Sestrin-Mediated Inhibition of Stress-Induced Intervertebral Disc Degradation Through the Enhancement of Autophagy

Abstract

Background/Aims: Intervertebral disc degeneration (IDD) is a pathological process that is the primary cause of low back pain and is potentially mediated by compromised stress defense. Sestrins (Sesn) promote cell survival under stress conditions and regulate AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signaling. Here, we investigated the expression of Sesn in normal and degraded nucleus pulposus (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: In human cultured NP cells, Sesn expression was significantly decreased in degraded NP cells at both the RNA and protein levels. The expression of Sesn1, 2, and 3 increased after stimulation by 2-deoxyglucose (2-DG), an endoplasmic reticulum stress inducer. 2-DG could also increase cell apoptosis, promote extracellular matrix (ECM) degradation, and positively regulate autophagy in NP cells. Sesn knockdown by small interfering RNA increased NP cell apoptosis and ECM degradation under basal culture conditions and in the presence of 2DG. Conversely, Sesn overexpression mediated by plasmid transfection repressed IDD by enhancing autophagy, which was associated with changes in mTOR but not AMPK activation. Conclusions: Sesn expression is suppressed in degraded NP cells. In addition, Sesn inhibits stress-induced cell apoptosis and ECM degradation by enhancing autophagy, which is modulated though mTOR activity. Suppression of Sesn might therefore represent an important cellular dysfunction mechanism in the process of IDD.

The potential role and trend of HIF‑1α in intervertebral disc degeneration: Friend or foe? (Review)

“…Autophagy is a non-apoptotic, programmed cell death that leads to the self-digestion and degradation of unwanted proteins and organelles to prevent cellular stress and maintain cell function (157). Cells can resist apoptosis and senescence by activating autophagy, which alleviates the progression of certain chronic degenerative diseases (158)(159)(160)(161)(162). Autophagy plays a crucial role in the pathogenesis of a number of degenerative diseases, including osteoarthritis (158) and IDD (159)(160)(161)(162).…”

“…Cells can resist apoptosis and senescence by activating autophagy, which alleviates the progression of certain chronic degenerative diseases (158)(159)(160)(161)(162). Autophagy plays a crucial role in the pathogenesis of a number of degenerative diseases, including osteoarthritis (158) and IDD (159)(160)(161)(162). The autophagy-related genes or proteins beclin 1, cathepsin B, damage-regulated autophagy modulator 1 and p65 were highly expressed in degenerated IVD tissues compared with normal, healthy IVD tissues (163).…”

“…The level of cellular autophagy changes accordingly as IVD degenerates and ages (160,164,168). There has been preliminary progress in the study of whether HIF-1α regulates IDD through autophagy in IVD cells under hypoxic conditions.…”

SESTRINs: Emerging Dynamic Stress-Sensors in Metabolic and Environmental Health

“…However, Sesn3 is somewhat redundant to Sesn2 in metabolic function and autophagy induction in liver and colon tissues (Lee et al, 2012;Ro et al, 2016). Although ectopically expressed Sestrin2 protein is mostly found in cytoplasm (Parmigiani et al, 2014), recent studies suggest that Sestrin2 is associated with mitochondria (Kim H. et al, 2020;Kovaleva et al, 2020), nucleus (Tu et al, 2018;Wang L.X. et al, 2020), and endoplasmic reticulum (ER) (Wang L.X.…”

Regeneration in Spinal Disease: Therapeutic Role of Hypoxia-Inducible Factor-1 Alpha in Regeneration of Degenerative Intervertebral Disc

“…Autophagy, the process of non-apoptotic, programmed cell death, is a physiological response to hypoxia and exhibits a complicated association with hypoxia [ 98 , 99 ]. The level of autophagy changes according to IVD degeneration and age [ 98 , 100 ]. It has been shown that NP cells show higher autophagy activity under normoxia than under hypoxia [ 98 , 101 ].…”