Hepatocyte growth factor regulates HIF-1α-induced nucleus pulposus cell proliferation through MAPK-, PI3K/Akt-, and STAT3-mediated signaling
Hepatocyte growth factor regulates HIF-1α-induced nucleus pulposus cell proliferation through MAPK-, PI3K/Akt-, and STAT3-mediated signaling
复制标题
DOI：
10.1002/jor.24679
复制
发表时间：
2020-04-12
影响因子：
2.8
通讯作者：
Kubo, Toshikazu
中科院分区：
文献类型：
--
作者：
Itsuji, Tomonori;Tonomura, Hitoshi;Kubo, Toshikazu
椎间盘对保持活动能力和支撑躯干很重要。如果这些椎间盘失去了它们的生物力学特征，就会出现腰痛。我们之前报道过肝细胞生长因子（HGF）促进细胞增殖，抑制髓核（NP）细胞的凋亡、炎症和基质降解。在本研究中，我们研究了HGF在缺氧条件下促进NP细胞增殖的分子机制。缺氧刺激促进适度的细胞增殖，HGF进一步上调细胞增殖。缺氧诱导因子（HIF-1 α）蛋白的表达在缺氧处理的细胞组中也上调，该蛋白有助于维持NP细胞的内稳态；HGF进一步增加了NP细胞中HIF-1 α的表达。此外，抑制HIF-1 α表达可显著降低NP细胞的增殖。MAPK抑制剂以剂量依赖的方式抑制HIF-1 α和pERK的表达以及细胞增殖。同样，抑制PI3K/Akt和STAT3通路也会降低HIF-1 α的表达和细胞增殖。这些结果表明，在缺氧条件下，HGF通过参与该通路的HIF-1 α -、MAPK-、PI3K/Akt-和stat3介导的信号通路促进NP细胞增殖。这些信号通路的控制可能是治疗缺氧条件下椎间盘退变的潜在治疗策略的目标。
Intervertebral discs are important for maintaining mobility and offer support to the body trunk. If these discs lose their biomechanical features, lower back pain can occur. We previously reported that hepatocyte growth factor (HGF) promotes cell proliferation and suppresses apoptosis, inflammation, and matrix degradation in nucleus pulposus (NP) cells. In the present study, we investigated the molecular mechanisms of how HGF promotes the proliferation of NP cells in hypoxic conditions. Hypoxic stimulation promoted modest cell proliferation, which was further upregulated by HGF. Expression of hypoxia-inducible factor (HIF-1 alpha) protein, which contributes to the maintenance of homeostasis in NP cells, was also upregulated in hypoxia-treated cell groups; HGF further increased HIF-1 alpha expression in NP cells. Additionally, knockdown of HIF-1 alpha expression significantly reduced the proliferation of NP cells. An MAPK inhibitor inhibited the expression of HIF-1 alpha and pERK, as well as cell proliferation in a dose-dependent manner. Similarly, inhibiting the PI3K/Akt and STAT3 pathways also decreased the expression of HIF-1 alpha and cell proliferation. These results show that under hypoxic conditions, HGF promotes NP cell proliferation via HIF-1 alpha-, MAPK-, PI3K/Akt-, and STAT3-mediated signaling which is involved in this pathway. The control of these signaling pathways may be a target for potential therapeutic strategies for the treatment of disc degeneration in hypoxic conditions.