You are here

| Adult Stem Cells

Induced Autophagy in Cartilage Endplate Stem Cells May Inhibit Intervertebral Disc Degeneration

Review of “Rapamycin Induced Autophagy Inhibits Inflammation-Mediated Endplate Degeneration by Enhancing Nrf2/Keap1 Signalling of Cartilage Endplate Stem Cells” from STEM CELLS by Stuart P. Atkinson

Researchers from the laboratories of Yue Zhou, Minghan Liu, and Chao Zhang (Army Military Medical University, Chongqing, PR China) recently described the existence of cartilage endplate stem cells (CESCs) [1] that aid the regeneration of human cartilage endplate (CEP) tissues under normal conditions [2]. However, chronic inflammation can alter the tissue microenvironment and the differentiation propensity of CESCs leading to calcification of the CEP. This process inhibits nutrient/waste product permeation to the intervertebral discs present within the vertebral column [3], leading to intervertebral disc degeneration [4] and significant lower back pain.

With the hope of elucidating the mechanisms governing CEP degeneration, the team now returns with a new STEM CELLS study that studies the link between the autophagy, a cellular homeostasis mechanism that clears damaged organelles and dysfunctional proteins, and the development of intervertebral disc degeneration [5, 6]. Excitingly, Zuo et al. now report that inducing autophagy in CESCs protects from chronic inflammation‐induced degeneration of CEP tissues and may represent a means to inhibit progression to intervertebral disc degeneration [7].

The authors began their study by analyzing fracture-induced CEP tissue degeneration in a mouse model, discovering that tissue deconstruction, cartilage matrix degradation, and an increase in the number of autophagosomes in cartilage tissue accompanied inflammatory cytokine expression. While the inhibition of autophagy by chloroquine treatment prompted an acceleration in the level of degeneration and an increase in calcification into bone tissue, activation of autophagy by rapamycin instead appeared to protect the injured knee from the unwanted consequences of inflammation.

To assess the role of the mesenchymal stem cell-like CESCs, the authors moved in vitro and studied the consequences of treating these CEP-resident stem cells with an inflammatory stimulus (tumor necrosis factor‐α). Interestingly, inflammation prompted an increase in reactive oxygen species levels, CESC senescence, and skewed the differentiation of CESCs towards the osteogenic lineage; however, inducing autophagy in CESCs through treatment with rapamycin helped to maintain the chondrogenic properties of CESCs, while inhibiting extracellular matrix protease expression and osteogenic differentiation. Specifically, increased autophagy prompted the elevated expression and increased nuclear translocation of the Nrf2 antioxidant protein regulator, thereby boosting the expression of antioxidant proteins and enhancing reactive oxygen species scavenging.

While the authors believe that their findings regarding the mechanisms involved in CEP degeneration will aid the development of various prevention and treatment approaches, they do note limitations to their study. These include the lack of studies in aged mice, instead mimicking the age-related dysfunction in autophagy through pharmacological means; the differences between CEP degeneration between mouse and human; and a lack of any studies using Nrf2‐knockout mice. 

Will further analyses in human CEP tissues and cells confirm the findings of this mouse study and point to a potentially efficient means to inhibit intervertebral disc degeneration? Stay tuned to the Stem Cells Portal to find out.

References

  1. Liu LT, Huang B, Li CQ, et al., Characteristics of stem cells derived from the degenerated human intervertebral disc cartilage endplate. PLoS One 2011;6:e26285.
  2. Yao Y, Deng Q, Song W, et al., MIF Plays a Key Role in Regulating Tissue-Specific Chondro-Osteogenic Differentiation Fate of Human Cartilage Endplate Stem Cells under Hypoxia. Stem Cell Reports 2016;7:249-62.
  3. Huang YC, Urban JP, and Luk KD, Intervertebral disc regeneration: do nutrients lead the way? Nature Reviews Rheumatology 2014;10:561-6.
  4. Foster NE, Anema JR, Cherkin D, et al., Prevention and treatment of low back pain: evidence, challenges, and promising directions. Lancet 2018;391:2368-2383.
  5. Jiang L, Yuan F, Yin X, et al., Responses and adaptations of intervertebral disc cells to microenvironmental stress: a possible central role of autophagy in the adaptive mechanism. Connective Tissue Research 2014;55:311-21.
  6. Zhang SJ, Yang W, Wang C, et al., Autophagy: A double-edged sword in intervertebral disk degeneration. Clinica Chimica Acta; International Journal of Clinical Chemistry 2016;457:27-35.
  7. Zuo R, Wang Y, Li J, et al., Rapamycin Induced Autophagy Inhibits Inflammation-Mediated Endplate Degeneration by Enhancing Nrf2/Keap1 Signaling of Cartilage Endplate Stem Cells. STEM CELLS 2019;37:828-840.