INTRODUCTION: Intervertebral disc degeneration (IDD) is the primary cause of low back pain, and compromised stress defense may mediate this pathological process . The Sestrins (Sesn) promote cell survival under stress conditions and regulate AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signaling. The aims of present study were to investigate the expression of Sesn in normal and degraded NP cells and its potential roles during IDD pathogenesis.
METHODS: Sesn expression in normal and degraded NP cells was determined by quantitative polymerase chain reaction and immunoblotting and immunohistochemistry, respectively. Sesn function was investigated by using Sesn knockdown and overexpression techniques with analysis of extracellular matrix (ECM), cell apoptosis, autophagy, AMPK, and mTOR activation.
RESULTS: The expression of Sesn were significantly reduced in degradated NP cells in DNA level, western blot and immunohistochemistry of human degradated NP cells also showed a corresponding reduction in protein levels. In human cultured NP cells, the expression of Sesn1, 2 and 3 increased after stimulated by 2-deoxyglucose (2DG), a Endoplasmic reticulum (ER) stress inducer. We also testified that 2-DG can increased cell apoptosis, promoted ECM degradation and positively regulated autophagy in NP cells. Sesn knockdown by siRNA increased NP cells apoptosis and ECM degradation under basal culture conditions and in the presence of 2DG. Sesn overexpression repressed IDD by enhancing autophagy , and this was related to changes in mTOR but not AMPK activation.
SIGNIFICANCE ER stress can induce IDD by promoting cell apoptosis and ECM degradation. Sesn can modulate mTOR activity and repress stress -induced IDD：by enhancing autophagy activation. Suppression of Sesn might be an important cellular dysfunction mechanism in the process of IDD.