SD0006 promotes nucleus pulposus cell proliferation via the p38MAPK/HDAC4 pathway

Area of Science:

• Biochemistry
• Cell Biology
• Molecular Biology

Background:

• p38 mitogen-activated protein kinase (p38MAPK) negatively regulates nucleus pulposus (NP) cell metabolism, contributing to intervertebral disc degeneration (IDD).
• Histone deacetylase 4 (HDAC4) influences cell proliferation and is modulated by p38MAPK, but its role in IDD remains unclear.
• The therapeutic potential of the p38 MAPK inhibitor SD0006 (SD) for IDD requires investigation.

Purpose of the Study:

• To investigate the effect of SD0006 (SD) on intervertebral disc degeneration (IDD) progression.
• To elucidate the underlying mechanism of SD's action in nucleus pulposus (NP) cells.
• To determine if SD regulates the p38MAPK/HDAC4 pathway in the context of IDD.

Main Methods:

• Nucleus pulposus (NP) cells were cultured and treated with IL-1β or Asiatic acid (AA) to induce p38MAPK activation and NP cell degradation.
• SD was applied to inhibit p38MAPK activation.
• Levels of phosphorylated p38MAPK (p-p38), HDAC4, PCNA, inflammatory factors, cell proliferation, and cell cycle were assessed using Western blot, RT-PCR, flow cytometry, and immunofluorescence.

Main Results:

• IL-1β/AA-induced p38MAPK activation decreased HDAC4 expression, reduced collagen-Ⅱ, and increased inflammatory markers (TNF-α, IL-6, MMP-3, ADAMTS), inhibiting NP cell proliferation.
• SD treatment counteracted these effects by upregulating HDAC4, reducing inflammation, and promoting NP cell proliferation.
• Inhibition of HDAC4 partially abolished the protective effects of SD, indicating its crucial role.

Conclusions:

• SD0006 (SD) mitigates NP cell degeneration by enhancing cell proliferation and suppressing inflammation.
• The therapeutic effect of SD is mediated through the p38MAPK/HDAC4 signaling pathway.
• SD shows promise as a therapeutic agent for intervertebral disc degeneration (IDD).