Department of Oral and Maxillofacial Pathology, Research Center for Tooth and Periodontal Regeneration (MRC), School of Dentistry and Institute of Oral Biology, Kyung Hee University, Seoul, Republic of Korea.
Department of Oral Anatomy and Developmental Biology, School of Dentistry, Kyung Hee University, Seoul, Republic of Korea.
J Dent Res. 2015 Feb;94(2):371-80. doi: 10.1177/0022034514563335. Epub 2014 Dec 15.
Inflammatory responses and osteoclast differentiation play pivotal roles in the pathogenesis of osteolytic bone diseases such as periodontitis. Although overexpression or inhibition of peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (PIN1) offers a possible therapeutic strategy for chronic inflammatory diseases, the role of PIN1 in periodontal disease is unclear. The aim of the present study was to evaluate PIN1 expression in periodontitis patients as well as the effects of PIN1 inhibition by juglone or PIN1 small-interfering RNA (siRNA) and of PIN1 overexpression using a recombinant adenovirus encoding PIN1 (Ad-PIN1) on the inflammatory response and osteoclastic differentiation in lipopolysaccharide (LPS)- and nicotine-stimulated human periodontal ligament cells (PDLCs). PIN1 was up-regulated in chronically inflamed PDLCs from periodontitis patients and in LPS- and nicotine-exposed PDLCs. Inhibition of PIN1 by juglone or knockdown of PIN1 gene expression by siRNA markedly attenuated LPS- and nicotine-stimulated prostaglandin E2 (PGE2) and nitric oxide (NO) production, as well as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression, whereas PIN1 overexpression by Ad-PIN1 increased it. LPS- and nicotine-induced nuclear factor (NF)-κB activation was blocked by juglone and PIN1 siRNA but increased by Ad-PIN1. Conditioned medium prepared from LPS- and nicotine-treated PDLCs increased the number of tartrate-resistant acid phosphatase-stained osteoclasts and osteoclast-specific gene expression. These responses were blocked by PIN1 inhibition and silencing but stimulated by Ad-PIN1. Furthermore, juglone and PIN1 siRNA inhibited LPS- and nicotine-induced osteoclastogenic cytokine expression in PDLCs. This study is the first to demonstrate that PIN1 inhibition exhibits anti-inflammatory effects and blocks osteoclastic differentiation in LPS- and nicotine-treated PDLCs. PIN1 inhibition may be a therapeutic strategy for inflammatory osteolysis in periodontal disease.
炎症反应和破骨细胞分化在溶骨性骨病（如牙周炎）的发病机制中起着关键作用。尽管肽基脯氨酰顺/反异构酶 NIMA 相互作用 1（PIN1）的过表达或抑制为慢性炎症性疾病提供了一种可能的治疗策略，但 PIN1 在牙周病中的作用尚不清楚。本研究旨在评估牙周炎患者中 PIN1 的表达，以及使用 juglone 或 PIN1 小干扰 RNA（siRNA）抑制 PIN1 以及使用编码 PIN1 的重组腺病毒（Ad-PIN1）过表达 PIN1 对脂多糖（LPS）和尼古丁刺激的人牙周韧带细胞（PDLC）中的炎症反应和破骨细胞分化的影响。慢性炎症 PDLC 中 PIN1 上调，牙周炎患者和 LPS-和尼古丁暴露的 PDLC 中也上调。Juglone 抑制 PIN1 或 siRNA 敲低 PIN1 基因表达显著减弱了 LPS 和尼古丁刺激的前列腺素 E2（PGE2）和一氧化氮（NO）的产生，以及环氧化酶-2（COX-2）和诱导型一氧化氮合酶（iNOS）的表达，而 Ad-PIN1 过表达则增加了它。Juglone 和 PIN1 siRNA 阻断了 LPS 和尼古丁诱导的核因子（NF）-κB 激活，但增加了 Ad-PIN1 的激活。LPS 和尼古丁处理的 PDLC 制备的条件培养基增加了抗酒石酸酸性磷酸酶染色的破骨细胞数量和破骨细胞特异性基因表达。这些反应被 PIN1 抑制和沉默阻断，但被 Ad-PIN1 刺激。此外，Juglone 和 PIN1 siRNA 抑制了 LPS 和尼古丁诱导的 PDLC 中破骨细胞生成细胞因子的表达。这项研究首次表明，PIN1 抑制在 LPS 和尼古丁处理的 PDLC 中表现出抗炎作用并阻断破骨细胞分化。PIN1 抑制可能是牙周病中炎症性骨溶解的一种治疗策略。
