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

Abstract

p38 mitogen-activated protein kinase (p38MAPK) is a critical negative regulator for nucleus pulposus (NP) cell metabolism contributing to intervertebral disc degeneration (IDD). Histone deacetylase 4 (HDAC4) has the ability to mediate cell proliferation and is affected by p38MAPK. It is unclear whether the p38 MAPK inhibitor SD0006 (SD) can regulate IDD. Our study aims to explore the effect of SD in the progression of IDD, as well as its potential mechanism. NP cells isolating from mild degenerated NP tissues were cultured, and IL-1β or Asiatic acid (AA) was used to activate p38MAPK and accelerate the NP cell degradation. Then, SD was used to reject the p38MAPK activation. After that, the levels of phosphorylated p38MAPK (p-p38), HDAC4, proliferating cell nuclear antigen (PCNA), inflammatory factor, proliferative cell rate, and cell cycle were determined by Western blot, RT-PCR, flow cytometry, and immunofluorescence, respectively. The results showed that the activation of p38MAPK by IL-1β and AA decreased the HDAC4 expression, affected the collagen-Ⅱ expression, upregulated the TNF-α, IL-6, MMP-3, and ADAMTS mRNA levels, and prevent the NP cell proliferation by mediating cell cycles. However, the application of SD alleviated the negative effect of p-p38 by upregulating HDAC4, anti-inflammation, and promoting cell proliferation, while the blocking of HDAC4 expression partly abolished the effect of SD. SD can prevent NP cell degeneration by promoting cell proliferation and suppressing inflammation via p38MAPK/HDAC4 pathway.