Hepatocyte growth factor regulates HIF-1α-induced nucleus pulposus cell proliferation through MAPK, PI3K/Akt, and STAT3 mediated signaling.

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-1alpha) protein, which contributes to the maintenance of homeostasis in NP cells, was also upregulated in hypoxia-treated cells groups; HGF further increased HIF-1alpha expression in NP cells. Additionally, knockdown of HIF-1alpha expression significantly reduced the proliferation of NP cells. A MAPK inhibitor inhibited the expression of HIF-1alpha and pERK, as well as and cell proliferation in a dose-dependent manner. Similarly, inhibiting the PI3K/Akt and STAT3 pathways also decreased the expression HIF-1alpha and cell proliferation. These results show that under hypoxic conditions, HGF promotes NP cell proliferation via HIF-1alpha, and MAPK, PI3K/Akt, and STAT3 mediated signaling 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. This article is protected by copyright. All rights reserved.