葛根素通过调控炎症因子抑制兔膝关节骨性关节炎

【】 目 的 研究葛根素对兔膝关节骨性关节炎的抑制作用及机制。方 法 将40只成年新西兰兔随机分为正常组,模型组,生理盐水组,葛根素组,每组10只,后三组构建兔膝关节骨性关节炎模型。模型构建成功后,生理盐水组和葛根素组分别膝关节内注射生理盐水、葛根素0.5 ml,5周共10次。药物注射完成后,切开膝关节肉眼观察关节面,抽取关节液采用ELISA法检测IL-1β、IL-10、TNF-α、COX2、 PGE2表达水平,Western blot 法检测关节软骨组织中MMP-2、Collagen II 蛋白表达水平。结 果 葛根素作用后膝关节软骨面病损程度明显减轻。葛根素作用后膝关节液中IL-1β、TNF-α、COX2、 PGE2表达水平降低,IL-10表达水平增加,而关节软骨组织中MMP-2表达降低,Collagen II 表达增加。结 论 葛根素可能参与了骨性关节炎中促炎因子与抑炎因子间的平衡,具有一定的抑制细胞外基质中胶原的降解作用,从而有可能减缓骨性关节炎的病程进展。     

膝关节骨性关节炎与髋关节退变的相关性研究

目的探讨膝关节骨性关节炎与髋关节退变的相关性,以指导临床治疗工作。方法创建一类去双前肢直立联合Malthus法模型,以该模型为基础检测各项指标,其宗旨是明确膝关节骨性关节炎与髋关节退变间的关联性。结果对HE、甲苯胺蓝、CollagenⅡ、MMP-13进行染色,进而其他组相比较,Hulth组大鼠膝关节软骨Mankin评分与MMP-13阳性细胞比例最高、CollagenⅡ阳性细胞比率最低;和其他组相比,Malthus组大鼠同侧髋关节软骨Mankin评分与MMP-13阳性细胞比例最高、CollagenⅡ阳性细胞比率最低,软骨退行病变最严重。膝关节骨性关节炎(KOA)患者中,膝关节疼痛、僵硬、关节活动范围减缩以及X线检查结果和髋关节对应症状无相关性或相关性微小。结论去双前肢直立联合Malthus组大鼠膝关节退变更为显著,大鼠的KOA可促使其髋关节退变更为严重化,对统计学结果进行分析,得出人体KOA和髋关节的退变之间无相关性的结论。     

独活寄生汤配合针灸治疗对膝关节骨性关节炎患者的疗效及其对炎症因子和膝关节功能改善的影响

目的:探究独活寄生汤配合针灸治疗对膝关节骨性关节炎患者的疗效及其对炎症因子(IL-1β、TNF-α和人基质金属蛋白酶-3(MMP-3)水平和膝关节功能改善的影响。方法:选取2016年12月—2018年2月间收治的膝关节骨性关节炎患者74例资料,按治疗方法的不同将其随机分为对照组(n=37)和治疗组(n=37);对照组患者给予采用针灸疗法治疗,治疗组患者在对照组基础上加用独活寄生汤治疗,比较两组患者治疗后的总有效率差异,以及治疗前后膝关节功能评分值和关节液中IL-1β、TNF-α、MMP-3水平测得值的变化情况。结果:治疗后治疗组患者的总有效率显著高于对照组(P<0.05);两组患者治疗前膝关节功能评分值及关节液中IL-1β、TNF-α、MMP-3水平测得值经组间比较其差异均无统计学意义(P>0.05),治疗后两组患者膝关节功能评分值和关节液中IL-1β、TNF-α及MMP-3水平测得值均显著低于治疗前(P<0.05);治疗组患者治疗后膝关节功能评分值和关节液中IL-1β、TNF-α及MMP-3水平测得值均低于对照组(P<0.05)。结论:采用独活寄生汤配合针灸疗法治疗膝关节骨性关节炎患者的疗效较为确切,有效改善了其关节液中炎症因子水平及膝关节功能。     

生物学因子p-p38、MMP-3、MMP-13对大鼠关节软骨的破坏作用

目的 检测大鼠骨性荚节炎(OA)中对软骨起破坏作用的细胞因子.方法 大鼠20只,以任一后腿膝关节作为实验组(OA),另一侧为手术对照组.OA组离断大鼠前交叉韧带及切除内外侧半月板前半部分建立大鼠骨性关节炎模型;对照组只切开关节囊,打开关节腔,缝合切口即可.饲养8周摄X线片后取关节软骨观察形态学的改变,免疫组化检测p-p38以及基质金属蛋白酶3(MMP-3)、基质金属蛋白酶13(MMP-13)的表达.结果 与对照组相比,OA组膝关节p-p38、MMP-3及MMP-13阳性细胞强表达,软骨被破坏,关节表面粗糙;对照组p-p38、MMP-3、MMP-13表达明显减少,软骨完整,关节表面光滑.结论 大鼠骨性关节炎软骨细胞中因生物学因子p-p38、MMP-3、MMP-13的过度表达与骨性关节炎软骨破坏有关.     

兔膝骨性关节炎软骨损伤及降钙素的保护作用

目的:探讨兔膝骨性关节炎(KOA)时的软骨损伤及降钙素(CT)的保护作用.方法:将36只健康大耳白兔随机分为空白对照组(A组)、模型组(B组)和CT治疗组(C组),B、C组采用改良Hulth法复制膝骨性关节炎模型,A组除切开皮肤和关节腔外,不做其他处理,从术后第6周开始C组每天皮下注射CT 5 U/kg,A、B组给与等量生理盐水皮下注射,连续注射20d后处死动物.观察关节软骨病理组织学和关节液肿瘤坏死因子(TNF)-α、一氧化氮(NO)及关节软骨Ⅱ型胶原及基质金属蛋白酶(MMP)-1的变化,以及降钙素对上述指标的影响.结果:与A组相比较,B组JP和Mankin’S评分升高,关节软骨损伤加重,关节液中TNF-α、NO水平升高(P＜0.05),关节软骨Ⅱ型胶原含量降低,MMP-1活性升高(P＜0.05);与B组相比,C组关节液中TNF-α、NO水平降低(P＜0.05),关节软骨损伤减轻、Ⅱ型胶原含量升高,MMP-1活性降低(P＜0.05).结论:CT可能通过抑制TNF-α、NO的表达而对KOA软骨损伤起保护作用.     

连续股神经阻滞对兔膝骨关节炎模型疼痛的疗效与作用机理初步研究

目的 探究连续股神经阻滞对兔膝骨性关节炎(KOA)模型的疼痛治疗效果及可能的作用机制.方法 建立KOA兔模型.观察空白组、模型组和实验组(A、B、C、D和E组)动物行为学的变化,比较疼痛反应,然后使用ELISA法检测各组兔滑膜液中TNF-α、IL-1和IL-6的表达,HE染色观察KOA兔滑膜软骨组织形态学变化,最后使用免疫组化的方法测定滑膜和软骨组织中基质金属蛋白酶-3 (MMP-3)及基质金属蛋白酶抑制剂-1(TIMP-1)的表达.结果 相比于模型组,连续股神经阻滞能显著缓解KOA兔的疼痛(P＜0.05或P＜0.01);滑膜软骨组织损伤及周围炎性反应明显减轻;实验组兔滑膜液中TNF-α、IL-1和IL-6的表达也显著下降(P＜0.05或P＜0.01),其中C组、D组和E组更为明显(P＜0.01);另外,连续骨神经阻滞处理使KOA兔滑膜和软骨组织中MMP-3和TIMP-1的表达显著下调(P＜0.05或P＜0.01),改善了MMP-3/TIMP-1的失衡.结论 连续骨神经阻滞可以显著缓解KOA兔的疼痛反应,改善滑膜软骨损伤,其机制可能与下调滑膜液中TNF-α、IL-1和IL-6的表达以及改善滑膜和软骨中MMP-3、TIMP-1的异常表达有关.     

膝骨性关节炎联合应用玻璃酸钠及复方倍他米松注射液治疗的临床研究

目的:观察分析膝骨性关节炎患者联合应用玻璃酸钠及复方倍他米松注射液治疗的临床疗效.方法:选择我院2017年11月—2019年11月收治的110例膝骨性关节炎患者为观察对象,按照入院顺序单双号分为两组:治疗组(n=55)、对照组(n=55).对照组患者采用玻璃酸钠关节腔内注射,治疗组患者玻璃酸钠与复方倍他米松注射液联合应用关节腔内注射.比较两组患者的临床疗效,采用视觉模拟评估法(VAS)、Lvsholm关节功能评分、WOMAC的疼痛量表评价两组疼痛程度及膝关节功能,检测比较两组治疗前后关节液基质金属蛋白酶-3(MMP-3)、MMP-9及白细胞介素1β(IL-1β)水平.结果:治疗组患者的治疗总有效率较对照组的显著提高(92.73％VS 78.18％,P<0.05).两组治疗后VAS、Lvsholm及WOMAC评分均降低,关节液MMP-3、MMP-9及IL-1β水平均降低(P<0.05).治疗组治疗后VAS、Lvsholm及WOMAC评分低于对照组,治疗后关节液MMP-3、MMP-9及IL-1β水平低于对照组(P<0.05).结论:玻璃酸钠与复方倍他米松注射液联合应用关节腔内注射治疗膝骨性关节炎可以取得满意效果,患者关节局部疼痛程度及膝关节功能明显改善,考虑作用机制可能与降低关节液MMP-3、MMP-9及IL-1β的水平有关.     

胶原诱导性关节炎大鼠在中药作用下对其关节炎指数、IL-1β、TNF-α、PGE2、 RANKL及OPG的影响探讨

目的 探讨胶原诱导性关节炎大鼠在中药作用下对其关节炎指数、白细胞介素1β(IL-1β)、肿瘤坏死因子(TNF-α)、前列腺素E2 (PGE2)、核因子-kB受体活化因子配体(RANKL)及护骨素(OPG)的影响.方法 取Wistar大鼠48只随机分为空白组、模型组、阳性组、A、B、C组.复制胶原诱导性关节炎大鼠模型,连续干预4周后,各组大鼠眼眶静脉取血,观察关节炎指数、IL-1β、TNF-α、PGE2、RANKL及OPG.结果 与空白组相比,其余各组大鼠关节炎指数均明显增加(P＜0.05).与模型组相比,阳性组、A、B、C组关节炎指数均明显降低(P＜0.05).与空白组相比,模型组血清IL-1β、TNF-α、PGE2、RANKL、OPG及RANKL/OPG水平均明显升高(P＜0.05).与模型组相比,阳性组、A、B、C组血清IL-1β、TNF-α、PGE2、RANKL、OPG及RANKL/OPG水平明显降低(P＜0.05),且A、B、C组大鼠血清IL-1β、TNF-α、PGE2水平抑制作用及对RANKL、OPG及RANKL/OPG的改善情况均优于阳性组(P＜0.05).组织病理学结果显示,A、B、C组可抑制CIA大鼠关节组织病理学改变.结论 自拟除痹汤可明显降低CIA模型大鼠的关节炎指数及关节组织病理学改变,下调IL-1β、TNF-α、PGE2水平,抑制RANKL、OPG,从而可以有效防治CIA.     

骨舒汤对骨性关节炎中血清NO和血液流变学的影响

目的:研究骨舒汤对骨性关节炎中血清一氧化氮(NO)和血液流变学的影响。方法:随机选择健康大耳白兔72只均分成6组,即空白(10mL生理盐水)、模型(10mL生理盐水)、壮骨关节丸(10mL,浓度:0.7g.mL-1)和骨舒汤高、中、低剂量(20、10、5mL,浓度:0.7g.mL-1)组。采用改良的Hulth法复制模型。ig给药,每天1次,连续8周。观察兔血清、软骨NO含量和血液流变学指标,电镜下观察兔膝关节切片。结果:模型组兔血清、软骨NO含量及血液流变学指标显著高于空白组(P<0.05)。骨舒汤高剂量组兔血清、软骨NO含量及血液流变学指标均较模型组显著下降(P<0.05)。切片可见,模型组兔骨切片可见坏死软骨细胞,排列紊乱,潮线不完整;骨舒汤高剂量组兔关节软骨面光滑、软骨细胞柱状排列,潮线完整。结论:高剂量骨舒汤可降低模型兔膝骨性关节炎血清和软骨中NO含量,同时降低血液流变学指标,调节血液功能,从而起到保护关节软骨的作用。     

基质金属蛋白酶13在软骨重塑和关节炎中的研究进展

关节炎是一种常见的慢性疾病,其主要特征是关节软骨的破坏和周围组织的慢性炎症。关节炎的发病机制比较复杂,受多种因素影响。近年来研究发现,关节软骨中基质金属蛋白酶(MMPs)的增加,是造成软骨细胞外基质(ECM)降解,从而引起软骨退化的重要原因。其中,MMP-13是促使其降解的主要酶,它能不可逆地降解Ⅱ型胶原,从而造成关节软骨的破坏。MMP-13可受到多种因素的影响,如IL-1β、TNF-α、Runx2可以诱导MMP-13的表达。MMP-13启动子区域的低甲基化也会诱导其表达,但可以通过抑制组蛋白乙酰化来降低其表达。除此之外,微小RNA也可以通过基因调控来降低MMP-13的表达。MMP-13的上调会导致软骨的退化,进而促进关节炎的进程。综上所述,MMP-13可作为关节炎中重要的治疗靶点,该文将对MMP-13在关节炎中的作用及其调节机制作一综述。     

舒筋健腰丸对骨关节炎大鼠关节软骨和血清中细胞因子的影响

目的研究舒筋健腰丸对骨关节炎大鼠的关节软骨和血清中细胞因子的影响。方法 90只SD大鼠随机编号,分为6组,每组15只：将双醋瑞因组,舒筋健腰丸低剂量组（0.75 g/kg）、中剂量组（1.5 g/kg）和高剂量组（3.0 g/kg）大鼠双膝关节腔均注射4%木瓜蛋白酶溶液0.2 m L,每隔3 d注射1次,连续注射3次即成模型。空白组和模型组给予等体积的生理盐水,4周后取材,检测血清中IL-1β、TNF-α、MMP-1、MMP-13的含量;切取关节,光镜下观察软骨组织。结果舒筋健腰丸各组均能降低大鼠血清中IL-1β、TNF-α、MMP-1、MMP-13的含量,且含量显著低于模型组（P〈0.05）;可显著的减缓骨关节炎所致的关节软骨损伤,促进软骨修复。结论舒筋健腰丸能够抑制血清中IL-1β、TNF-α、MMP-1、MMP-13的升高,达到治疗骨关节炎的作用。     

Berberine inhibits the interleukin-1 beta-induced inflammatory response via MAPK downregulation in rat articular chondrocytes

Osteoarthritis (OA) is one of the most chronic degenerative arthritic diseases, which gradually results in chondrocyte changes, articular cartilage degeneration, subchondral bone sclerosis, joint pain, swelling, and dysfunction. Berberine (BBR) has various confirmed biological activities, such as anti-inflammatory and antioxidant activities. However, the effect of BBR on the production of inflammation-associated proteins, including inducible nitric oxide synthase (iNOS), cyclooxygenase (Cox)-2, metalloproteinases (MMPs), Collagen II, TNF-α, and IL-6 via the MAPK (mitogen-activated protein kinases) pathway in IL-1β-stimulated rat chondrocytes, has not yet been studied. Thus, the purpose of this study was to evaluate whether BBR would decrease the production of inflammation-associated proteins through the MAPK signal pathway. Rat chondrocytes were cultured and pretreated with BBR at different concentrations (0, 25, 50, and 100 μM) and then stimulated with or without IL-1β (10 ng/mL). The mRNA expression of iNOS, COX-2, MMP-3, MMP-13, TNF-α, and IL-6 was measured by real-time polymerase chain reaction (RT-PCR), and the protein expression of iNOS, COX-2, Collagen II, MMP-3,MMP-13, and MAPKs were measured by Western blotting. The results showed that the expression of iNOS, COX-2, MMP-3, MMP-13, TNF-α, and IL-6 increased in the IL-1β-treated group and BBR showed an ability to inhibit the elevated expression under the pretreatment. Furthermore, the IL-1β-induced downregulation of Collagen II could be ameliorated by BBR. Moreover, the expression of MAPKs was significantly decreased by BBR. These results demonstrated that BBR had the anti-catabolic and anti-inflammation abilities that were through the MAPKs in IL-1β-induced rat chondrocytes. These findings may provide a novel therapeutic choice for treatment of OA using BBR.     

膝骨性关节炎的发病机制及降钙素的治疗作用

目的探讨膝骨性关节炎(KOA)的发病机制及降钙素(CT)的治疗作用。方法 36只白兔随机均分为空白对照组(A组)、KOA模型组(B组)、CT 5U.kg-1.d-1治疗组(C组)。20d后处死动物,检测血清及关节液超氧化物歧化酶(SOD)活性及丙二醛(MDA)、一氧化氮(NO)含量,HE染色观察关节软骨病理组织学变化,免疫组织化学染色法检测软骨组织Ⅱ型胶原和基质金属蛋白酶1(MMP-1)蛋白表达情况。结果与A组相比,B组关节软骨损伤加重,Mankin’s评分、MDA及NO含量、MMP-1蛋白表达增加(P<0.05),SOD活性及Ⅱ型胶原含量降低(P<0.05);而C组能明显逆转B组上述各观察指标的改变过程(P<0.05)。结论 KOA的发生与机体氧化-抗氧化系统、细胞外基质合成-分解代谢系统的失衡密切相关,且CT对KOA的治疗作用与这两个系统失衡的恢复有关。     

Efficacy and mechanism of action of KHBJ-9B,a new herbal medicine,and its major compound triterpenoids in human cartilage culture and in a rabbit model of collagenase-induced osteoarthritis

KHBJ-9B has been formulated by n-butanol fraction from 2 herbs known to have cartilage protection and anti-inflammatory effects. We elected to determine the osteoarthritic efficacy and mechanism of KHBJ-9B on human osteoarthritis cartilage explants culture and in a rabbit model of collagenase-induced osteoarthritis (CIA). The major chemical composition and quantification of KHBJ-9B was determined by high performance liquid chromatography. The efficacy of KHBJ-9B and its major compounds on cartilage protective effects such as inhibition of GAG release and type II collagen degradation, and their cytotoxicity in IL-1β-treated human cartilage culture were examined. The mechanism of action of KHBJ-9B and its major compounds were evaluated by measuring inflammatory cytokines (IL-1β and TNF-α) and matrix proteinases (ADAMTS-4, ADAMTS-5, MMP-1, MMP-13 and TIMP-3) in IL-1β-treated human cartilage cultures. Also, the therapeutic effect of KHBJ-9B was confirmed using a collagenase-induced osteoarthritis (CIA) rabbit model. KHBJ-9B and 3 combined triterpenoids potently inhibited the release of proteoglycan and type II collagen in a dose dependent manner without cytotoxicity in IL-1β-treated human cartilage explants culture, whereas its single major compounds (betulin, pimaradienoic acid and betulinic acid) and COX-2 inhibitor (NS398) showed little inhibition even at high concentrations. KHBJ-9B and the combination of 3 triterpenoids markedly inhibited the level of IL-1β and TNF-α, and down-regulated the level of aggrecanases, ADAMTS-4, ADAMTS-5, MMP-1 and MMP-13, and up-regulated TIMP-3 in human cartilage explants culture. However, standard compounds and NS398 do not much affect the level of TNF-α, aggrecanases, and TIMP-3 in cartilage explants culture. In in vivo studies, KHBJ-9B significantly suppressed the stiffness level and global histologic score. Cartilage loss was significantly inhibited in the knee joint in a dose dependent manner, and this was associated with the finding that loss of proteoglycan, degradation of aggrecan and type II collagen was markedly reduced. These results suggest that the effect of KHBJ-9B is bigger than the effects of its single major compounds of triterpenoids or celecoxib inhibitors on cartilage protection and anti-inflammation in human cartilage and in in vivo model of osteoarthritis, and thus has potential for use in osteoarthritis treatment.     

Ivabradine abrogates TNF-α-induced degradation of articular cartilage matrix

Ivabradine is most commonly used for the treatment of worsening cardiac failure in patients who cannot tolerate the maximum dose of β-blockers or in whom treatment with β-blockers is contraindicated. While ivabradine is regarded as a highly selective “funny current” (I_f) inhibitor, the molecular mechanism behind the effect of this drug remains poorly understood. In the present study, we applied ivabradine in the context of osteoarthritis by treating primary human chondrocytes with tumor necrosis factor-α (TNF-α) and measuring degradation of the articular cartilage matrix as well as the expression of various enzymes and pro-inflammatory cytokines. Our results indicate that ivabradine significantly abrogated TNF-α-induced up-regulation of matrix metalloproteinase-3 (MMP-3), MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4, and ADAMTS-5 at both the gene and protein levels. Notably, ivabradine attenuated TNF-α-induced reduction of type II collagen and aggrecan at both the mRNA and protein levels. Also, we found that ivabradine inhibited the expression and secretion of interleukin-6 (IL-6) and interleukin-1β (IL-1β) as well as the production of reactive oxygen species (ROS). Mechanistically, our results indicate that ivabradine abolished the activation of nuclear factor (NF-κB) by inhibiting nuclear translocation of NF-κB p65. Knockdown of HCN2 enhanced the protective effects of ivabradine against TNF-α- induced degradation of both type II collagen and aggrecan, suggesting that the inhibitory effects of ivabradine in ECM degradation might be mediated by HCN2. Our findings demonstrate that ivabradine may indeed have a potential application in preventing excessive degradation of the articular cartilage matrix, thereby preventing the pathological development and progression of osteoarthritis.     

Therapeutic effect of Siegesbeckia pubescens on cartilage protection in a rabbit collagenase-induced model of osteoarthritis

Siegesbeckia pubescens (S. pubescens) was widely used to alleviate symptoms of osteoarthritis (OA) in traditional medicine. However, the mechanism of action of S. pubescens remains unresolved. In the present study, we determined the physiological relevance of S. pubescens on cartilage protection in collagenase-induced osteoarthritis (CIA) in rabbits. The right knees of rabbits were injected intra-articularly with collagenase, and rabbits were orally administered with distilled water (vehicle), S. pubescens (100, 400 mg/kg) or celecoxib (100 mg/kg) once a day for 28 days after the initiation of the CIA. S. pubescens significantly suppressed the stiffness and global histological score including articular cartilage and synovial layer in CIA. Proteoglycan, aggrecan, and type II collagen expression was significantly increased in the rabbit knee joints of the S. pubescens-treated group. However, celecoxib had no effect on cartilage protection in CIA. The expression level of ADAMTS-4, ADAMTS-5, MMP-1, MMP-3, and MMP-13 were dose-dependently decreased in the S. pubescens-treated group. In contrast, the level of TIMP-1 dose-dependently increased. The pro-inflammatory cytokines involved in cartilage destruction, such as IL-1beta, and inflammatory mediators containing PGE(2) and NO were also inhibited in the S. pubescens-treated group. These results indicate that the cartilage protective effect of S. pubescens works through down-regulation of inflammatory mediators and aggrecanases and MMPs, while up-regulating TIMP-1 in the CIA rabbit model.     

Cryptotanshinone protects against IL-1β-induced inflammation in human osteoarthritis chondrocytes and ameliorates the progression of osteoarthritis in mice

Osteoarthritis (OA) is a common degenerative disease characterized by progressive erosion of articular cartilage, subchondral bone sclerosis and synovitis. Cryptotanshinone (CTS), an active component extracted from the root of Salvia miltiorrhiza Bunge, has been shown to have potent anti-inflammatory effects. However, its effects on OA have not been clearly elucidated. This study aimed to assess the effect of CTS on human OA chondrocytes and mice OA models. Human OA chondrocytes were pretreated with CTS (5, 10 and 20 μM) for 2 h and subsequently stimulated with IL-1β for 24 h. Production of NO, PGE2, IL-6, TNF-α was evaluated by the Griess reaction and ELISA. The protein expression of COX-2, iNOs, MMP-3, MMP13, COX-2, ADAMTS-5, JNK, p-JNK, ERK, p-ERK, p38, p-p38, p-IKKα/β, p65, p-p65, IκB-α, and p-IκB-α was tested by Western blot. In vivo, the severity of OA was determined by histological analysis. We found that CTS significantly inhibited the IL-1β-induced production of NO and PGE2; expression of COX-2, iNOS, MMP-3, MMP-13, and ADAMTS-5. Furthermore, CTS in dramatically suppressed IL-1β-stimulated NF-κB and MAPK activation. Immunofluorescence staining demonstrated that CTS could suppress IL-1β-induced phosphorylation of p65 nuclear translocation. In vivo, treatment of CTS prevented the destruction of cartilage and the thickening of subchondral bone in mice OA models. These results indicate that the therapeutic effect of CTS on OA is accomplished through the inhibition of both NF-κB and MAPK signaling pathways. Our findings provide the evidence to develop CTS as a potential therapeutic agent f or patients with OA.     

Fisetin inhibits IL-1β-induced inflammatory response in human osteoarthritis chondrocytes through activating SIRT1 and attenuates the progression of osteoarthritis in mice

Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage degradation and inflammation. Fisetin, a polyphenol extracted from fruits and vegetables, has been reported to have anti-inflammatory effects. Our study aimed to investigate the effect of fisetin on OA both in vitro and in vivo. In vitro, chondrocytes were pretreated with fisetin alone or fisetin combined with sirtinol (an inhibitor of SIRT1) for 2 h before IL-1β stimulation. Production of NO, PGE2, TNF-α and IL-6 were evaluated by the Griess reaction and ELISAs. The mRNA (COX-2, iNOS, MMP-3, MMP-13, ADAMTS-5, Sox-9, aggrecan and collagen-II) and protein expression (COX-2, iNOS, MMP-3, MMP-13, ADAMTS-5 and SIRT1) were measured by qRT-PCR and Western blot respectively. Immunofluorescence was used to assess the expression of collagen-II and SIRT1. SIRT1 activity was quantified with SIRT1 fluorometric assay kit. The in vivo effect of fisetin was evaluated by gavage in mice OA models induced by destabilization of the medial meniscus (DMM). We found that fisetin inhibited IL-1β-induced expression of NO, PGE2, TNF-α, IL-6, COX-2, iNOS, MMP-3, MMP-13, ADAMTS-5. Besides, fisetin remarkably decreased IL-1β-induced degradation of Sox-9, aggrecan and collagen-II. Furthermore, fisetin significantly inhibited IL-1β-induced SIRT1 decrease and inactivation. However, the inhibitory effect of fisetin was obvious abolished by sirtinol, suggesting that fisetin exerts anti-inflammatory effects through activating SIRT1. In vivo, fisetin-treated mice exhibited less cartilage destruction and lower OARSI scores. Moreover, fisetin reduced subchondral bone plate thickness and alleviated synovitis. Taken together, these findings indicate that fisetin may be a potential agent in the treatment of OA.     

Esculentoside A protects against osteoarthritis by ameliorating inflammation and repressing osteoclastogenesis

Osteoarthritis is a relatively common disorder of articular deterioration related to cartilage damage, subchondral bone remodelling, inflammation and metabolism. Agents that can inhibit cartilage degradation and osteoclastogenesis are required for the prevention and treatment of osteoarthritis. Esculentoside A, the highest concentration triterpene saponin isolated from the root of Phytolacca esculenta, has commonly been used for the treatment of chronic bronchitis. However, the role esculentoside A plays in ameliorating osteoarthritis has not been reported. We found that esculentoside A suppresses the expression of IL-1β-induced inflammatory and metabolic factors (IL-6, IL-8, TNF-α, MMP2, MMP3 and MMP13). In addition, esculentoside A restrains osteoclast formation by inhibiting the marker gene expression of NFATc1 and c-Fos. Our results indicate that esculentoside A markedly suppresses IL-1β-induced NF-κB and MAPK signalling pathway activation in chondrocytes, and inhibits RANKL-induced osteoclast precursor generation. Finally, treatment with esculentoside A inhibits the progressive cartilage degeneration and osteoclastogenesis in osteoarthritis mouse models. In summary, these results demonstrate that esculentoside A could be a latent therapeutic reagent for the treatment of osteoarthritis.