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.

FIGURE 1

(A) Schematic diagram of the structure of mTOR and the functions of its components. (B) Schematic structure of mTORC1, mTORC2 and mTORC3. mTOR, mammalian target of rapamycin

FIGURE 2

The mTOR‐mediated signalling pathway. Growth factors, hypoxia and stress, amino acids, energy stress, and TNF‐α activate mTORC1 by stimulating different signalling axes involved in regulating protein translation, lipid and sugar metabolism, lysosomal biogenesis, nucleotide metabolism, and autophagy. The activation of mTORC2 is involved in autophagy, cell survival, osteogenic differentiation, and senescence. The mTORC3 participates in cell proliferation. mTOR, mammalian target of rapamycin; TNF‐α, tumour necrosis factor‐alpha

FIGURE 3

Challenges of mTOR‐based treatment of IDD. Autophagy, oxidative stress, inflammation, ECM homeostasis, senescence, and apoptosis mediated by mTOR signalling can markedly influence IVD cell fate and IDD pathophysiology. Inhibiting or activating mTOR signalling can affect the above‐mentioned pathophysiological processes and is beneficial to delay the progression of IDD. Therefore, the function of targeting mTOR signalling in IDD requires further clarification. IDD, intervertebral disc degeneration; IVD, intervertebral disc; mTOR, mammalian target of rapamycin