TIGAR impedes compression‐induced intervertebral disc degeneration by suppressing nucleus pulposus cell apoptosis and autophagy

다국어 초록 (Multilingual Abstract)

To investigate whether TP53‐induced glycolysis and apoptosis regulator (TIGAR) participates in compression‐induced intervertebral disc (IVD) degeneration, and to determine the regulatory effect of TIGAR on nucleus pulposus (NP) cell autophagy and apoptosis following compression‐induced injuries. IVD tissues were collected from human patients undergoing surgery (n = 20) and skeletally mature Sprague‐Dawley rats (n = 15). Initially, the effect of compression on the expression of TIGAR was evaluated with in vivo and in vitro models. In addition, TIGAR was silenced to investigate the regulatory effect of TIGAR on compression‐induced intracellular reactive oxygen species (ROS) levels, autophagy, and apoptosis in rat NP cells. Furthermore, the P53 inhibitor pifithrin‐α (PFTα) and SP1 inhibitor mithramycin A were employed to detect expression level changes of TIGAR and autophagy‐associated target molecules. TIGAR expression of NP cells increased gradually in human degenerative IVDs and in rat NP cells under compression both in vivo and in vitro. TIGAR knockdown enhanced compression‐induced intracellular ROS generation and the NADPH/NADP+ and GSH/GSSG ratios. Moreover, TIGAR knockdown amplified the compression‐induced caspase‐3 activation and the apoptosis rate of rat NP cells. Likewise, knockdown of TIGAR significantly accelerated LC3B expression and autophagosome formation in rat NP cells during compression‐induced injuries. The results also established that mithramycin A could inhibit TIGAR expression and autophagy levels in NP cells under compression conditions, while PFTα had no similar effect. Our data demonstrated that TIGAR acted as an important endogenous negative regulator of ROS levels, which might inhibit compression‐induced apoptosis and autophagy through SP1‐dependent mechanisms.
TP53‐induced glycolysis and apoptosis regulator (TIGAR) is involved in compression stress‐induced intervertebral disc degeneration (IVDD) and nucleus pulposus (NP) cell damage. TIGAR increased NADPH generation to reduce intracellular reactive oxygen species, apoptosis, and excessive autophagy, and promote NP cell survival during stress induced‐injuries. TIGAR upregulation induced by compression stress is also regulated by the transcription factor SP1. This study provides a new concept about the pathogenesis of compression stress‐induced IVDD.