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。     

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。     

软骨寡聚基质蛋白在关节炎中的作用

研究表明在骨性关节炎和类风湿性关节炎患者血清中软骨寡聚基质蛋白(cartilage oligomeric matrix protein,COMP)可以在出现关节形态学改变以前就在生化代谢方面表现异常,为早期诊断提供了新思路,其可以作为反映早期关节软骨破坏和骨关节疾病急性活动程度的指标。从而能在病变不可逆发展之前及早防治,逆转或延缓病变进展。COMP是关节炎疾病的诊断与判断疾病进展和缓解潜在生物学标志物。本文就软骨寡聚基质蛋白及其在关节炎中的作用作一综述。     

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.     

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。     

间充质干细胞来源外泌体在膝骨关节炎微环境中的作用

骨关节炎是一种涉及所有关节成分（包括关节软骨、软骨下骨、滑膜、韧带、关节囊和关节周围肌肉）的关节退行性疾病，会导致严重的残疾，其中最常见的是膝骨关节炎（knee osteoarthritis，KOA）。外泌体是一种由不同细胞分泌的直径为40~100 nm的胞外囊泡，可以传递DNA、微小RNA、mRNA、蛋白质等多种物质，并通过多种方式进行细胞间的信息传递和功能调节。间充质干细胞（mesenchymal stem cells，MSCs）可以从骨髓、脂肪、滑膜及外周血等组织分离，是一类具有多向分化潜能的祖细胞，以干细胞为基础的疗法可以修复软骨损伤，对抗KOA的发展，间充质干细胞能够分泌多种营养因子来调节受损的微环境，其中间充质干细胞来源的外泌体被认为在KOA炎症反应及软骨细胞代谢中发挥着重要的作用，其能够调节膝骨关节微环境中B细胞、T细胞、滑膜细胞、软骨细胞代谢及其细胞外基质的分解与合成平衡，维持软骨稳态。近期有多项研究表明，不同组织来源的间充质干细胞外泌体对骨关节炎均有明确的治疗作用，本文就MSCs来源的外泌体治疗KOA的具体机制进行综述，以期对干细胞治疗KOA提供理论依据。     

几丁聚糖衍生物防治骨性关节病概况

骨性关节病 (骨关节炎 ,增生性、创伤性关节炎等 )是影响中老年人健康的常见疾病 ,如 40岁以上的女性约有 40 %膝关节就出现不同程度的临床症状。骨关节病是人体关节器官退化过程中表现出来的一种病理状态 ,骨关节的软骨基质和滑膜表面受到破坏和流失 ,即引起各种症状。退行性骨关节炎以及各种关节损伤 ,包括关节外伤、手术导致的创伤性骨关节炎 ,是临床常见又尚未能解决的问题。近年来 ,关节软骨保护学说 ,尤其是糖胺类药物作为软骨保护剂应用 ,使骨关节病的研究领域得到开拓 ,对预防骨性关节病的发生或减轻病变程度 ,缓解症状及改善关节功…     

膝骨关节炎患者关节液和滑膜中IL-6、MMP-13、VEGF的表达及与病情进展的关系

目的:研究膝骨关节炎(KOA)患者关节液和滑膜中白细胞介素-6(IL-6)、基质金属蛋白酶-13(MMP-13)、血管内皮生长因子(VEGF)的表达及与病情进展的关系。方法:选择自2017年1月到2017年6月在我院就诊的KOA患者30例进行研究,其中维吾尔族和汉族各15例,分别记为维吾尔族组和汉族组。另选同期在我院接受骨折修复和截肢等手术治疗的10例无骨关节炎的患者作为对照组。对比各组IL-6、MMP-13及VEGF水平以及关节软骨中水通道蛋白3(AQP3)阳性表达率,对比维吾尔族组和汉族组软骨不同区域内AQP3阳性表达,分析KOA患者关节液和滑膜中IL-6、MMP-13、VEGF及关节软骨中AQP3的阳性表达与病情进展的相关性。结果:维吾尔族组和汉族组关节液和滑膜中IL-6、MMP-13及VEGF水平均分别高于对照组,差异均有统计学意义(均P0.05)。维吾尔族组和汉族组关节软骨中AQP3阳性表达率均分别明显高于对照组,且维吾尔族组明显高于汉族组,差异均有统计学意义(均P0.05)。维吾尔族组和汉族组浅层软骨磨损严重区的AQP3阳性表达率明显高于软骨深层区和软骨下骨区,差异均有统计学意义(均P0.05)。Spearman相关性分析显示,KOA患者关节液和滑膜中IL-6、MMP-13、VEGF及关节软骨中AQP3的阳性表达与病情进展均呈正相关(均P0.05)。结论:KOA患者关节液和滑膜中IL-6、MMP-13、VEGF水平及关节软骨中AQP3阳性表达均异常升高,以上指标参与了病情的进展,且AQP3阳性表达高低还与民族有关,临床上可考虑将这些指标作为监测KOA患者病情的靶点。     

骨性关节炎软骨细胞凋亡的研究

骨性关节炎是一种以软骨下骨改变和软骨退化为特征的关节退行性疾病.研究证实软骨细胞凋亡在骨性关节炎发生发展中起到关键作用.因此,研究骨关节炎软骨细胞凋亡机制及研发或筛选抗软骨细胞凋亡的药物必将给骨关节炎的防治开辟一条崭新的途径.     

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。     

Mesenchymal stem cell therapy in osteoarthritis: advanced tissue repair or intervention with smouldering synovial activation?

Although it is generally accepted that osteoarthritis is a degenerative condition of the cartilage, other tissues such as synovium in which immunological and inflammatory reactions occur contribute to the development of joint pathology. This sheds new light on the potential mechanism of action of mesenchymal stem cell therapy in osteoarthritis. Rather than tissue repair due to local transformation of injected mesenchymal stem cells to chondrocytes and filling defects in cartilage, such treatment might suppress synovial activation and indirectly ameliorate cartilage damage. Desando and co-workers report in Arthritis Research & Therapy that intra-articular delivery of adipose-derived stem cells attenuates progression of synovial activation and joint destruction in osteoarthritis in an experimental rabbit model. Clinical studies are warranted to see whether this approach might be a novel way to combat development of joint destruction in inflammatory subtypes of osteoarthritis.     

Upregulated expression of CCR3 in osteoarthritis and CCR3 mediated activation of fibroblast-like synoviocytes

ObjectivesUpregulated expression of CC chemokine receptor (CCR)3 was observed in osteoarthritis (OA) cartilage and chondrocytes, but expression of CCR3 on synovial tissue of OA remains unknown. Fibroblast-like synoviocyte (FLS) invasion in synovium appears one of the features of OA, but expression and function of CCR3 on FLS remain uninvestigated. We therefore explored them in the present study.MethodsEnzymatically dispersed synovial tissue cells were analyzed by flowcytometry. Primary cultured FLS isolated from OA synovium were challenged and the expression of CCR3, eotaxin-1 and matrix metalloproteinase (MMP)-9 was determined by quantitative real-time PCR (qPCR) and ELISA.ResultsApproximately 4.5% dispersed OA synovial tissue cells are CCR3+ cells. Among them, 58.4% cells are CD90+CD14−CD3− cells (representing FLS) and 36.7% are CD8+ cells, indicating that FLS are major population of CCR3+ cells in the synovial tissue. Levels of eotaxin-1 and MMP-9 in OA synovial fluid (SF) were greater than that in OA plasma and in healthy control (HC) plasma. Eotaxin-1 induced up to 5.8 and 7.2-fold increases in the expression of MMP-9 mRNA and protein, respectively following 12 h incubation with FLS, which was inhibited by antagonist of CCR3 SB328437 and an inhibitor of ERK U0126, indicating that action of eotaxin-1 on FLS seemed via CCR3 and ERK signaling pathway. IL-1β and TNF-α was found to elicit release of eotaxin-1 from OA FLS.ConclusionFLS via eotaxin-1 and its receptor CCR3 plays an important role in the pathogenesis of OA, which strengthen the concept that OA is likely an inflammation related disease.     

B cell clonal expansion and somatic hypermutation of Ig variable heavy chain genes in the synovial membrane of patients with osteoarthritis

Inflammatory mediators have been explored as possible factors in the initiation and/or progression of osteoarthritis (OA). This study shows that synovial infiltration by B lymphocytes is present in almost half of the knee OA cases. The degree of B lymphocyte infiltration is associated with more pronounced synovial inflammation and with the presence of plasma cells and lymphoid follicles in more severe cases. To examine whether these B cells are merely bystanders or could be involved in the pathogenesis of OA, we analyzed the Ig H chain variable region (V(H)) genes of B cells recovered from the synovial membrane of five OA patients with marked B cell infiltration. Sequence analysis of CDR3 regions of rearranged VDJ genes revealed clonal or oligoclonal B cell expansions in all cases. Expanded B cell clones in four of five OA patients showed clustered somatic mutations, occurring mainly in the CDRs and with a high replacement-to-silent ratio (>2.9), indicating that these cells are postgerminal center B cells that had been positively selected through their Ag receptor. These data demonstrate the presence in inflamed knee OA synovium of clonally expanded, Ag-driven B cells that may contribute to the development or progression of the disease.     

Plasma proteins take their toll on the joint in osteoarthritis

In their recent study, Sohn and colleagues identify multiple plasma proteins in the synovial fluid of patients with osteoarthritis (OA) and demonstrate the capacity of several of the proteins to activate macrophages via the innate immune receptor Toll-like receptor-4 (TLR-4). The authors speculate that the plasma proteins transit into the synovial compartment at sites of tissue damage where the endothelial barrier may be compromised, thus bringing them into contact with the articular surface and cells within the synovium. These results demonstrate a novel mechanism by which synovial inflammation can be initiated in patients with OA and how this process may contribute to the pathogenesis of OA joint pathology.     

Transforming growth factor-beta in synovial fluids modulates Fc gamma RII (CD16) expression on mononuclear phagocytes.

Mononuclear phagocytes in the synovium of patients with arthritis, in contrast to blood monocytes, were found to express a third receptor for the constant region of Ig (Fc gamma RIII), in addition to Fc gamma RI and Fc gamma RII. Previously identified on mature mononuclear phagocytes or phagocytes exposed to transforming growth factor-beta (TGF-beta) in vitro, this study documents the presence of Fc gamma RIII (CD16) expressing cells at an inflammatory site. Furthermore, the presence of CD16 on the majority of the LeuM3 (CD14) positive synovial monocytic cells could be mimicked by exposing blood monocytes to synovial fluids from patients with rheumatoid arthritis (17 of 19) and synovial fluids from patients with osteoarthritis (4 of 4). In additional studies, the soluble factor in inflammatory synovial fluids responsible for regulating CD16 expression was found to be consistent with the presence of TGF-beta. Inhibition of the activity in synovial fluids with a neutralizing antibody to TGF-beta confirmed a role for this peptide in synovial phagocytic cell CD16 expression. Moreover, signal transduction through CD16 on synovial phagocytes resulted in augmented extracellular release of superoxide anion that may contribute to tissue damage and other inflammatory sequelae. Identification of TGF-beta and its association with upregulation of CD16 at sites of chronic inflammation may provide insight into the destructive lesions associated with inflammatory arthropathies.     

Differential expression, function and response to inflammatory stimuli of 11beta-hydroxysteroid dehydrogenase type 1 in human fibroblasts: a mechanism for tissue-specific regulation of inflammation

Stromal cells such as fibroblasts play an important role in defining tissue-specific responses during the resolution of inflammation. We hypothesized that this involves tissue-specific regulation of glucocorticoids, mediated via differential regulation of the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). Expression, activity and function of 11beta-HSD1 was assessed in matched fibroblasts derived from various tissues (synovium, bone marrow and skin) obtained from patients with rheumatoid arthritis or osteoarthritis. 11beta-HSD1 was expressed in fibroblasts from all tissues but mRNA levels and enzyme activity were higher in synovial fibroblasts (2-fold and 13-fold higher mRNA levels in dermal and synovial fibroblasts, respectively, relative to bone marrow). Expression and activity of the enzyme increased in all fibroblasts following treatment with tumour necrosis factor-alpha or IL-1beta (bone marrow: 8-fold and 37-fold, respectively, compared to vehicle; dermal fibroblasts: 4-fold and 14-fold; synovial fibroblasts: 7-fold and 31-fold; all P < 0.01 compared with vehicle). Treatment with IL-4 or interferon-gamma was without effect, and there was no difference in 11beta-HSD1 expression between fibroblasts (from any site) obtained from patients with rheumatoid arthritis or osteoarthritis. In the presence of 100 nmol/l cortisone, IL-6 production--a characteristic feature of synovial derived fibroblasts--was significantly reduced in synovial but not dermal or bone marrow fibroblasts. This was prevented by co-treatment with an 11beta-HSD inhibitor, emphasizing the potential for autocrine activation of glucocorticoids in synovial fibroblasts. These data indicate that differences in fibroblast-derived glucocorticoid production (via the enzyme 11beta-HSD1) between cells from distinct anatomical locations may play a key role in the predeliction of certain tissues to develop persistent inflammation.