Abstract

Degenerative disc disease is a highly prevalent, global health problem that represents the primary cause of back pain and is associated with neurological disorders, including radiculopathy, myelopathy, and paralysis, resulting in worker disability and socioeconomic burdens. The intervertebral disc is the largest avascular organ in the body, and degeneration is suspected to be linked to nutritional deficiencies. Autophagy, the process through which cells self‐digest and recycle damaged components, is an important cell survival mechanism under stress conditions, especially nutrient deprivation. Autophagy is negatively controlled by the mammalian target of rapamycin (mTOR) signaling pathway. mTOR is a serine/threonine kinase that detects nutrient availability to trigger the activation of cell growth and protein synthesis pathways. Thus, resident disc cells may utilize autophagy and mTOR signaling to cope with harsh low‐nutrient conditions, such as low glucose, low oxygen, and low pH. We performed rabbit and human disc cell and tissue studies to elucidate the involvement and roles played by autophagy and mTOR signaling in the intervertebral disc. In vitro serum and nutrient deprivation studies resulted in decreased disc cell proliferation and metabolic activity and increased apoptosis and senescence, in addition to increased autophagy. The selective RNA interference‐mediated and pharmacological inhibition of mTOR complex 1 (mTORC1) was protective against inflammation‐induced disc cellular apoptosis, senescence, and extracellular matrix catabolism, through the induction of autophagy and the activation of the Akt‐signaling network. Although temsirolimus, a rapamycin derivative with improved water solubility, was the most effective mTORC1 inhibitor tested, dual mTOR inhibitors, capable of blocking multiple mTOR complexes, did not rescue disc cells. In vivo, high levels of mTOR‐signaling molecule expression and phosphorylation were observed in human intermediately degenerated discs and decreased with age. A mechanistic understanding of autophagy and mTOR signaling can provide a basis for the development of biological therapies to treat degenerative disc disease.

Highlights

  • Research Foundation, Grant/Award Number: 312; Japan Society for the Promotion of Science, Grant/Award Numbers: JP15H03033, JP15K10406, JP16K20051, JP26893151; Kobe University School of Medicine Alumni

  • We performed rabbit and human disc cell and tissue studies to elucidate the involvement and roles played by autophagy and mammalian target of rapamycin (mTOR) signaling in the intervertebral disc

  • In human disc nucleus pulposus cells, protective effects were observed for mTOR complex 1 (mTORC1), but not mTORC2, inhibitors against inflammation-induced disc cellular apoptosis, senescence, and matrix catabolism through the induction of autophagy and Akt mechanistic investigations to clarify the roles played by autophagy and mTOR signaling must be conducted

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Summary

Japan Orthopaedics and Traumatology

Research Foundation, Grant/Award Number: 312; Japan Society for the Promotion of Science, Grant/Award Numbers: JP15H03033, JP15K10406, JP16K20051, JP26893151; Kobe University School of Medicine Alumni. In human disc nucleus pulposus cells, protective effects were observed for mTORC1, but not mTORC2, inhibitors against inflammation-induced disc cellular apoptosis, senescence, and matrix catabolism through the induction of autophagy and Akt mechanistic investigations to clarify the roles played by autophagy and mTOR signaling must be conducted. We performed in vitro and in vivo studies of human and rabbit disc cells and tissues, modulated by the graded supply of nutrition, RNA interference (RNAi), and pharmacological agents, to elucidate the involvement and roles played by autophagy and mTOR signaling in the intervertebral disc. This brief review introduces our study findings and interpretations, discussing the future applications of therapeutically modulating biological autophagy and/or mTOR signaling to treat degenerative disc disease

IN RABBIT DISC CELLS
SIGNALING MODULATION IN HUMAN DISC
We examined the in vivo involvement of mTOR signaling in human
These effects were primarily
Findings
RE FE R ENC E S
Full Text
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