type affected static and dynamic muscle force control, kinesthesia, and perceived comfort in healthy subjects. New-generation experimental knee and ankle orthoses may thus be recommended for prophylactic joint bracing during physical activity and to improve the compliance for orthosis use, particularly in patients who require long-term bracing.     

Plasma and synovial fluid inflammatory cytokine profiles in primary knee osteoarthritis

Objective: The objective of this study is to compare inflammatory cytokine levels in primary knee osteoarthritis (OA) patients and healthy controls.

Methods: A total of 32 knee OA patients and 14 healthy controls were enrolled. A multiplex immunoassay was utilized for 10 cytokines in plasma and synovial fluid.

Results: Plasma IL-2, IL-4, and IL-6 concentrations were significantly greater in knee OA patients than controls. Moreover, both plasma IL-4 and IL-6 were positively correlated with the radiographic severity of knee OA.

Conclusions: Plasma IL-4 and IL-6 may serve as biomarkers reflecting the severity of OA.