Insulin-like growth factor 2 promotes osteoclastogenesis increasing inflammatory cytokine levels under hypoxia
Insulin-like growth factor 2 promotes osteoclastogenesis increasing inflammatory cytokine levels under hypoxia
复制标题
胰岛素样生长因子 2 促进破骨细胞生成，增加缺氧条件下炎症细胞因子水平
DOI：
10.1016/j.jphs.2022.03.007
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发表时间：
2022
影响因子：
3.5
通讯作者：
Aoyama Mineyoshi
中科院分区：
文献类型：
--
作者：
Kondo Takao;Aoki Hiromasa;Otsuka Yuto;Kawaguchi Yohei;Waguri-Nagaya Yuko;Aoyama Mineyoshi
骨质疏松症是由于破骨细胞（OC）的异常形成和激活导致骨重建失衡而引起的。炎症部位的缺氧促进包括人类在内的各种物种的OC形成和激活。我们以前报道过胰岛素样生长因子2（IGF 2）在缺氧条件下破骨细胞生成中起重要作用。在我们目前的研究中，我们专注于破骨细胞在缺氧的IGF 2信号转导机制。我们证实，在常氧条件下，添加IGF 2促进破骨细胞生成。相反，IGF 2中和抗体抑制破骨细胞在常氧和缺氧条件下。IGF 2的添加增加了磷酸化Akt（Thr 308和Ser 473）和NF-κB（Ser 536）的水平，表明Akt-NF-κB通路的激活。IGF 2还增加了诱导型一氧化氮合酶的表达，该酶通过一氧化氮的产生促进破骨细胞的生成。编码炎性细胞因子（如肿瘤坏死因子-α、白细胞介素（IL）-1β和IL-6）的基因表达水平上调，表明IGF 2通过激活Akt-NF-κB途径增加炎性细胞因子的表达来促进破骨细胞生成。这些结果表明，IGF 2是骨质疏松症和类风湿性关节炎的一个有前途的治疗靶点。
Osteoporosis is caused by an imbalance in bone remodeling due to abnormal osteoclast (OC) formation and activation. Hypoxia at the site of inflammation promotes OC formation and activation in various species, including humans. We previously reported that insulin-like growth factor 2 (IGF2) plays an important role in osteoclastogenesis under hypoxia. In our present study, we focused on the mechanism of osteoclastogenesis in regard to IGF2 signaling under hypoxia. We confirmed that the addition of IGF2 promoted osteoclastogenesis under normoxic conditions. Conversely, IGF2-neutralizing antibodies inhibited osteoclastogenesis under both normoxic and hypoxic conditions. IGF2 addition increased levels of phosphorylated Akt (Thr308 and Ser473) and NF-κB (Ser536), indicating activation of the Akt–NF-κB pathway. IGF2 also increased the expression of inducible nitric oxide synthase, which promotes osteoclastogenesis via nitric oxide production. Expression levels of genes encoding inflammatory cytokines, such as tumor necrosis factor-α, interleukin (IL)-1β, and IL-6, were upregulated, indicating that IGF2 promotes osteoclastogenesis by increasing the expression of inflammatory cytokines via activation of the Akt–NF-κB pathway. These results suggest that IGF2 is a promising therapeutic target for osteoporosis and rheumatoid arthritis.