Advanced glycation end products regulate anabolic and catabolic activities via NLRP3-inflammasome activation in human nucleus pulposus cells.

Abstract

Intervertebral disc degeneration is widely recognized as a cause of lower back pain, neurological dysfunction and other musculoskeletal disorders. The major inflammatory cytokine IL-1β is associated with intervertebral disc degeneration; however, the molecular mechanisms that drive IL-1β production in the intervertebral disc, especially in nucleus pulposus (NP) cells, are unknown. In some tissues, advanced glycation end products (AGEs), which accumulate in NP tissues and promote its degeneration, increase oxidative stress and IL-1β secretion, resulting in disorders, such as obesity, diabetes mellitus and ageing. It remains unclear whether AGEs exhibit similar effects in NP cells. In this study, we observed significant activation of the NLRP3 inflammasome in NP tissues obtained from patients with degenerative disc disease compared to that with idiopathic scoliosis according to results detected by Western blot and immunofluorescence. Using NP cells established from healthy tissues, our in vitro study revealed that AGEs induced an inflammatory response in NP cells and a degenerative phenotype in a NLRP3-inflammasome-dependent manner related to the receptor for AGEs (RAGE)/NF-κB pathway and mitochondrial damage induced by mitochondrial reactive oxygen species (mtROS) generation, mitochondrial permeability transition pore (mPTP) activation and calcium mobilization. Among these signals, both RAGE and mitochondrial damage primed NLRP3 and pro-IL-1β activation as upstream signals of NF-κB activity, whereas mitochondrial damage was critical for the assembly of inflammasome components. These results revealed that accumulation of AGEs in NP tissue may initiate inflammation-related degeneration of the intervertebral disc via activation of the NLRP3 inflammasome.

• Authors: Yu Song, Yan Wang, Yukun Zhang, Wen Geng, Wei Liu, Yong Gao, Shuai Li, Kun Wang, Xinghuo Wu, Liang Kang, Cao Yang
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 21 Issue 7 Pg. 1373-1387 (07 2017) ISSN: 1582-4934 [Electronic] England
• PMID: 28224704 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Chemical References

• Antigens, Neoplasm
• Glycation End Products, Advanced
• Inflammasomes
• Interleukin-1beta
• NLR Family, Pyrin Domain-Containing 3 Protein
• Reactive Oxygen Species
• MOK protein, human
• Mitogen-Activated Protein Kinases

Topics

• Antigens, Neoplasm (genetics, metabolism)
• Glycation End Products, Advanced (genetics, metabolism)
• Humans
• Inflammasomes (genetics, metabolism)
• Inflammation (genetics, pathology)
• Interleukin-1beta (genetics, metabolism)
• Intervertebral Disc Degeneration (genetics, metabolism, pathology)
• Low Back Pain (genetics, pathology)
• Mitochondria (metabolism, pathology)
• Mitogen-Activated Protein Kinases (genetics, metabolism)
• NLR Family, Pyrin Domain-Containing 3 Protein (genetics)
• Nucleus Pulposus (metabolism, pathology)
• Oxidative Stress (genetics)
• Reactive Oxygen Species (metabolism)
• Scoliosis (genetics, pathology)