MicroRNA基因调控在膝骨关节炎发生发展作用中的研究进展

MicroRNA(miRMA)是一种从哺乳动物细胞内发现的非编码小分子RNA,在基因的表达调控中起到了非常重要的作用,特别是转录后调节机制方面。近年来,miRNA在疾病发生发展过程中的作用已经成为研究热点。膝骨关节炎是一种常见的老年性疾病,其病因及发病机制至今尚未完全明确,目前细胞因子通过调节炎症反应,成骨破骨细胞增值、凋零、分化在膝骨关节炎发病机制中的作用越来越受到关注。而最新的研究表明,炎性介质、成骨破骨细胞增殖分化及各种细胞因子的转录表达都与miRNA有着密切的关联,这提示miRNA在膝骨关节炎的发生发展中起重要作用。由此可以想到,通过改变相关miRNA的表达可能会从更高的调节水平改变膝骨关节炎的表达,从而起到了治疗的目的。本文正是基于MicroRNA基因调控,探讨膝骨关节炎的发病机制,为临床提供更多的治疗思路。     

膝骨性关节炎合并骨质疏松症调节机制的研究进展

膝骨性关节炎和骨质疏松症都是与年龄增长相关的骨与关节退行性疾病,两者在发病机制、病理变化、调节机制、临床治疗等方面存在着诸多的共同点,在膝骨关节炎和骨质疏松症的进程中通过复杂的调节机制维持骨代谢平衡、减轻炎症、保护关节软骨、稳定膝关节,进而延缓膝关节的退变;虽然两者间复杂的调节机制已有研究,但是仍然不完善。本研究从炎症、生物力学、激素与骨代谢、遗传、蛋白等方面对膝骨性关节炎并骨质疏松症的调节机制进行了综述,以期为临床防治该病提供新的思路和理论依据。     

白细胞介素-17在风湿病中的作用及中医药干预研究进展

白细胞介素-17(IL-17)是近年来发现的一种重要的细胞因子,在风湿病、癌症及炎性疾病的发生、发展中具有重要的作用。关于IL-17和辅助性T细胞（Th17）的作用机制是免疫学关注的重点,尤其是在2015年首个靶向IL-17抑制剂司库奇尤单抗获批用于银屑病治疗之后,关于IL-17的深入研究、靶向IL-17抑制剂的临床应用及临床潜在适应症更是研究的热点。综述IL-17与风湿病的关系及中医药干预研究进展,发现中医药可通过抑制炎症因子、维持免疫细胞平衡、调节IL-17细胞和IL-23/IL-17轴平衡,从而干预IL-17及相关因子表达,进而改善风湿病患者的症状,可为风湿病的治疗及中医药干预提供新的思路。     

白细胞介素-37的免疫效应及其意义

白细胞介素-37（IL-37）属于白细胞介素1家族（IL-1F）,新近研究发现,其在炎症的发展和调节中扮演重要角色[1]。Kumar等[2]在2000年首次发现了这个 IL-1家族的新成员；2001年,Dunn 等[3]将其定义为 IL-1家族第7因子（IL-1 F7）。此后研究显示,IL-1 F7可与 IL-18受体α链和 IL-18结合蛋白（IL-18 binding protein,IL-18BP）结合,从而产生有限的抗炎效应[4-5]。成熟的 IL-1F7能够转移进入细胞核并与Smad3结合形成复合物,通过调节基因转录抑制促炎细胞因子的生成[6]。正是基于 IL-1 F7独特的免疫抑制特性,近期将其命名为 IL-37[7]。本文对 IL-37的分类和分布、作用机制、生物学效应、相关疾病意义等方面研究动态进行综述。     

膝骨关节炎炎性因子及信号通路的研究进展

膝骨关节炎是关节炎中最常见的类型,以关节软骨变形、退化、患者感到关节疼痛活动不适为表现,影响了患者的生活质量,加重了社会的医疗负担。膝骨关节炎的发病机制十分复杂,本文对膝骨关节炎涉及的炎性因子及信号通路进行综述,发现所涉及的炎性因子大多为白细胞介素类,如IL-1β、IL-6、IL-15、IL-17、IL-18等,以及肿瘤坏死因子类,如TNF-α。这些炎性因子通过激活相应通路以及促进炎性介质释放,从而加重膝骨关节炎。膝骨关节炎涉及的炎性信号通路纷繁复杂,Notch通路、Wnt通路、SDF-1/CXCR4通路、TLRs通路、MAPKs通路、Hippo-YAP通路、OPG-RANK-RANKL通路和TGF-β通路等均可参与膝骨关节炎的调节,其中与炎性机制相关的通路以MAPKs通路、TLRs通路为主。不同的信号通路均可引起膝关节软骨的破坏,促进软骨细胞凋亡,最终导致膝关节内环境稳态的进一步失衡。同时,信号通路的激活又能促进炎性因子的释放,故在炎性因子与信号通路级联反应作用下,膝骨关节炎不断加重。     

microRNA-223调控NF-κB信号通路干预骨关节炎的研究进展

骨关节炎作为老年疾病中的一种退行性疾病,对它的研究一直被认为是重点和难点,而如何延缓骨关节炎的进展成为最主要的问题。microRNA-223作为骨科疾病的关键调节因子,其表达的变化对延缓骨关节炎的进展具有调节作用。由于核因子-κB(nuclear factor-kappa B, NF-κB)信号通路作为经典的与骨关节炎相关的信号通路,对骨关节炎的发生及发展可进行调节,且研究发现microRNA-223可以通过对NF-κB信号通路的调控,延缓骨关节炎的进展。本文就microRNA-223对NF-κB信号通路在骨关节炎发病中的作用进行综述,以期为microRNA-223在治疗骨关节炎方面提供一些新的治疗思想。     

JAK3抑制剂托法替尼治疗类风湿关节炎研究进展

类风湿关节炎(RA)作为一种自身免疫性疾病,其发病机制和治疗措施始终为研究热点.近年许多研究试图从细胞内信号转导通路寻找治疗契机并已取得一定进展.研究发现,JAK/STAT信号转导通路在RA发病中起着重要作用.新型口服药物托法替尼(tofacitinib)能够选择性抑制细胞内JAK3信号转导通路,抑制CD4+T细胞增殖,进一步阻断白细胞介素(IL)-17、干扰素-γ、IL-6、IL-8等细胞因子合成和分泌,抑制RA患者滑膜成纤维细胞增殖及已损伤的软骨组织进一步破坏.Ⅱ期、Ⅲ期临床试验结果显示,托法替尼能够明显减少RA患者临床症状和体征,尚未发现明显的毒性不良反应.该文就JAK/STAT信号转导通路及其对RA作用机制、托法替尼治疗机制和临床研究现状作一综述.     

IL-1在骨关节炎发病机制中的作用及相关基因治疗

IL-1在骨关节炎发病机制中具有重要作用,而IL-1β在整个致炎过程中处于核心地位.IL-1β通过细胞表面的IL-1RⅠ来完成细胞内的信号传递,IL-1RⅡ则没有信号传递作用.IL-1与IL-1RⅠ结合后,在细胞内主要通过MAPK途径和NF-κB途径来影响细胞核内的基因转录和转录后修饰,从而使软骨细胞合成PGE2、NO、细胞因子、MMP、蛋白聚糖酶,引起关节炎症和软骨基质降解.IL-1活性主要受IL-1R和IL-1Ra的调节,IL-1Ra可竞争性结合IL-1RⅠ,阻止IL-1通过IL-1RⅠ进行的信号传递.已有研究将sIL-1RII和IL-1Ra作为目的基因,通过调控IL-1活性来达到保护软骨和治疗骨关节炎的作用.联合基因转基因治疗与单个基因转录相比,在抑制基质降解、促进基质合成方面可能有更好的作用.     

甲状旁腺激素及其受体与骨关节炎的关系研究进展

骨关节炎是一种以关节软骨破坏、软骨下骨的硬化和滑膜反应为特征的慢性疾病.目前发现甲状旁腺激素(Parathyroid hormone,PTH)能够抑制骨关节炎患者软骨细胞终末期成熟分化,有明显软骨保护、延缓骨关节炎进展的作用.通过研究PTH、PTHR与骨关节炎的关系,对骨关节炎治疗及预后将起到重要的指导作用.     

破骨细胞在类风湿关节炎致骨破坏病理变化中的作用及其调控

类风湿关节炎(RA)是一种严重的慢性自身免疫性炎症性疾病,关节软骨及骨破坏是RA的主要病理变化,是患者致残的主要原因。破骨细胞(OC)在RA骨破坏的病理过程中起关键作用,其调控依赖于OC形成、分化及活化的过程。巨噬细胞、滑膜成纤维细胞等是OC形成的主要来源,促炎性细胞因子在这个过程中起重要作用。主要的是RANK/RANKL/OPG、MCSF、TNF、IL-1和IL-17,这些细胞因子通过不同的信号传导通路促进OC的成熟及分化;此外,有些细胞因子对OC的分化及骨吸收作用产生负性调控作用,如IL-27、IL-4、IL-10、IFN-γ,大部分细胞因子通过RANK/RANKL/OPG系统,直接或间接作用于OC,两者之间的平衡决定骨破坏的结局。这些细胞因子通过多条信号传导通路介导OC对骨破坏的调控作用,其中NFATc1是关键的调节因子,如RANKL通过NF-κB/AP-1/c-fos和钙离子信号通路两条信号通路,调节NFATc1的活化,促进OC分化;TNF通过激活NF-κB,JNK和p38通路,活化NFATc1促进OC形成,还包括MAPK、STAT等通路。深入了解OC的病理过程及骨形成和骨吸收机制,监测及干扰促进OC活化的细胞因子,为早期RA的治疗提供新的靶点。     

Role for innate immunity in rheumatoid arthritis

Innate immunity is the first line of defense against pathogenic microorganisms (bacteria, viruses, fungi, and parasites). After a long period of neglect, innate immunity is again recognized as a key mechanism not only in preventing invasion of the body by microorganisms, but also in contributing to the pathogenesis of autoimmune and inflammatory diseases by deviating the immune response or promoting the emergence of a regulatory response. The many factors involved in innate immunity often act in parallel or in alternation to generate adaptive immune responses. Innate immune responses are specific for groups of molecules or macromolecules found in components of microorganisms, usually the cell wall. The cellular and protein effectors of innate immunity are found in the rheumatoid synovium, and an increasing body of evidence indicates that they are directly involved in joint inflammation and in destruction of the joint cartilage and bone. In addition, they may have regulatory effects on inflammation and immunity. Whether innate immune mechanisms are causes or consequences of inflammation, and whether they regulate or amplify adaptive immune responses, they constitute a target of choice for new antiinflammatory and immunoregulating treatment strategies.     

The role of inflammatory cytokines in diabetic nephropathy

Cytokines act as pleiotropic polypeptides regulating inflammatory and immune responses through actions on cells. They provide important signals in the pathophysiology of a range of diseases, including diabetes mellitus. Chronic low-grade inflammation and activation of the innate immune system are closely involved in the pathogenesis of diabetes and its microvascular complications. Inflammatory cytokines, mainly IL-1, IL-6, and IL-18, as well as TNF-alpha, are involved in the development and progression of diabetic nephropathy. In this context, cytokine genetics is of special interest to combinatorial polymorphisms among cytokine genes, their functional variations, and general susceptibility to diabetic nephropathy. Finally, the recognition of these molecules as significant pathogenic mediators in diabetic nephropathy leaves open the possibility of new potential therapeutic targets.     

肿瘤坏死因子受体相关因子6与骨代谢的研究进展

TRAF6是肿瘤坏死因子受体相关因子家族(TRAFs)中既可与肿瘤坏死因子受体(TNFR)超家族结合,又可与白细胞介素-1受体/Toll样受体(IL-1R/TLR)超家族相互作用来传递细胞外信号的一种细胞内接头蛋白,在炎症反应、免疫应答、骨代谢中发挥着重要作用。本文现就TRAF6在骨代谢中的研究进展作一综述。     

Complement takes its Toll: an inflammatory crosstalk between Toll-like receptors and the receptors for the complement anaphylatoxin C5a

The innate immune system is responsible for a rapid inflammatory response to pathogens that is essential for the clearance of infections. Although this response is vital, it is nonetheless potentially harmful, and dysregulated inflammation is a feature of many disease states. Thus, the mechanisms that regulate the release of soluble mediators of inflammation are an active focus of investigation. The activation by infections of two key components of the innate immune system, the Toll-like receptors (TLRs) and complement, leading to the release of soluble mediators of inflammation, is critical to microbial killing and clearance. Both TLRs and complement are independently capable of triggering pro-inflammatory responses, but their synergistic interaction resulting from a substantial crosstalk markedly amplifies those responses and may contribute to the pathophysiology of diseases such as sepsis.     

Gut microbiome and bone

The gut microbiome is now viewed as a tissue that interacts bidirectionally with the gastrointestinal, immune, endocrine and nervous systems, affecting the cellular responses in numerous organs. Evidence is accumulating of gut microbiome involvement in a growing number of pathophysiological processes, many of which are linked to inflammatory responses. More specifically, data acquired over the last decade point to effects of the gut microbiome on bone mass regulation and on the development of bone diseases (such as osteoporosis) and of inflammatory joint diseases characterized by bone loss. Mice lacking a gut microbiome have bone mass alteration that can be reversed by gut recolonization. Changes in the gut microbiome composition have been reported in mice with estrogen-deficiency osteoporosis and have also been found in a few studies in humans. Probiotic therapy decreases bone loss in estrogen-deficient animals. The effect of the gut microbiome on bone tissue involves complex mechanisms including modulation of CD4⁺T cell activation, control of osteoclastogenic cytokine production and modifications in hormone levels. This complexity may contribute to explain the discrepancies observed betwwen some studies whose results vary depending on the age, gender, genetic background and treatment duration. Further elucidation of the mechanisms involved is needed. However, the available data hold promise that gut microbiome manipulation may prove of interest in the management of bone diseases.     

Domino effect of hypomagnesemia on the innate immunity of Crohn's disease patients

Digestive diseases play major role in development and complications of other disorders including diabetes.For example,Crohn’s disease(CD)is an inflammatory bowel disease associated with Mycobacterium avium subspecies paratuberculosis.The inflammation is a complex process that involves the activity of both innate and adaptive immune responses.CD lesions are primarily due to T cell response,however;innate immune response has a significant role in initiating its pathogenesis.Toll-like receptors and NOD-like receptors promote the activity of nuclear factor(NF)-κB pathway for cytokines production.This results in the production of high levels of tumor necrosis factor-α,interleukin(IL)-1βand IL-6.Moreover,intestinal inflammation of CD is related to increased activity of NMDA receptors and the release of substance P.Imbalanced magnesium homeostasis in CD is a frequent finding in CD,Diabetes and others.The loss of such a major mineral affects many physiological processes in the body including its role as an immunomodulator.This review aims to(1)describe the significance of hypomagnesemia in the release of pro-inflammatory mediators in CD;(2)demonstrate effects of magnesium on pathways like NF-κB;(3)address the role of hypomagnesemia in the activity of CD;and(4)examine possible future research to establish a standard magnesium supplementation strategy;helping patients with CD or other disorders to maintain a sustained remission.     

Pannexin1在炎症中的作用及其作为脓毒症治疗靶点的前景

背景 Pannexin(Panx)1通道是新型缝隙连接Panx家族的亚型之一,广泛表达于各种细胞上,是细胞间和细胞内外代谢产物及信号分子转运的重要通道之一. 目的 探讨Panx 1参与的炎症和免疫反应在脓毒症病理过程中的作用及其作为脓毒症治疗靶点的意义. 内容 从病理生理学的角度,综述Panx1介导的ATP释放在机体先天性和后天性免疫过程中的机制,着重阐明其与脓毒症病程的关联性,为Panx1抑制剂药物治疗脓毒症提供理论依据. 趋向 有关Panx1在炎症性疾病、癫痫、肿瘤等领域的研究越来越多,而Panx1在脓毒症中也起到了重要作用,所以Panx1将有可能成为治疗脓毒症的新靶点.     

The concept of the inflammasome and its rheumatologic implications

The inflammasome is a proteolytic complex that regulates IL1β and IL-18 secretion in macrophages and dendritic cells. Its plays a vital role in the control of the inflammatory and cellular responses to infectious and danger signals and is an essential part of the innate immune system. Four different inflammasomes have been identified so far, and the NLRP3-inflammasome has been the best-studied in relation to human disease. Activation of the NLRP3-inflammasome by microcrystals, such as monosodium urate (MSU) and basic calcium phosphate (BCP) crystals, leads to IL1β release, which in turn triggers local inflammation. Dysfunction of the NLRP3-inflammasome due to mutations of the NLRP3 gene is the cause of the auto-inflammatory syndrome CAPS. The symptoms and signs of inflammation in both conditions respond to IL1 blockade. IL1 inhibitors have also been used successfully in other idiopathic inflammatory diseases, suggesting that dysregulated inflammasome activity contributes to the pathogenesis of multiple diseases, but the precise underlying mechanisms remain to be identified.     

Nuclear medicine techniques in the diagnosis of orthopaedic diseases

Nuclear medicine techniques show metabolic processes, allowing the diagnoses of many bone and joint disorders. For most orthopaedic indications three-phase bone scintigraphy is used, showing inflammatory bone and joint diseases, traumatic and post-operative disorders as well as necrotic or malignant changes. In addition to bone scintigraphy, there are radiopharmaceuticals to depict inflammatory processes. Finally, positron emission tomography is a modern imaging technique used mainly for tumor diagnostics, but also for detection of inflammation.