骨桥蛋白在骨关节炎中的研究进展

骨关节炎（osteoarthritis,OA）是临床最常见的一类关节疾病,表现为关节软骨纤维化、皲裂、溃疡、脱失等进行性关节软骨破坏及关节边缘骨赘形成,并伴有不同程度的滑膜炎症。随着我国社会老龄化进程的加剧,OA发病率有逐年增高的趋势。据一项流行病学资料表明,我国40岁以上的中老年群体中,OA发病率高达46.3%,其中大约有80%的人群存在关节活动受限。     

瘦素对骨关节炎影响的研究进展

瘦素(Leptin)是脂肪因子的一种,可以在骨关节炎(OA)患者的血浆、滑液、软骨中被检测到。OA是一种最常见的关节疾病,其可以发生于全身的多个关节,以骨质和滑膜组织新陈代谢的改变、关节软骨的破坏和由此引起的关节软骨的减少为特征。瘦素是一种由肥胖(0b)基因编码的一个小的非糖基化肽激素。最开始,瘦素仅仅被认为是一种脂肪细胞源性的小分子(16KD),在下丘脑中枢水平作为一个饱感因子介导食物摄入量减少,并增加能量的消耗。现在已经发现,瘦素在机体内可发挥多种生理作用,并与OA病情有关。本文通过对瘦素与OA、软骨、肥胖、生物标志物、脂联素等之间的联系做一综述,以了解瘦素与OA之间的联系,为OA的治疗方面的进一步研究提供帮助。     

miR-21在骨关节炎中作用机制的研究进展

骨关节炎(osteoarthritis,OA)是一种好发于老年人的慢性退行性关节疾病。OA的发病机制复杂,目前尚无有效的治疗手段能够完全逆转OA的病程进展。随着老龄化社会的发展,OA患者逐渐增多,给患者家庭和社会带来的经济压力越来越大。因此,深入阐明OA的发病机制,找到有效的早期分子诊断标志物或潜在的治疗靶点意义重大。miRNA(microRNA)是近几年研究较多的一种非编码RNA。大量研究显示,miR-21在OA软骨降解和关节疼痛的发生中均发挥重要作用。因此,该文通过综述miR-21与OA的相关文献,探究lncRNA、MMPs、GDF-5、FGF和TLR7等分子在miR-21调控OA的过程中可能起到的关键作用,总结miR-21对OA的具体调控机制,以期为OA早期分子诊断标志物和潜在治疗靶点的相关研究提供方向和依据。     

低强度脉冲超声在骨关节炎研究中的应用进展

骨关节炎（osteoarthritis，OA）是一种退行性关节疾病，以软骨变性、骨硬化和慢性滑膜炎症为主要病理特征。关节置换术是目前治疗终末期OA的唯一有效方式，但其预后较差，且人工关节寿命有限。因此，OA的研究重点已经转移为疾病预防和早期治疗。低强度脉冲超声（low-intensity pulsed ultrasound，LIPUS）不仅可以促进骨折的愈合和再生，而且在软组织修复、再生和抗炎等方面也发挥重要作用，已有研究证明LIPUS在软组织再生中具有潜在作用。简要介绍了LIPUS的治疗机制及其与OA发病机制的联系，总结了目前LIPUS用于预防OA的发生、发展以及促进关节软骨组织再生的基础和临床研究进展，以期为LIPUS未来做为预防关节软骨退变的潜在治疗方法提供理论依据。     

生物磁谱分析技术在OA患者关节液磨屑颗粒评估中的初步应用

目的:随着人群的老龄化,骨关节炎(osteoarthritis,OA)已成为老年人最常见的疾病之一,严重影响老年人生活质量。而OA传统的诊断方法敏感性差,往往在确诊时,疾病已经发展到了晚期。本研究拟运用生物磁谱分析技术(bio-ferrography)来初步分析研究OA患者关节液中磨屑颗粒的参数,进而为OA的早期诊断提供依据。方法:选取符合纳入标准的2017年9月至2017年12月我科住院收治的OA患者。采集患者关节液后,运用bio-ferrography技术分离、收集关节液中的软骨磨屑颗粒和骨性磨屑颗粒,进一步通过扫描电镜(scanning electron microscope,SEM)观测磨屑颗粒的外形、数量和大小等参数。结果:随着患者OA等级的进展,软骨颗粒和骨性颗粒的数量均在增加,磨屑颗粒外形变得越来越锐利和不规则。在Kellgren-Lawrence(K-L)1级OA患者的关节液中,无骨性颗粒的存在,在K-L 1～3级OA患者的关节液中,软骨颗粒数量显著多于骨性颗粒。结论:我们初步探讨了通过bio-ferrography技术观测OA患者关节液中的磨屑颗粒,并评估了不同K-L分级OA患者关节液中磨屑颗粒的统计学特点,为今后建立以bio-ferrography技术为基础的OA早期诊断标准奠定了基础。     

促进老年退行性骨关节炎软骨内源性修复的化合物研究进展

老年退行性骨关节炎(OA)是由关节损伤、肥胖和衰老等因素引起的一种退行性疾病,最终引起关节软骨损伤,导致运动功能障碍。软骨细胞及细胞外基质是软骨组织的主要成分,它们的损伤是引起OA的根本原因。目前OA的治疗仅限于缓解症状,而随着干细胞的发现及对软骨细胞的深入认识,开发增强软骨内源性修复的药物是OA治疗的重要方向。目前研究发现,kartogenin等化合物可以促进间充质干细胞选择性的分化为软骨细胞而起到修复作用,此外,一些化合物还可以调控软骨细胞的信号通路,起到促进软骨细胞增殖、抑制软骨细胞凋亡、抑制基质金属蛋白酶活性、增加细胞外基质合成等作用,从而维持软骨细胞的数量、促进软骨基质的合成而抑制其降解。这些方法比常规通过微创刺激内源性干细胞或移植自体细胞更加安全、有效。本文就化合物对促进老年退行性骨炎软骨内源性修复的研究进行综述,为发现更多的有效化合物提供基础。     

压应力对软骨细胞的影响

骨关节炎(osteoarthritis, OA)是一种以关节软骨退变、软骨下骨重塑、骨赘形成、关节内滑膜炎症反应和广泛血管生成为特征的慢性退行性疾病。其发生受遗传、环境、代谢、生物化学和机械应力等诸多因素的共同影响,其中机械应力异常为主要诱因。在机械应力异常导致OA的过程中,软骨组织的稳定状态被打破,软骨细胞作为软骨组织中唯一的细胞也会发生相应的变化。压应力是机械应力的一种,最新研究表明,压应力可对软骨细胞的形态、代谢状态、表型、细胞活性产生影响。因此,该文综述了近年来压应力对软骨细胞影响的相关文献,为OA的机制和治疗有关研究提供理论基础。     

骨关节炎相关生物标志物

骨关节炎（osteoarthritis）是关节软骨进展的退化性疾病,并累及周围组织结构的病变,是致老年人伤残主要原因之一。目前,以临床表现和影像学诊断为主,缺乏早期检测和预后评估的有效方法。生物标志物的检查是具有前景的研究方向,在关节软骨结构改变之前,各种生物标志物代谢发生变化,其能帮助诊断和预测骨关节炎的发生发展及其预后。然而,生物标志物在临床诊断和治疗相关的应用仍需加以证实。通过广泛查阅近年有关骨关节炎相关分子生物诊断的相关文献,有助于了解生物标志物对于骨关节炎的早期诊断意义和临床应用前景。本文就关节软骨、骨和滑膜等不同组织类型相关的生物标志物进行综述。     

NF-κB信号通路在骨关节炎中的作用

骨关节炎(osteoarthritis, OA)是一种世界范围的慢性退行性关节疾病,对其发病机制的研究一直是临床研究的热点问题。核因子-κB(nuclear factor-kappa B, NF-κB)信号通路参与软骨退化、滑膜炎症、软骨下硬化等OA重要病理过程,与OA的发生和发展关系密切,或可成为OA治疗的潜在新靶点。本文就NF-κB信号通路在OA发病中的研究成果进行综述,以期更好地了解其发病机制,为OA的诊疗提供参考和依据。     

白介素-1β诱导关节软骨细胞凋亡的分子机理

骨关节炎(OA)是一种退行性病变,表现为局限性、进行性关节软骨破坏及关节边缘骨赘形成,并伴有不同程度的滑膜炎症。软骨细胞是成熟关节软骨中唯一的细胞类型,它负责细胞外基质的合成和更新,并维持基质的完整。目前OA的发病机制尚不明确,但越来越多的研究发现致炎细胞因子白细胞介素-1β(IL-1β)起着重要的作用。IL-1β能诱导软骨细胞凋亡,其机制有一氧化氮(NO)、活性氧(ROS)和丝裂原激活的蛋白激酶(MAPK)等途径。IL-1β也是OA病变进展中破坏软骨细胞代谢平衡的主要细胞因子之一。对IL-1β诱导关节软骨细胞凋亡的分子机理的深入研究,将有助于新药的研发和骨关节病的治疗。     

Suppression of aggrecanase: a novel protective mechanism of dehydroepiandrosterone in osteoarthritis?

Aggrecanase-mediated aggrecan degradation is a significant event in the early stages of osteoarthritis (OA). There has been much interest in the possible role of these aggrecanases, mainly aggrecanase-1 (ADAMTS4) and aggrecanase-2 (ADAMTS5), as therapeutic targets in OA. The deficiency of current pharmaceutical treatments is that they mainly target the symptoms of OA but do not address the fundamental mechanism behind OA which is the destruction of articular cartilage. Therefore, a treatment which would protect or regenerate cartilage on the cellular level would be desirable. Dehydroepiandrosterone (DHEA), classified as an adrenal androgen, is recently proposed to be “disease-modifying”, and has been found to counteract proinflammatory effects of catabolic cytokines, suggesting that it has a protective effect for osteoarthritic cartilage. The suppression by DHEA of some members of the MMP family in OA has been well demonstrated, however, the effect of DHEA on aggrecanases remains unknown. This article reviews recent findings with regard to aggrecanases as critical catabolic enzymes and DHEA as a therapeutic agent in OA, and further discusses the possible relationship between aggrecanase and DHEA in the progression of OA.     

Most recent developments in strategies to reduce the progression of structural changes in osteoarthritis: today and tomorrow

Osteoarthritis (OA), the most common of all arthritic conditions, is a social and financial burden to all nations. The most recent research has significantly advanced our understanding of the cause of OA and risk factors associated with it. These findings have provided useful information that has helped in the daily management of patients with OA. Some preventative measures and a number of therapeutic agents and drugs are available, which may help to reduce the progression of OA in certain patients. Moreover, the most recent progress in research has significantly enhanced our knowledge of the factors involved in the development of the disease and of the mechanisms responsible for its progression. This has allowed identification of several new therapeutic targets in a number of pathophysiological pathways. Consequently, the field is opening up to a new era in which drugs and agents that can specifically block important mechanisms responsible for the structural changes that occur in OA can be brought into development and eventually into clinical trials.     

Efficacy of a progressive walking program and glucosamine sulphate supplementation on osteoarthritic symptoms of the hip and knee: a feasibility trial

Introduction  

Management of osteoarthritis (OA) includes the use of non-pharmacological and pharmacological therapies. Although walking is commonly recommended for reducing pain and increasing physical function in people with OA, glucosamine sulphate has also been used to alleviate pain and slow the progression of OA. This study evaluated the effects of a progressive walking program and glucosamine sulphate intake on OA symptoms and physical activity participation in people with mild to moderate hip or knee OA.     

Is early osteoarthritis associated with differences in joint congruence?

Previous studies suggest that osteoarthritis (OA) is related to abnormal or excessive articular contact stress. The peak pressure resulting from an applied load is determined by many factors, among which is shape and relative position and orientation of the articulating surfaces or, referring to a more common nomenclature, joint congruence. It has been hypothesized that anatomical differences may be among the causes of OA. Individuals with less congruent joints would likely develop higher peak pressure and thus would be more exposed to the risk of OA onset. The aim of this work was to determine if the congruence of the first carpometacarpal (CMC) joint differs with the early onset of OA or with sex, as the female population has a higher incidence of OA. 59 without and 38 with early OA were CT-scanned with their dominant or arthritic hand in a neutral configuration. The proposed measure of joint congruence is both shape and size dependent. The correlation of joint congruence with pathology and sex was analyzed both before and after normalization for joint size. We found a significant correlation between joint congruence and sex due to the sex-related differences in size. The observed correlation disappeared after normalization. Although joint congruence increased with size, it did not correlate significantly with the onset of early OA. Differences in joint congruence in this population may not be a primary cause of OA onset or predisposition, at least for the CMC joint.     

Inhibition of alkaline phosphatase activity by okadaic acid, a protein phosphatase inhibitor

This paper reports on a potential physiological target of okadaic acid (OA), the toxin metabolite responsible for shellfish poisoning and, consequently, human intoxication. OA is a potent promoter of tumor activity, most likely by inhibiting protein phosphatase 1 and 2A (Adv. Cancer. Res. 61 (1993) 143). However, all of its cellular targets have not yet been characterized. The interaction of OA with alkaline phosphatase (ALP) has been investigated in view of its protein phosphatase inhibition activity. Kinetic analysis of ALP from Escherichia coli, human placental and calf intestinal ALP has shown that OA acts as a non-competitive inhibitor of ALP. The bacterial enzyme displays a higher affinity for OA (K(i) 360 nM) than the eukaryotic proteins (human placental ALP, K(i) 2.05 microM; calf intestinal ALP, K(i) 3.15 microM). The inhibition by OA suggests a putative role of ALP in the phosphorylation status, through regulation of the phosphorylation/dephosphorylation equilibrium of proteins with phosphoseryl or phosphothreonyl residues.     

Lipid metabolism and osteoarthritis: lessons from atherosclerosis

Osteoarthritis (OA) is an age-related degenerative disease comprising the main reason of handicap in the Western world. Interestingly, to date, there are neither available biomarkers for early diagnosis of the disease nor any effective therapy other than symptomatic treatment and joint replacement surgery. OA has long been associated with obesity, mainly due to mechanical overload exerted on the joints. Recent studies however, point to the direction that OA is a metabolic disease, as it also involves non-weight bearing joints. In fact, altered lipid metabolism may be the underlying cause. First, adipokines have been shown to be key regulators of OA pathogenesis. Second, epidemiological studies have shown serum cholesterol to be a risk factor for OA development. Third, lipid deposition in the joint is observed at the early stages of OA before the occurrence of histological changes. Fourth, proteomic analyses have shown an important connection between OA and lipid metabolism. Finally, recent gene expression studies reveal a deregulation of cholesterol influx and efflux and in the expression of lipid metabolism-related genes. Interestingly, lipids and lipid metabolism are known to be implicated in the development and progression of another age-related degenerative disease, atherosclerosis (ATH). Thus, although it is tempting to speculate that the osteoarthritic chondrocyte has been transformed to foam cell, it has not been proven yet. However, this may be an intriguing theory linking ATH and OA, which may open new avenues to novel therapeutic interventions for OA taking advantage of previous knowledge from ATH.     

Proteomics of osteoarthritic chondrocytes and cartilage

Osteoarthritis (OA) is characterized by irreversible destruction of the articular cartilage. OA affects more than 100 million individuals worldwide and has a major impact on patients’ quality of life. The lack of effective therapy that prevents, inhibits or reverses the progress of OA often leaves only the option of surgical interventions. Thus, identification of the factors that contribute to OA pathogenesis is necessary for better understanding of OA pathobiology and discovery of effective therapies. Recent proteomic studies have been conducted to identify pathological mediators and biomarkers of OA, which have pinpointed novel pathways involved in cartilage degeneration. This article summarizes the recent findings, compares major techniques used in OA proteomics and discusses key proteins in OA and their potential use as therapeutic targets.     

Osteoactivin, an anabolic factor that regulates osteoblast differentiation and function

Osteoactivin (OA) is a novel glycoprotein that is highly expressed during osteoblast differentiation. Using Western blot analysis, our data show that OA protein has two isoforms, one is transmembranous and the other is secreted into the conditioned medium of primary osteoblasts cultures. Fractionation of osteoblast cell compartments showed that the mature, glycosylated OA isoform of 115 kDa is found in the membranous fraction. Both OA isoforms (secreted and transmembrane) are found in the cytoplasmic fraction of osteoblasts. Overexpression of EGFP-tagged OA in osteoblasts showed that OA protein accumulates into vesicles for transportation to the cell membrane. We examined OA protein production in primary osteoblast cultures and found that OA is maximally expressed during the third week of culture (last stage of osteoblast differentiation). Glycosylation studies showed that OA isoform of 115 kDa is highly glycosylated. We also showed that retinoic acid (RA) stimulates the mannosylation of OA protein. In contrast, tunicamycin (TM) strongly inhibited N-glycans incorporation into OA protein. The functional role of the secreted OA isoform was revealed when cultures treated with anti-OA antibody, showed decreased osteoblast differentiation compared to untreated control cultures. Gain-of-function in osteoblasts using the pBABE viral system showed that OA overexpression in osteoblast stimulated their differentiation and function. The availability of a naturally occurring mutant mouse with a truncated OA protein provided further evidence that OA is an important factor for terminal osteoblast differentiation and mineralization. Using bone marrow mesenchymal cells derived from OA mutant and wild-type mice and testing their ability to differentiate into osteoblasts showed that differentiation of OA mutant osteoblasts was significantly reduced compared to wild-type osteoblasts. Collectively, our data suggest that OA acts as a positive regulator of osteoblastogenesis.     

Imaging of experimental osteoarthritis in small animal models

Normally, tissue alterations in small animal models for osteoarthritis (OA) are assessed by time-consuming and destructive histology or biochemical assays. Some high resolution imaging modalities are used for longitudinal monitoring of the OA disease process in vivo. microCT is one of these imaging modalities, which is known for superb high-resolution imaging of bone architecture alterations. A major drawback of microCT is that it has low soft-tissue contrast, which makes direct imaging of cartilage impossible. The use of microCT in combination with negatively charged radiopaque contrast agents enables imaging of cartilage degeneration. We demonstrate the possibility of microCT to image cartilage degeneration as a consequence of experimental OA, by the use contrast enhanced microCT in vivo in a rat model for OA. Furthermore, for the assessment of alterations in molecular processes involved in OA we used the recently developed technique of multi pinhole SPECT. This enables us to assess molecular processes involved in experimental OA in a rat at sub-millimeter level. Here we show quantification of subchondral bone turnover in an OA rat knee. These new techniques demonstrate the possibilities of quantitative experimental OA assessment in small animal models such as mice and rats and might enable substitution of the conventional destructive methods.     

Role of iNOS in osteoarthritis: Pathological and therapeutic aspects

Accumulating evidence suggests that inflammation has a key role in the pathogenesis of osteoarthritis (OA). Nitric oxide (NO) has been established as one of the major inflammatory mediators in OA and drives many pathological changes during the development and progression of OA. Excessive production of NO in chondrocytes promotes cartilage destruction and cellular injury. The synthesis of NO in chondrocytes is catalyzed by inducible NO synthase (iNOS), which is thereby an attractive therapeutic target for the treatment of OA. A number of direct and indirect iNOS inhibitors, bioactive compounds, and plant-derived small molecules have been shown to exhibit chondroprotective effects by suppressing the expression of iNOS. Many of these iNOS inhibitors hold promise for the development of new, disease-modifying therapies for OA; however, attempts to demonstrate their success in clinical trials are not yet successful. Many plant extracts and plant-derived small molecules have also shown promise in animal models of OA, though further studies are needed in human clinical trials to confirm their therapeutic potential. In this review, we discuss the role of iNOS in OA pathology and the effects of various iNOS inhibitors in OA.