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。     

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。     

滑膜细胞在骨关节炎中的研究进展

骨关节炎（osteoarthritis，OA）作为最常见的退行性关节疾病，其主要临床特点是软骨的破坏降解，进而导致关节功能丧失，严重影响患者的生活质量. 越来越多的证据表明，除了软骨组织，OA的病理改变还涉及滑膜、骨以及软骨下骨在内的多个组织系统. 其中，滑膜作为组织系统的重要组成部分，其病变在OA中的作用日益突出. 滑膜细胞分为A型滑膜巨噬细胞和B型滑膜成纤维细胞，在OA中发挥着不同但又密切联系的作用. 本文综述不同类型滑膜细胞在OA中的作用，为进一步认识OA发病机制及治疗方法提供科学的理论依据.     

致炎细胞因子在骨性关节炎病理生理中的作用

骨性关节炎(OA)是一种退行性病变,表现为关节软骨破坏,关节边缘骨赘形成,并伴有不同程度滑膜炎症,其病因学和发病机制还不是十分清楚。研究表明致炎细胞因子在骨性关节炎病发病的病理生理过程中起着重要的作用。本综述讨论目前关于致炎细胞因子在OA病理生理中的作用机制以及抗致炎细胞因子在治疗OA中的新进展。     

骨关节炎相关细胞因子及蛋白的研究进展

骨关节炎（osteoarthritis,OA）是人体中轴关节及外周运动关节最常见的退行性疾病,该病的临床症状表现为疼痛、关节僵硬和关节活动受限,罹患该病非常痛苦,严重影响生活质量,是成年人疼痛、运动功能障碍和致残的常见原因之一。OA是临床上常见的骨关节疾病,老年人多发,是老年人丧失劳动力的重要原因,对社会经济影响很大。国内外对OA的发病机制做了大量的研究,但其确切的病因及病理机制尚未完全阐明。目前,OA没有特效治愈方法,治疗目标局限于使用止痛药来缓解疼痛,并最终行人工关节置换手术。即使人工关节置换手术成功,人造关节寿命也是有限的,其他严重问题还有植入物的松动和失败等。因此,对该病病因、病理机制的探索成为目前的热点和焦点,也是解决OA这个问题的关键。本文就近年来研究较热门的骨关节炎相关细胞因子及蛋白做一综述。     

白细胞介素-2最新研究进展

白细胞介素-2作为一种细胞生长因子,不仅能诱导T细胞增殖和分化,而且能增强机体的免疫监视功能,在细胞调节中发挥着不可替代的作用。了解白细胞介素的结构、功能及作用机制,更有利于对白细胞性质的研究及应用。重组白细胞介素-2目前在抗肿瘤治疗应用中发挥重要作用,此外关于白细胞介素-2与抗感染、自身免疫疾病等方面的研究也相当广泛。就白细胞介素-2在国内外研究进展进行综述。     

治疗类风湿关节炎的研究进展

生物制剂在类风湿性关节炎治疗中的应用虽然不到二十年的时间,却取得了较大的效果,并且逐渐成为一种常规的疗法.根据类风湿关节炎发病机制中的不同作用环节,人们开发出了分别针对细胞因子和淋巴细胞的各种各样的生物制剂.本文介绍生物制剂主要作用的对象有肿瘤坏死因子、白细胞介素、淋巴细胞等,他们是类风湿性关节炎各个发病环节中的重要部分.这些生物制剂对于顽固性RA患者有很好的治疗作用,且有较好的安全性.     

复方黄柏液联合派瑞松治疗脂溢性皮炎的临床研究

目的:探讨复方黄柏液联合派瑞松治疗脂溢性皮炎的临床疗效及其对患者血清白细胞介素-8(IL-8)、白细胞介素-2(IL-2)及白细胞介素-10(IL-10)水平的影响。方法:选择于我院就诊的脂溢性皮炎患者120例,随机分为实验组和对照组,每组各60例。对照组患者采用派瑞松进行治疗,实验组患者采用复方黄柏液联合派瑞松进行治疗。比较治疗前后两组患者血清白细胞介素-2(IL-2)、白细胞介素-8(IL-8)、白细胞介素-10(IL-10)水平,并比较治疗后脂溢性皮炎复发率、复发间隔天数及临床治疗效果。结果:治疗后,与对照组相比,实验组患者血清IL-10水平及复发率明显较低(P0.05);血清IL-2、IL-8水平及临床总有效率较高(P0.05);痊愈至复发的间隔时间较长(P0.05)。结论:复方黄柏液联合派瑞松能够明显提高脂溢性皮炎的临床治疗效果,降低临床复发率,可能与缓解机体的炎症反应有关。     

外泌体对骨关节炎的影响

骨关节炎(osteoarthritis,OA)的发病主要与关节内生物力学改变、关节软骨磨损以及合成分解代谢紊乱有关。关节内代谢平衡主要依靠一系列细胞内分子(激酶级联、自噬、转录因子和表观遗传机制等)和细胞外刺激(细胞因子、激素和机械应力等)的调节。外泌体作为一种分泌到细胞外发挥作用的囊泡状物质,广泛参与细胞间信息交流。外泌体能够通过内部含有的m RNA、miRNA和蛋白质等生物活性分子对骨关节炎病程发展产生一定的影响,且不同干细胞来源的外泌体对OA的作用存在一定的差异。该文通过综述近年来有关外泌体对骨关节炎疗效研究的文献报道,为后续进一步探究外泌体对OA作用机制及其相关研究提供理论参考和依据。     

白细胞介素的分子生物学研究

现代生化技术和分子克隆技术使白细胞介素(Interleukine,IL)的研究进入黄金时代。已经阐明六种IL的生物学功能和生化特性并建立了基因无性繁殖系。这些工作对于从理论上寻求免疫活性细胞相互调控的分子机制和探索自身免疫性疾病、免疫缺陷病和恶性肿瘤等难症的发病机理具有极大促进作用。基因重组白细胞介素(rIL)将成为前程无量的临床治疗用生物制剂。     

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。     

Loss of sclerostin promotes osteoarthritis in mice via β-catenin-dependent and -independent Wnt pathways

IntroductionSclerostin is a Wnt inhibitor produced by osteocytes that regulates bone formation. Because bone tissue contributes to the development of osteoarthritis (OA), we investigated the role of sclerostin in bone and cartilage in a joint instability model in mice.MethodsTen-week-old SOST-knockout (SOST-KO) and wild-type (WT) mice underwent destabilization of the medial meniscus (DMM). We measured bone volume at the medial femoral condyle and osteophyte volume and determined the OA score and expression of matrix proteins. Primary murine chondrocytes were cultured with Wnt3a and sclerostin to assess the expression of matrix proteins, proteoglycan release and glycosaminoglycan accumulation.ResultsSclerostin was expressed in calcified cartilage of WT mice with OA. In SOST-KO mice, cartilage was preserved despite high bone volume. However, SOST-KO mice with DMM had a high OA score, with increased expression of aggrecanases and type X collagen. Moreover, SOST-KO mice with OA showed disrupted anabolic–catabolic balance and cartilage damage. In primary chondrocytes, sclerostin addition abolished Wnt3a-increased expression of a disintegrin and metalloproteinase with thrombospondin motifs, matrix metalloproteinases and type X collagen by inhibiting the canonical Wnt pathway. Moreover, sclerostin inhibited Wnt-phosphorylated c-Jun N-terminal kinase (JNK) and rescued the expression of anabolic genes. Furthermore, sclerostin treatment inhibited both Wnt canonical and non-canonical JNK pathways in chondrocytes, thus preserving metabolism.ConclusionSclerostin may play an important role in maintaining cartilage integrity in OA.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-015-0540-6) contains supplementary material, which is available to authorized users.     

Vitamin D attenuates inflammation,fatty infiltration,and cartilage loss in the knee of hyperlipidemic microswine

BackgroundOsteoarthritis (OA) of the knee joint is a degenerative process resulting in cartilage loss. Recent evidence suggests that OA is not merely a disease of cartilage but a disease of the entire knee joint and that inflammation may play an important role. OA has been associated with vitamin D deficiency. Vitamin D as an immunomodulator and anti-inflammatory agent may attenuate inflammation in the knee. The aim of this study was to assess the anti-inflammatory effect of vitamin D on inflammation in the knee.MethodsThis study was conducted with 13 microswine on a high cholesterol diet categorized into three groups of vitamin D-deficient, vitamin D-sufficient, and vitamin D supplementation. After 1 year, microswine were killed, and their knee joint tissues were harvested. Histological and immunofluorescence studies were carried out on the tissue specimens to evaluate the effect of vitamin D status.ResultsHistological and immunofluorescence studies of the knee joint tissues showed (1) increased inflammation in the knee joint tissues, (2) fatty infiltration in quadriceps muscle, patellar tendon, and collateral ligaments, and (3) chondrocyte clustering in the vitamin D-deficient and vitamin D-sufficient groups compared with the vitamin D supplementation group. Architectural distortion of the quadriceps muscle, patellar tendon, and collateral ligaments was also seen in the areas of inflammatory foci and fatty infiltration in the vitamin D-deficient group.ConclusionsDecreased inflammation and fatty infiltration in the vitamin D supplementation group suggest the potential role of vitamin D in attenuating inflammation and fatty infiltration as well as in protecting the architecture of the tissue in the knee joint.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-016-1099-6) contains supplementary material, which is available to authorized users.     

Progress in the use of mesenchymal stromal cells for osteoarthritis treatment

Literature review of MSCs in the treatment of osteoarthritis in the past five yearsOsteoarthritis (OA) is one of the most common chronic joint diseases, with prominent symptoms caused by many factors. However, current medical interventions for OA have resulted in poor clinical outcomes, demonstrating that there are huge unmet medical needs in this area. Cell therapy has opened new avenues of OA treatment. Different sources of mesenchymal stromal cells (MSCs) may have different phenotypes and cellular functions. Pre-clinical and clinical studies have demonstrated the feasibility, safety and efficacy of MSC therapy. Mitogen-activated protein kinase, Wnt and Notch signaling pathways are involved in the chondrogenesis of MSC-mediated treatments. MSCs may also exert effective immunoregulatory and paracrine effects to stimulate tissue repair. Therapy with extracellular vesicles containing cytokines, which are secreted by MSCs, might be a potential treatment for OA.     

Detecting cathepsin activity in human osteoarthritis via activity-based probes

IntroductionLysosomal cathepsins have been reported to contribute to Osteoarthritis (OA) pathophysiology due to their increase in pro-inflammatory conditions. Given the causal role of cathepsins in OA, monitoring their specific activity could provide means for assessing OA severity. To this end, we herein sought to assess a cathepsin activity-based probe (ABP), GB123, in vitro and in vivo.MethodsProtein levels and activity of cathepsins B and S were monitored by immunoblot analysis and GB123 labeling in cultured primary chondrocytes and conditioned media, following stimuli with tumor necrosis factor alpha (TNFα) and/or Interleukin 1 beta (IL-1β). Similarly, cathepsin activity was examined in sections of intact cartilage (IC) and degraded cartilage (DC) regions of OA. Finally, synovial fluid (SF) and serum from donors with no signs of diseases, early OA, late OA and rheumatoid arthritis (RA) patients were analyzed with GB123 to detect distinct activity levels of cathepsin B and S.ResultsCathepsin activity in cell lysates, conditioned media explants and DC sections showed enhanced enzymatic activity of cathepsins B and S. Further histological analysis revealed that cathepsin activity was found higher in superficial zones of DC than in IC. Examining serum and SF revealed that cathepsin B is significantly elevated with OA severity in serum and SF, yet levels of cathepsin S are more correlated with synovitis and RA.ConclusionsBased on our data, cathepsin activity monitored by ABPs correlated well with OA severity and joint inflammation, directing towards a novel etiological target for OA, which possesses significant translational potential in developing means for non-invasive detection of early signs of OA.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-015-0586-5) contains supplementary material, which is available to authorized users.     

JNK pathway in osteoarthritis: pathological and therapeutic aspects

Context: Osteoarthritis (OA) is a common chronic degenerative joint disease resulting in physical disability and reduced quality of life. Different biochemical signaling pathways are involved in the progression of OA, including the c-Jun NH2-terminal kinase (JNK) signal transduction pathway.

Objective: In this study, we have reviewed the recent updates on the association of JNK pathway with OA.

Methods: In this review, we have explored the databases like PubMed, Google Scholar, Medline, Scopus, etc., and collected the most relevant papers of JNK signaling pathway involved in the pathogenesis and therapeutics of OA

Results: JNK has been shown by scientific studies to be activated (phosphorylated) in OA that can play a key role in the cartilage destruction. Activation of JNK causes the phosphorylation of c-Jun that causes decreased proteoglycan synthesis and enhanced production of matrix metalloproteinase 13 (MMP-13). Overproduction of MMP-13 by chondrocytes plays a central role in cartilage degeneration in OA. Thus, targeting JNK pathway might be a promising therapeutic application for the prevention and treatment of OA. A number of JNK-inhibitors have been used in vitro and in vivo studies; however, not yet been translated into human use.

Conclusions: This review study indicates that JNK pathway plays an important role in development and progression of OA, and targeting the JNK pathway might be a potential approach for the treatment of OA in future.     

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。     

Prognostic factors for progression of clinical osteoarthritis of the knee: a systematic review of observational studies

IntroductionWe performed a systematic review of prognostic factors for the progression of symptomatic knee osteoarthritis (OA), defined as increase in pain, decline in physical function or total joint replacement.MethodWe searched for available observational studies up to January 2015 in Medline and Embase according to a specified search strategy. Studies that fulfilled our initial inclusion criteria were assessed for methodological quality. Data were extracted and the results were pooled, or if necessary summarized according to a best evidence synthesis.ResultsOf 1,392 articles identified, 30 met the inclusion criteria and 38 determinants were investigated. Pooling was not possible due to large heterogeneity between studies. The best evidence synthesis showed strong evidence that age, ethnicity, body mass index, co-morbidity count, magnetic resonance imaging (MRI)-detected infrapatellar synovitis, joint effusion and baseline OA severity (both radiographic and clinical) are associated with clinical knee OA progression. There was moderate evidence showing that education level, vitality, pain-coping subscale resting, MRI-detected medial femorotibial cartilage loss and general bone marrow lesions are associated with clinical knee OA progression. However, evidence for the majority of determinants was limited (including knee range of motion or markers) or conflicting (including age, gender and joint line tenderness).ConclusionStrong evidence was found for multiple prognostic factors for progression of clinical knee OA. A large variety in definitions of clinical knee OA (progression) remains, which makes it impossible to summarize the evidence through meta-analyses. More research on prognostic factors for knee OA is needed using symptom progression as an outcome measure. Remarkably, only few studies have been performed using pain progression as an outcome measure. The pathophysiology of radiographic factors and their relation with symptoms should be further explored.     

Pharmacological treatment with diacerein combined with mechanical stimulation affects the expression of growth factors in human chondrocytes

BackgroundOsteoarthritis (OA) as the main chronic joint disease arises from a disturbed balance between anabolic and catabolic processes leading to destructions of articular cartilage of the joints. While mechanical stress can be disastrous for the metabolism of chondrocytes, mechanical stimulation at the physiological level is known to improve cell function. The disease modifying OA drug (DMOAD) diacerein functions as a slowly-acting drug in OA by exhibiting anti-inflammatory, anti-catabolic, and pro-anabolic properties on cartilage. Combining these two treatment options revealed positive effects on OA-chondrocytes.MethodsCells were grown on flexible silicone membranes and mechanically stimulated by cyclic tensile loading. After seven days in the presence or absence of diacerein, inflammation markers and growth factors were analyzed using quantitative real-time PCR and enzyme linked immune assays. The influence of conditioned medium was tested on cell proliferation and cell migration.ResultsTensile strain and diacerein treatment reduced interleukin-6 (IL-6) expression, whereas cyclooxygenase-2 (COX2) expression was increased only by mechanical stimulation. The basic fibroblast growth factor (bFGF) was down regulated by the combined treatment modalities, whereas prostaglandin E2 (PGE2) synthesis was reduced only under OA conditions. The expression of platelet-derived growth factor (PDGF) and vascular endothelial growth factor A (VEGF-A) was down-regulated by both.ConclusionsFrom our study we conclude that moderate mechanical stimulation appears beneficial for the fate of the cell and improves the pharmacological effect of diacerein based on cross-talks between different initiated pathways.General significanceCombining two different treatment options broadens the perspective to treat OA and improves chondrocytes metabolism.