Oral Oncology Clinic, Research Institute and Hospital, National Cancer Center, Goyang-Si, Gyeonggi-Do 10408, Republic of Korea.
Department of Oral Biochemistry and Program in Cancer and Developmental Biology, Dental Research Institute, Seoul National University School of Dentistry, Seoul 03080, Republic of Korea.
Cell Death Differ. 2018 Feb;25(2):268-281. doi: 10.1038/cdd.2017.153. Epub 2017 Sep 22.
Osteoporosis affects millions of people worldwide by promoting bone resorption and impairing bone formation. Bisphosphonates, commonly used agents to treat osteoporosis, cannot reverse the substantial bone loss that has already occurred by the time of diagnosis. Moreover, their undesirable side-effects, including osteonecrosis of the jaw, have been reported. Here, we demonstrated that a new bioactive core vitronectin-derived peptide (VnP-16) promoted bone formation by accelerating osteoblast differentiation and activity through direct interaction with β1 integrin followed by FAK activation. Concomitantly, VnP-16 inhibited bone resorption by restraining JNK-c-Fos-NFATc1-induced osteoclast differentiation and αvβ3 integrin-c-Src-PYK2-mediated resorptive function. Moreover, VnP-16 decreased the bone resorbing activity of pre-existing mature osteoclasts without changing their survival rate. Furthermore, VnP-16 had a strong anabolic effect on bone regeneration by stimulating osteoblast differentiation and increasing osteoblast number, and significantly alleviated proinflammatory cytokine-induced bone resorption by restraining osteoclast differentiation and function in murine models. Moreover, VnP-16 could reverse ovariectomy-induced bone loss by both inhibiting bone resorption and promoting bone formation. Given its dual role in promoting bone formation and inhibiting bone resorption, our results suggest that VnP-16 could be an attractive therapeutic agent for treating osteoporosis.
骨质疏松症通过促进骨吸收和损害骨形成影响着全球数百万人。双膦酸盐是一种常用于治疗骨质疏松症的药物，但在诊断时已经发生的大量骨质流失无法逆转。此外，它们的不良反应，包括颌骨坏死，已经有报道。在这里，我们证明了一种新的生物活性核心 vitronectin 衍生肽（VnP-16）通过与 β1 整合素直接相互作用，随后激活 FAK，促进成骨细胞分化和活性，从而促进骨形成。同时，VnP-16 通过抑制 JNK-c-Fos-NFATc1 诱导的破骨细胞分化和 αvβ3 整合素-c-Src-PYK2 介导的吸收功能来抑制骨吸收。此外，VnP-16 降低了预先存在的成熟破骨细胞的骨吸收活性，而不改变其存活率。此外，VnP-16 通过刺激成骨细胞分化和增加成骨细胞数量对骨再生具有很强的合成代谢作用，并通过抑制破骨细胞分化和功能在小鼠模型中显著缓解促炎细胞因子诱导的骨吸收。此外，VnP-16 可以通过抑制骨吸收和促进骨形成来逆转卵巢切除引起的骨丢失。鉴于其在促进骨形成和抑制骨吸收方面的双重作用，我们的结果表明 VnP-16 可能是治疗骨质疏松症的一种有吸引力的治疗剂。
