Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University, 3200 South University Drive, Fort Lauderdale, FL 33328, USA.
Department of Periodontics and Endodontics, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8525, Japan.
Cells. 2023 Apr 8;12(8):1109. doi: 10.3390/cells12081109.
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.
破骨细胞（OC）介导的骨吸收增加是牙周炎和类风湿关节炎（RA）的共同病理特征，这暗示着它们可能具有共同的发病机制。抗瓜氨酸化波形蛋白（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，其在牙周炎背景下对 OC 生成的影响仍有待阐明。在一项体外实验中，外源性 CV 的添加可促进来自小鼠骨髓细胞的抗酒石酸酸性磷酸酶（TRAP）阳性多核 OC 的发育，并增加蚀斑的形成。然而，Cl-amidine（一种不可逆的泛肽基精氨酸脱亚氨酶（PAD）抑制剂）抑制了 RANKL 刺激的 OC 前体中 CV 的产生和分泌，这表明波形蛋白的瓜氨酸化发生在 OC 前体中。另一方面，抗波形蛋白中和抗体抑制了体外核因子 kappa-B 受体激活剂配体（RANKL）诱导的 OC 生成。PKC-δ 抑制剂 Rottlerin 可阻断 CV 诱导的 OC 生成上调，同时下调 OC 生成相关基因，包括破骨细胞刺激跨膜蛋白（OC-STAMP）、TRAP 和基质金属蛋白酶 9（MMP9）以及细胞外信号调节激酶（ERK）丝裂原激活蛋白（MAP）激酶磷酸化。在没有抗 CV 抗体的情况下，在诱导的小鼠牙周炎骨吸收病变中发现可溶性 CV 和携带波形蛋白的单核细胞水平升高。最后，局部注射抗波形蛋白中和抗体可抑制小鼠诱导的牙周骨丢失。综上所述，这些结果表明细胞外释放的 CV 促进了牙周炎中的 OC 生成和骨吸收。
