Interleukin-6 and chondrocyte mineralisation act in tandem to promote experimental osteoarthritis
Interleukin-6 and chondrocyte mineralisation act in tandem to promote experimental osteoarthritis
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DOI：
10.1136/annrheumdis-2015-207487
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发表时间：
2016-07-01
影响因子：
27.4
通讯作者：
Busso, Nathalie
中科院分区：
文献类型：
--
作者：
Nasi, Sonia;So, Alexander;Busso, Nathalie
目的碱性磷酸钙(BCP)晶体和白介素6(IL-6)参与了骨关节炎(OA)的发病。我们推测，这两个因素可能在一个相互作用的扩增环中相连，从而导致OA。方法原代小鼠软骨细胞和人软骨外植体与BCP的一种形式的羟基磷灰石(HA)晶体孵育，检测细胞因子和基质降解酶的调节。体外检测IL-6刺激软骨细胞钙化的能力。使用化学抑制剂研究了HA对软骨细胞影响的机制，并通过量化软骨细胞矿化相关基因的表达来研究介导IL-6诱导的钙化的途径。结果在软骨细胞中，BCP晶体通过Syk、PI3、JAK2、STAT3等信号通路刺激软骨细胞分泌IL-6，并在自分泌环中进一步放大。外源IL-6促进钙化相关基因：焦磷酸通道Ank、钙通道Annexin 5和钠/磷共转运体Pit-1的含钙晶体形成和上调。用IL-6抑制剂处理软骨细胞可显著抑制IL-6诱导的晶体形成。在半月板切除的小鼠，观察到BCP晶体在关节周围沉积增加，并与软骨退化和IL-6表达相关。结论BCP晶体与IL-6形成正反馈环，导致骨性关节炎的发生。靶向含钙晶体形成和/或IL-6是治疗骨性关节炎的有前景的策略。
Objectives Basic calcium phosphate (BCP) crystal and interleukin 6 (IL-6) have been implicated in osteoarthritis (OA). We hypothesise that these two factors may be linked in a reciprocal amplification loop which leads to OA.Methods Primary murine chondrocytes and human cartilage explants were incubated with hydroxyapatite (HA) crystals, a form of BCP, and the modulation of cytokines and matrix-degrading enzymes assayed. The ability of IL-6 to stimulate chondrocyte calcification was assessed in vitro. The mechanisms underlying the effects of HA on chondrocytes were investigated using chemical inhibitors, and the pathways mediating IL-6-induced calcification characterised by quantifying the expression of genes involved in chondrocyte mineralisation. The role of calcification in vivo was studied in the meniscectomy model of murine OA (MNX), and the link between IL-6 and cartilage degradation investigated by histology.Results In chondrocytes, BCP crystals stimulated IL-6 secretion, further amplified in an autocrine loop, through signalling pathways involving Syk and PI3 kinases, Jak2 and Stat3 molecules. Exogenous IL-6 promoted calcium-containing crystal formation and upregulation of genes involved in calcification: the pyrophosphate channel Ank, the calcium channel Annexin5 and the sodium/phosphate cotransporter Pit-1. Treatment of chondrocytes with IL-6 inhibitors significantly inhibited IL-6-induced crystal formation. In meniscectomised mice, increasing deposits of BCP crystals were observed around the joint and correlated with cartilage degradation and IL-6 expression. Finally, BCP crystals induced proteoglycan loss and IL-6 expression in human cartilage explants, which were reduced by an IL-6 inhibitor.Conclusions BCP crystals and IL-6 form a positive feedback loop leading to OA. Targeting calcium-containing crystal formation and/or IL-6 are promising therapeutic strategies in OA.