巴戟天环烯醚萜苷下调GSK-3β抑制JAK2/STAT3和NF-κB通路减轻Ⅱ型胶原诱导的关节炎大鼠骨破坏的机制

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中文摘要：探讨巴戟天环烯醚萜苷(Morinda officinalis iridoid glycosides，MOIG)对类风湿关节炎(rheumatoid arthritis，RA)大鼠骨丢失的治疗作用，并对脂多糖(lipopolysaccharide，LPS)诱导的破骨细胞功能和活性的作用机制。应用牛Ⅱ型胶原诱导类风湿关节炎大鼠(type Ⅱ collagen-induced rheumatoid arthritis rats，CIA)为模型(实验中所有操作均获得浙江中医药大学生物伦理委员会批准，批准号:IACUC-20180410-03)，灌胃给药8周，显微CT观察CIA大鼠的骨小梁微结构变化，LPS诱导破骨细胞模型进一步观察体外抗炎症性骨质疏松的作用机制。结果表明MOIG显著增加CIA大鼠骨密度，改善骨小梁微结构。体外实验表明，MOIG抑制破骨细胞形成分化、抗酒石酸酸性磷酸酶活性和F-actin环的形成，抑制TNF受体相关因子6(TNF receptor associated factor 6，TRAF6)的募集和核因子κB抑制蛋白[inhibitor of nuclear factor kappa-B(NF-κB)，IκBα]的降解及p65的磷酸化表达，从而抑制NF-κB通路的激活;同时有效抑制破骨细胞活化T-细胞核因子1(nuclear factor of activated T-cells cytoplasmic 1，NFATc1)和c-Fos(cellular oncogene fos)的表达，以及基质金属蛋白酶 9(matrix metalloproteinase 9，MMP9)和组织蛋白酶 K(cathepsin K，CtsK)的活性;MOIG还抑制 Janus激酶2(Janus activating kinase 2，JAK2)/信号传导和转录激活蛋白 3(signal transducer and activator of transcription 3，STAT3)蛋白的磷酸化表达，从而抑制 JAK2/STAT3 通路的激活。进一步研究发现，MOIG显著抑制丝氨酸/苏氨酸激酶-3β(glycogen synthase kinase-3β，GSK-3β)的活性，GSK-3β基因沉默显著抑制破骨细胞F-actin环的形成、p65的磷酸化以及STAT3信号的激活，且MOIG和GSK-3β基因沉默同时作用后的效果没有明显差异。因此，MOIG可通过调控GSK-3β抑制JAK2/STAT3和NF-κB通路的激活来减缓RA的骨破坏。

外文标题：Mechanism of Morinda officinalis iridoid glycosides alleviates bone deterioration in type Ⅱ collagen-induced arthritic rats through down-regulating GSK-3β to inhibit JAK2/STAT3 and NF-κB signaling pathway

外文摘要：This study aimed to investigate the therapeutic effects of Morinda officinalis iridoid glycosides(MOIG)on bone loss of rheumatoid arthritis(RA)rats,and the mechanism of osteoclast function and activity induced by lipopolysaccharide(LPS).RA rats were established by injecting bovin type Ⅱ collagen.The Bio-ethic Committee of Zhejiang Chinese Medical University approved all experimental protocols associated with this study(IACUC-20180410-03).The collagen-induced arthritis(CIA)rats were administered drug by gavage for 8 weeks;the femoral trabecular micro-structure changes were observed in CIA rats by micro-CT;the LPS-induced osteoclasts model further observed the effect and mechanism of anti-inflammatory osteoporosis in vitro.The results indicated that MOIG could markedly increase bone mineral density(BMD)in CIA rats,improve trabecular micro-structure.In vitro studies demonstrated that MOIG could significantly inhibit osteoclastogensis and differentiation,suppress tartrate resistant acid phosphatase(TRAP)activity,F-actin ring formation,TNF receptor associated factor 6(TRAF6)recruitment,and inhibitor of nuclear factor kappa-Bα(IκBα)degradation as well as p65 phosphorylation,thereby repressing nuclear factor kappa-B(NF-κB)signaling pathway activation.Subsequently,MOIG effectively inhibited osteoclast nuclear factor of activated T-cells c1(NFATc1)and cellular oncogene Fos(c-Fos)expression,as well as bone resorption related protein activity including matrix metalloprotein 9(MMP-9)and cathepsin K(CtsK).Meanwhile,MOIG also repressed the phosphorylation expression of Janus activating kinase 2(JAK2)and signal transducer and activator of transcription 3(STAT3),thereby inhibiting JAK2/STAT3 signaling pathway activation.Moreover,further studies found that MOIG could suppress glycogen synthase kinase-3β(GSK-3β)activity,and GSK-3β gene silencing could markedly inhibit oetsoclast F-actin ring formation as well as the phosphorylation expression of p65 and STAT3.Of note,compared with GSK-3β gene silencing group,there was no significant difference in the group treated with both MOIG with GSK-3β gene silencing simultaneously.Thus,the results suggested that MOIG may inhibit NF-κB signaling pathway and JAK2/STAT3 signaling pathway activation via regulating GSK-3β,thereby alleviating bone destruction in RA.

外文关键词：

Morinda officinalis iridoid glycosiderheumatoid arthritisbone lossosteoclastNF-κB signaling pathwayJAK2/STAT3 signaling pathway

作者：

沈燚、孙艺琦、李鹤鸣、叶欣园、杜金蔓、鲍荣华、张泉龙、秦路平、张巧艳

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作者单位：

浙江中医药大学药学院,浙江杭州 310053

杭州市富阳中医骨伤医院,浙江杭州 311400

关键词：

巴戟天环烯醚萜苷类风湿关节炎骨丢失破骨细胞 NF-κB通路 JAK2/STAT3通路

基金：

浙江省自然科学基金重点项目浙江省自然科学基金重点项目国家自然科学基金项目

项目编号：

LZ22H280002LBY21H06000282374099

出版年：

2024

DOI：

10.16438/j.0513-4870.2024-0189

药学学报

中国药学会中国医学科学院药物研究所

药学学报

CSTPCD北大核心

影响因子：1.274

ISSN：0513-4870

年,卷(期)：2024.59(10)