title: 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.affiliation: Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Song
authors.affiliation: Department of Physical Education, China University of Geosciences, Wuhan, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Yukun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: China Medical University, Shenyang, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Geng
authors.affiliation: Department of Orthopedics, First Hospital of Wuhan, Wuhan, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Xinghuo
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Kang
authors.affiliation: Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Cao
authors.initials: C
authors.lastname: Yang
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics* / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000235:genetics / Q000378:metabolism; D006801:Humans; D058847:Inflammasomes / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000235:genetics* / Q000473:pathology; D053583:Interleukin-1beta / Q000235:genetics* / Q000378:metabolism; D055959:Intervertebral Disc Degeneration / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017116:Low Back Pain / Q000235:genetics / Q000473:pathology; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics*; D000070614:Nucleus Pulposus / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D012600:Scoliosis / Q000235:genetics / Q000473:pathology
chemical_list: D000951:Antigens, Neoplasm; D017127:Glycation End Products, Advanced; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D017382:Reactive Oxygen Species; C498978:MOK protein, human; D020928:Mitogen-Activated Protein Kinases
keywords: IL-1β; NLRP3 inflammasome; advanced glycation end products; calcium; human nucleus pulposus cells; intervertebral disc degeneration; mitochondrial damage