Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Suzhou, 215006, Jiangsu, China.
Department of Orthopedics, Hai'an People's Hospital, Hai'an 226600, Jiangsu, China.
Biochim Biophys Acta Mol Basis Dis. 2024 Jan;1870(1):166888. doi: 10.1016/j.bbadis.2023.166888. Epub 2023 Sep 16.
Intervertebral disc degeneration (IVDD) is considered one of the main reasons for low back pain (LBP). To date, the specific pathology of IVDD remains unclear. The annulus fibrosus (AF) is an important part of the intervertebral disc, and AF cell oxidative stress, apoptosis plays a vital role in disc degeneration. Protein phosphatase 2 A (PP2A), a serine/threonine phosphatase, has regulatory functions in various processes, including apoptosis and autophagy. However, thus far, the effect of PP2A on IVDD is not clear.
AF cells derived from caudal intervertebral discs in SD rats were used to analyze the levels of oxidative stress, apoptosis and degeneration as well as PP2A expression. A PP2A agonist (FTY720), inhibitor (microcystin-LR) and siRNA (si-PPP2CA) were employed in IVDD induced by HO to investigate the levels of apoptosis and degeneration. The p38/MAPK signal pathways were evaluated, and a p38 inhibitor (SB203580) and ERK inhibitor (U0126) were added for verification. Finally, FTY720 and microcystin-LR were administered to IVDD rats to assess the effects on levels of apoptosis and degeneration and the relief of IVDD.
The expression of PP2A was increased in rat AF cells after HO intervention. The levels of apoptosis and degeneration were higher with upregulation of PP2A but were significantly reduced after inhibition of PP2A. The PP2A inhibitor relieved cell apoptosis and degeneration by downregulating the p38/MAPK pathway. In vivo, the knockdown of PP2A resulted in a more complete morphology of discs and less apoptotic and degenerative expression.
This study suggests that the downregulation of PP2 A could reduce AF cell apoptosis and degeneration via the p38/MAPK pathway. It also revealed that the inhibition of PP2 A is expected to be a therapeutic target for IVDD.
椎间盘退变（IVDD）被认为是腰痛（LBP）的主要原因之一。迄今为止，IVDD 的具体病理学仍不清楚。纤维环（AF）是椎间盘的重要组成部分，AF 细胞氧化应激、凋亡在椎间盘退变中起着至关重要的作用。蛋白磷酸酶 2A（PP2A）是一种丝氨酸/苏氨酸磷酸酶，在包括凋亡和自噬在内的各种过程中具有调节作用。然而，到目前为止，PP2A 对 IVDD 的影响尚不清楚。
使用 SD 大鼠尾椎间盘中分离的 AF 细胞分析氧化应激、凋亡和退变水平以及 PP2A 表达。HO 诱导的 IVDD 中使用 PP2A 激动剂（FTY720）、抑制剂（微囊藻-LR）和 siRNA（si-PPP2CA），以研究凋亡和退变水平。评估 p38/MAPK 信号通路，并添加 p38 抑制剂（SB203580）和 ERK 抑制剂（U0126）进行验证。最后，给予 FTY720 和微囊藻-LR 治疗 IVDD 大鼠，评估对凋亡和退变水平的影响及对 IVDD 的缓解作用。
HO 干预后大鼠 AF 细胞中 PP2A 的表达增加。上调 PP2A 会导致更高的凋亡和退变水平，但抑制 PP2A 后显著降低。PP2A 抑制剂通过下调 p38/MAPK 通路减轻细胞凋亡和退变。在体内，下调 PP2A 导致椎间盘形态更完整，凋亡和退变表达更少。
本研究表明，下调 PP2A 通过 p38/MAPK 通路可减少 AF 细胞凋亡和退变。它还表明，抑制 PP2A 可能成为 IVDD 的治疗靶点。
