Extracellular Release of Citrullinated Vimentin Directly Acts on Osteoclasts to Promote Bone Resorption in a Mouse Model of Periodontitis.
Extracellular Release of Citrullinated Vimentin Directly Acts on Osteoclasts to Promote Bone Resorption in a Mouse Model of Periodontitis.
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破骨细胞（OC）介导的骨吸收是牙周炎和类风湿关节炎（RA）的共同病理特征，暗示可能存在共同的发病机制。瓜氨酸波形蛋白（CV）的自身抗体是RA的代表性生物标志物，据报道可促进破骨细胞生成（OC-生成）。然而，其对牙周炎背景下OC发生的影响仍有待阐明。在体外实验中，外源性CV的加入上调了小鼠骨髓细胞中抗酒石酸酸性磷酸酶（TRAP）阳性多核OC的发育，并增加了吸收陷窝的形成。然而，Cl-脒，一种不可逆的泛肽精氨酸脱亚胺酶（PAD）抑制剂，抑制了RANKL刺激的OC前体的CV的产生和分泌，表明波形蛋白的瓜氨酸发生在OC前体中。另一方面，抗波形蛋白中和抗体在体外抑制核因子κ B受体激活因子配体（RANKL）诱导的OC发生。蛋白激酶C（PKC）-δ抑制剂Rottlerin可阻断CV诱导的OC发生上调，同时下调破骨细胞刺激跨膜蛋白（OC-STAMP）、TRAP和基质金属肽酶9（MMP 9）等OC发生相关基因以及细胞外信号调节激酶（ERK）丝裂原活化蛋白（MAP）激酶磷酸化。在不存在抗CV抗体的情况下，在小鼠牙周炎诱导的骨吸收病变中发现可溶性CV和波形蛋白单核细胞水平升高。最后，局部注射抗波形蛋白中和抗体可抑制小鼠牙周骨丢失。总之，这些结果表明，细胞外释放的CV促进OC的发生和骨吸收的牙周炎。
Elevated osteoclast (OC)-mediated bone resorption, a common pathological feature between periodontitis and rheumatoid arthritis (RA), implicates a possible mutually shared pathogenesis. The autoantibody to citrullinated vimentin (CV), a representative biomarker of RA, is reported to promote osteoclastogenesis (OC-genesis). However, its effect on OC-genesis in the context of periodontitis remains to be elucidated. In an in vitro experiment, the addition of exogenous CV upregulated the development of Tartrate-resistant acid phosphatase (TRAP)-positive multinuclear OCs from mouse bone marrow cells and increased the formation of resorption pits. However, Cl-amidine, an irreversible pan-peptidyl arginine deiminase (PAD) inhibitor, suppressed the production and secretion of CV from RANKL-stimulated OC precursors, suggesting that the citrullination of vimentin occurs in OC precursors. On the other hand, the anti-vimentin neutralizing antibody suppressed in vitro Receptor activator of nuclear factor kappa-Β ligand (RANKL)-induced OC-genesis. The CV-induced upregulation of OC-genesis was abrogated by the Protein kinase C (PKC)-δ inhibitor Rottlerin, accompanied by the downmodulation of OC-genesis-related genes, including Osteoclast stimulatory transmembrane protein (OC-STAMP), TRAP and Matrix Metallopeptidase 9 (MMP9) as well as extracellular signal-regulated kinase (ERK) mitogen-activated protein (MAP)-kinase phosphorylation. Elevated levels of soluble CV and vimentin-bearing mononuclear cells were found in the bone resorption lesions of periodontitis induced in mice in the absence of an anti-CV antibody. Finally, local injection of anti-vimentin neutralizing antibody suppressed the periodontal bone loss induced in mice. Collectively, these results indicated that the extracellular release of CV promoted OC-genesis and bone resorption in periodontitis.
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