Emerging role and therapeutic implication of mTOR signalling in intervertebral disc degeneration

Abstract

Intervertebral disc degeneration (IDD), an important cause of chronic low back pain (LBP), is considered the pathological basis for various spinal degenerative diseases. A series of factors, including inflammatory response, oxidative stress, autophagy, abnormal mechanical stress, nutritional deficiency, and genetics, lead to reduced extracellular matrix (ECM) synthesis by intervertebral disc (IVD) cells and accelerate IDD progression. Mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase that plays a vital role in diverse degenerative diseases. Recent studies have shown that mTOR signalling is involved in the regulation of autophagy, oxidative stress, inflammatory responses, ECM homeostasis, cellular senescence, and apoptosis in IVD cells. Accordingly, we reviewed the mechanism of mTOR signalling in the pathogenesis of IDD to provide innovative ideas for future research and IDD treatment.

Oxidative stress in intervertebral disc degeneration: Molecular mechanisms, pathogenesis and treatment

“…At present, some studies suggest that autophagy disorder in IVD cells may be an important factor in IDD. 167,212 TBHP treatment resulted in decreased levels of LC3II/I and increased levels of p62 in NPCs, indicating that autophagic flux decreased under oxidative stress, while intervention with autophagic agonists restored autophagic flux and inhibited degeneration of NPCs. 130,213 In addition, Chen et al 214 also showed that the autophagy agonist Nar increased autophagic flux and protected human NPCs from TNF-α-induced inflammatory, oxidative stress damage by activating the AMPK/SIRT1 signalling axis.…”

“…At present, some studies suggest that autophagy disorder in IVD cells may be an important factor in IDD 167,212 . TBHP treatment resulted in decreased levels of LC3II/I and increased levels of p62 in NPCs, indicating that autophagic flux decreased under oxidative stress, while intervention with autophagic agonists restored autophagic flux and inhibited degeneration of NPCs 130,213 .…”

“…165,166 Recently, studies have shown that mTOR signalling is essential for maintaining IVD homeostasis. 167 Kang et al 130 showed that CUR increased LC3-II/LC3-I ratio and Beclin-1 levels and decreased P62 levels by regulating AMPK/ mTOR/ULK1 signalling pathway in NPCs, which in turn inhibited TBHP-induced apoptosis, senescence and ECM degradation in NPCs by promoting autophagy. In addition, EB transcription factor EB (TFEB) is the main transcription regulator of lysosome and autophagy genes.…”

“…226,227 TNF-α and IL-1β can significantly increase the production of monocyte chemoattractant protein-1, IL-6, IL-8 and PGE2 in IVD cells, leading to an inflammatory cascade and a persistent local inflammatory microenvironment by means of positive feedback between proinflammatory cytokines. 14,167 In addition, proinflammatory cytokines can promote the expression of ECM degrading enzymes (MMPs, ADAMTS), cell senescence and death in the IVD, leading to ECM degradation and destruction of the IVD structure. 228,229 Furthermore, the inflammatory reaction can induce the infiltration of blood vessels and nerve endings, which further aggravate the deterioration of IVD microenvironment and IVD derived LBP.…”

“…mTOR plays an important role in various degenerative diseases such as osteoarthritis, diabetes, atherosclerosis and Parkinson's disease through its involvement in the regulation of protein synthesis, cellular senescence, autophagy, apoptosis and immunity 165,166 . Recently, studies have shown that mTOR signalling is essential for maintaining IVD homeostasis 167 . Kang et al 130 showed that CUR increased LC3‐II/LC3‐I ratio and Beclin‐1 levels and decreased P62 levels by regulating AMPK/mTOR/ULK1 signalling pathway in NPCs, which in turn inhibited TBHP‐induced apoptosis, senescence and ECM degradation in NPCs by promoting autophagy.…”