title: Role of death receptor, mitochondrial and endoplasmic reticulum pathways in different stages of degenerative human lumbar disc.
abstract: Intervertebral disc (IVD) cell apoptosis has been suggested to play an important role in promoting the degeneration process. It has been demonstrated that IVD cell apoptosis occurs through either death receptor, mitochondrial or endoplasmic reticulum (ER) pathway. Our study aimed to explore the relationship among these three pathways and grade of IVD degeneration (IVDD). IVDs were collected from patients with lumbar fracture, vertebral tumor, disc herniation or spondylolisthesis. IVDs were distinguished by MRI and histomorphological examination, cell apoptosis was detected by TUNEL staining. Biomarkers of these three apoptosis pathways were detected by RT-PCR and Western blot. Furthermore, the correlation between apoptosis pathways biomarkers and disc pathology were analyzed. Nucleus pulposus cell density decreased with degeneration process, and increased apoptotic ratio. ER pathway was predominant in mild stage of IVDD (GRP78, GADD153 upregulation and caspase-4 activation), death receptor pathway was predominant in mild and moderate stages (Fas, FasL up-regulation and caspase-8 activation) and mitochondrial pathway was predominant in moderate and severe stages (Bcl-2 down-regulation, Bax up-regulation, cytochrome-c accumulation in cytoplasm and caspase-9 activation). There were significant differences in the expressions of Fas, FasL, Bax, GADD153, cytochrome-c and cleaved caspase-8/9/3 between contained and non-contained discs. In conclusion, apoptosis occurs via these three apoptosis pathways together in IVDD. ER pathway plays a more critical role in the mild compared to moderate and severe stages, death receptor pathway in mild and moderate, and mitochondrial pathway in moderate and severe stages of IVDD. Disc cells apoptosis may progress rapidly after herniation, and may depend on the type of herniation.
authors: Department of Orthopaedics, First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Second Road, Guangzhou, 510080, China.
authors: Hua
authors: H
authors: Wang
authors: Hui
authors: H
authors: Liu
authors: Zhao-Min
authors: ZM
authors: Zheng
authors: Kui-Bo
authors: KB
authors: Zhang
authors: Tai-Ping
authors: TP
authors: Wang
authors: Shilabant-Sen
authors: SS
authors: Sribastav
authors: Wen-Sheng
authors: WS
authors: Liu
authors: Ting
authors: T
authors: Liu
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000502:physiology*; D015415:Biomarkers / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000502:physiology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D053222:Fas Ligand Protein / Q000378:metabolism; D005260:Female; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007403:Intervertebral Disc / Q000473:pathology*; D055959:Intervertebral Disc Degeneration / Q000473:pathology / Q000503:physiopathology*; D008159:Lumbar Vertebrae / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000502:physiology*; D053218:Receptors, Death Domain / Q000502:physiology*; D051742:Transcription Factor CHOP / Q000378:metabolism; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051025:bcl-Associated Death Protein / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
chemical_list: C494826:BAX protein, human; D015415:Biomarkers; C497249:DDIT3 protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; D053222:Fas Ligand Protein; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D053218:Receptors, Death Domain; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D019014:fas Receptor; D051742:Transcription Factor CHOP; D045304:Cytochromes c; D053148:Caspase 3; D053453:Caspase 9