Monomeric C-Reactive Protein Binds and Neutralizes Receptor Activator of NF-κB Ligand-Induced Osteoclast Differentiation.
Monomeric C-Reactive Protein Binds and Neutralizes Receptor Activator of NF-κB Ligand-Induced Osteoclast Differentiation.
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单体 C 反应蛋白结合并中和 NF-κB 配体诱导的破骨细胞分化的受体激活剂
DOI：
10.3389/fimmu.2018.00234
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发表时间：
2018
影响因子：
7.3
通讯作者：
Wu Y
中科院分区：
文献类型：
--
作者：
Jia ZK;Li HY;Liang YL;Potempa LA;Ji SR;Wu Y
C - 反应蛋白（CRP）是类风湿关节炎（RA）的一种既定标志物，但其在发病机制中的作用尚不明确。在此，我们表明CRP以一种依赖于构象以及核因子 - κB受体活化因子配体（RANKL）的方式调节破骨细胞的分化，破骨细胞是RA中关节炎症和骨侵蚀的核心介质。天然构象的CRP没有作用，而单体构象（mCRP）通过核因子 - κB和磷脂酶C信号通路积极调节破骨细胞分化。此外，mCRP能够结合破骨细胞分化的主要驱动因子RANKL，并消除其活性。RANKL的结合和抑制是由mCRP的胆固醇结合序列（CBS）介导的。与体外实验结果相符的是，CRP基因敲除会加剧脂多糖诱导的小鼠骨吸收。这些结果表明，mCRP可能通过抑制病理性破骨细胞分化在关节炎症中起到保护作用，并且CBS肽可被开发为一种潜在的RANKL抑制剂。
C-reactive protein (CRP) is an established marker of rheumatoid arthritis (RA) but with ill-defined actions in the pathogenesis. Here, we show that CRP regulates the differentiation of osteoclasts, a central mediator of joint inflammation and bone erosion in RA, in a conformation- and receptor activator of NF-κB ligand (RANKL)-dependent manner. CRP in the native conformation is ineffective, whereas the monomeric conformation (mCRP) actively modulates osteoclast differentiation through NF-κB and phospholipase C signaling. Moreover, mCRP can bind RANKL, the major driver of osteoclast differentiation, and abrogate its activities. The binding and inhibition of RANKL are mediated by the cholesterol binding sequence (CBS) of mCRP. Corroborating the in vitro results, CRP knockout exacerbates LPS-induced bone resorption in mice. These results suggest that mCRP may be protective in joint inflammation by inhibiting pathological osteoclast differentiation and that the CBS peptide could be exploited as a potential RANKL inhibitor.