OCLI-023, a Novel Pyrimidine Compound, Suppresses Osteoclastogenesis In Vitro and Alveolar Bone Resorption In Vivo.
OCLI-023, a Novel Pyrimidine Compound, Suppresses Osteoclastogenesis In Vitro and Alveolar Bone Resorption In Vivo.
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DOI：
10.1371/journal.pone.0170159
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Park EK
中科院分区：
文献类型：
--
作者：
Ihn HJ;Lee T;Kim JA;Lee D;Kim ND;Shin HI;Bae YC;Park EK
破骨细胞分化和活化的异常增加导致各种骨吸收疾病，包括牙周炎、类风湿性关节炎和骨质疏松症。含有嘧啶环的化合物已被证明可以调节多种生物过程。因此，为了鉴定抗骨吸收剂，我们合成了一系列含嘧啶环的化合物，并发现OCLI-023在体外抑制破骨细胞的分化和活化。OCLI-023直接抑制核因子-κB配体受体激活剂（RANKL）诱导的骨髓巨噬细胞向破骨细胞的分化，而无细胞毒性反应。OCLI-023还下调RANKL诱导的破骨细胞标志物的mRNA表达，并抑制肌动蛋白环和吸收陷窝的形成。OCLI-023减弱RANKL诱导的c-Jun N-末端激酶活化和活化B细胞信号传导途径的核因子κ轻链增强子活化。在小鼠牙周炎模型中，结扎导致第二磨牙牙骨质-釉质连接处（CEJ）与牙槽骨嵴（ABC）之间的距离增加，OCLI-023可显著降低CEJ与ABC之间的距离;组织学分析显示，OCLI-023可显著降低结扎导致的破骨细胞数量增加。这些数据表明OCLI-023在体外对破骨细胞分化和破骨细胞活性以及在体内对结扎诱导的骨丢失具有抑制作用，并且OCLI-023可以被提出作为新型抗骨吸收化合物。
An abnormal increase in osteoclast differentiation and activation results in various bone-resorptive diseases, including periodontitis, rheumatoid arthritis, and osteoporosis. Chemical compounds containing pyrimidine ring have been shown to regulate a variety of biological processes. Therefore, in order to identify an antiresorptive agent, we synthesized a series of pyrimidine ring-containing chemical compounds, and found that OCLI-023 suppressed the differentiation and activation of osteoclasts in vitro. OCLI-023 directly inhibited receptor activator of nuclear factor-κB ligand (RANKL)-induced differentiation of bone marrow macrophages into osteoclasts, without a cytotoxic response. OCLI-023 also downregulated the RANKL-induced mRNA expression of osteoclast markers as well as inhibited the formation of actin rings and resorption pits. OCLI-023 attenuated the RANKL-induced activation of c-Jun N-terminal kinase and nuclear factor kappa-light-chain-enhancer of activated B cell signaling pathways. In a mouse model of periodontitis, ligature induced an increase of distance between cementoenamel junction (CEJ) and alveolar bone crest (ABC) in the second molar, and OCLI-023 significantly reduced it. Histological analysis showed ligature-induced increase of osteoclast numbers was also significantly reduced by OCLI-023. These data demonstrated the inhibitory effect of OCLI-023 on osteoclast differentiation and activity of osteoclasts in vitro, as well as on ligature-induced bone loss in vivo, and OCLI-023 can be proposed as a novel anti-resorptive compound.