Mannan-Binding Lectin Attenuates Inflammatory Arthritis Through the Suppression of Osteoclastogenesis
Mannan-Binding Lectin Attenuates Inflammatory Arthritis Through the Suppression of Osteoclastogenesis
复制标题
甘露聚糖结合凝集素通过抑制破骨细胞生成减轻炎症性关节炎
DOI：
10.3389/fimmu.2019.01239
复制
发表时间：
2019-06-04
影响因子：
7.3
通讯作者：
Zuo, Daming
中科院分区：
文献类型：
--
作者：
Dong, Lijun;Wu, Jun;Zuo, Daming
甘露聚糖结合凝集素(MBL)是宿主天然免疫系统中的重要成分，主要由肝脏产生并分泌到循环中。据报道，血清MBL水平低与关节炎风险增加有关。然而，MBL在关节炎发病机制中的作用机制尚不清楚。在这项研究中，我们研究了MBL在实验性小鼠佐剂性关节炎(AIA)过程中的确切作用。与野生型C57BL/6 AIA小鼠相比，MBL缺陷(MBL-/-)AIA小鼠表现出显著的炎症反应，包括软骨损伤加重，组织病理学特征增强，以及高水平的酒石酸抗性酸性磷酸酶(TRAP)阳性细胞。MBL蛋白在体外可明显抑制核因子-kappaB受体激活剂(RANKL)和巨噬细胞集落刺激因子(M-CSF)诱导的人血单核细胞的破骨细胞形成。机制研究证实，MBL通过下调p38信号通路和随后的c-fos核转位以及激活活化的T细胞核因子C1(NFATc1)途径来抑制破骨细胞的分化。重要的是，我们提供的证据表明，在关节炎患者中，MBL浓度与血清I型前胶原氨基端前肽(PINP)和I型胶原C端肽(β-CTX)水平呈负相关，这是骨转换的血清标志物。我们的研究揭示了MBL在破骨细胞形成中意想不到的功能，从而为MBL缺乏患者的炎性关节炎和其他骨相关疾病提供了新的见解。
Mannan-binding lectin (MBL) is a vital element in the host innate immune system, which is primarily produced by the liver and secreted into the circulation. Low serum level of MBL is reported to be associated with an increased risk of arthritis. However, the underlying mechanism by which MBL contributes to the pathogenesis of arthritis is poorly understood. In this study, we investigated the precise role of MBL on the course of experimental murine adjuvant-induced arthritis (AIA). MBL-deficient (MBL-/-) AIA mice showed significantly increased inflammatory responses compared with wild-type C57BL/6 AIA mice, including exacerbated cartilage damage, enhanced histopathological features and high level of tartrate-resistant acid phosphatase (TRAP)-positive cells. MBL protein markedly inhibited the osteoclast formation from human blood monocytes induced by receptor activator of nuclear factor-kappa B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) in vitro. Mechanistic studies established that MBL inhibited osteoclast differentiation via down-regulation of p38 signaling pathway and subsequent nuclear translocation of c-fos as well as activation of nuclear factor of activated T-cells c1 (NFATc1) pathway. Importantly, we have provided the evidence that concentrations of MBL correlated negatively with the serum levels of amino-terminal propeptide of type I procollagen (PINP) and C-terminal telopeptide of type I collagen (beta-CTX), serum markers of bone turnover, in patients with arthritis. Our study revealed an unexpected function of MBL in osteoclastogenesis, thus providing new insight into inflammatory arthritis and other bone-related diseases in patients with MBL deficiency.