Fas/S1P1 crosstalk via NF-κB activation in osteoclasts controls subchondral bone remodeling in murine TMJ arthritis
Fas/S1P1 crosstalk via NF-κB activation in osteoclasts controls subchondral bone remodeling in murine TMJ arthritis
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DOI：
10.1016/j.bbrc.2017.07.006
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发表时间：
2017-09-02
影响因子：
3.1
通讯作者：
Tanaka, Eiji
中科院分区：
文献类型：
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作者：
Hutami, Islamy Rahma;Izawa, Takashi;Tanaka, Eiji
软骨下骨小梁骨转换增强是类风湿性关节炎(RA)的一个特征，它是骨吸收和骨形成活动之间失衡的结果。为了研究介导骨吸收的破骨细胞的形成和激活，研究了一种Fas缺陷的MRL/IPR小鼠模型，该模型自发地发生自身免疫性关节炎并表现出骨量减少。对MRL/LPR小鼠和MRL+/+小鼠的颞下颌关节软骨下松质骨(TMJ)进行了不同的分析。最初，从MRL/LPR小鼠获得的骨髓巨噬细胞在体外观察到更多的破骨细胞产生，这是由于核因子-kappa B以及Akt和MAPK对核因子-kappa B受体激活剂配体(RANKL)的磷酸化增强。1-磷酸鞘氨醇受体1(SIP1)在髁突软骨中的表达也显著上调。S1P(1)被发现在S1P诱导的破骨细胞前体细胞的迁移和通过rac1的下游信号传递中是必需的。当人工合成的核因子-kappaB抑制肽SN50应用于MRL/IPR小鼠时，软骨下骨小梁丢失减少，破骨细胞生成标志物的产生和鞘氨醇激酶(Sphk)1/S1P(1)信号转导均减少。因此，本研究结果提示，Fas/S1P(1)信号通路通过激活破骨细胞前体细胞中的核因子-kappaB，是TMJ类风湿关节炎发病机制中的关键因素。(C)2017 Elsevier Inc.保留所有权利。
Enhanced turnover of subchondral trabecular bone is a hallmark of rheumatoid arthritis (RA) and it results from an imbalance between bone resorption and bone formation activities. To investigate the formation and activation of osteoclasts which mediate bone resorption, a Fas-deficient MRL/Ipr mouse model which spontaneously develops autoimmune arthritis and exhibits decreased bone mass was studied. Various assays were performed on subchondral trabecular bone of the temporomandibular joint (TMJ) from MRL/lpr mice and MRL+/+ mice. Initially, greater osteoclast production was observed in vitro from bone marrow macrophages obtained from MRL/lpr mice due to enhanced phosphorylation of NF-kappa B, as well as Akt and MAPK, to receptor activator of nuclear factor-kappa B ligand (RANKL). Expression of sphingosine 1-phosphate receptor 1 (SIP1) was also significantly upregulated in the condylar cartilage. S1P(1) was found to be required for S1P-induced migration of osteoclast precursor cells and downstream signaling via Rac1. When SN50, a synthetic NF-kappa B-inhibitory peptide, was applied to the MRL/Ipr mice, subchondral trabecular bone loss was reduced and both production of osteoclastogenesis markers and sphingosine kinase (Sphk) 1/S1P(1) signaling were reduced. Thus, the present results suggest that Fas/S1P(1) signaling via activation of NF-kappa B in osteoclast precursor cells is a key factor in the pathogenesis of RA in the TMJ. (C) 2017 Elsevier Inc. All rights reserved.