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.

Inflammation intensity-dependent expression of osteoinductive Wnt proteins is a key link between inflammation and ectopic new bone formation in AS. Activation of both the canonical Wnt/β-catenin and noncanonical Wnt/PKCδ pathways is required for inflammation-induced new bone formation.

The aim of this study was to analyze the relationship between intervertebral disc degeneration and low back pain (LBP). Rat L4/5 disc degeneration model was established by annular puncture using a 0.4 mm needle anteriorly or posteriorly. In both anterior and posterior puncture models, magnetic resonance imaging (MRI) and histological analyses revealed marked disc degeneration 2 weeks after puncture. Cytokine expression was up-regulated in different level in nucleus pulposus (NP) from 3 days after puncture. Pain behavioral tests indicated that the anterior disc puncture did not induce pain behavior changes, whereas the posterior disc puncture resulted in mechanical allodynia from 1 day to 21 days after injury. Besides, cytokine expression was significantly increased in dorsal root ganglion (DRG) at 1 and 2 weeks after posterior puncture, but not after the anterior puncture. These findings indicate the NP of the degenerative disc expresses different levels of inflammatory cytokines, and posterior disc puncture produced mechanical allodynia. Keywords: intervertebral disc degeneration; low back pain; animal model; annulus fibrosus rupture; cytokine Low back pain (LBP) is a significant source of morbidity. Approximately 70% of the population experience LBP during their lives. 1 Although the exact cause of LBP is unclear, degeneration of intervertebral disc (IVD) is thought to drive LBP. 2,3 However, the relationship between intervertebral disc degeneration (IVDD) and LBP remains incompletely understood. Many patients with IVDD do not suffer from LBP. 4 Further investigation is needed to elucidate the relationship between IVDD and LBP.Inflammatory response plays an important role in the process of disc degeneration and LBP. Cytokines, such as tumor necrosis factor alpha (TNF-a), interleukin (IL)-1, and IL-6 are key factors associated with disc degeneration and LBP in human discs. [5][6][7] These inflammatory cytokines are involved in catabolic programs, angiogenesis, and nerve ingrowth in human discs. 8,9 However, the direct relationship between cytokine expression and pain symptoms is still unclear.Animal models are widely used to investigate the mechanisms underlying LBP and develop potential therapies. 10,11 IVD puncture models are popular among researchers, particularly posterior annulus fibrosus (AF) puncture and anterior AF puncture. It was previously shown that posterior lumbar AF puncture could induce pain behavior changes in rats. 12 A recent study further suggested that pain behavior changes might be related to the epidural presence of oozed nucleus pulposus (NP) in the posterior puncture model. 13 In this study, anterior disc puncture did not significantly change spontaneous pain behavior. The essential difference between posterior and anterior disc puncture is the location of the AF rupture. It seems that posterior AF rupture plays an important role in pain behavior changes in the rat disc puncture model.In the current study, we hypothesize that both expression of cytokines and posterior AF ruptu...

BackgroundStudies showed that upregulation of Nav1.6 increased the neuronal excitability and participated in neuropathic pain in the dorsal root ganglion (DRG). However, the molecular mechanisms underlying Nav1.6 upregulation were not reported yet.MethodsThe paw withdrawal threshold was measured in the rodents following lumbar 5 ventral root transection (L5-VRT). Then qPCR, western blotting, immunoprecipitation, immunohistochemistry, and chromatin immunoprecipitation assays were performed to explore the molecular mechanisms in vivo and in vitro.ResultsWe found that the levels of Nav1.6 and phosphorylated STAT3 were significantly increased in DRG neurons following L5-VRT, and TNF-α incubation also upregulated the Nav1.6 expression in cultured DRG neurons. Furthermore, immunoprecipitation and chromatin immunoprecipitation assays demonstrated that L5-VRT increased the binding of STAT3 to the Scn8a (encoding Nav1.6) promoter and the interaction between STAT3 and p300, which contributed to the enhanced transcription of Scn8a by increasing histone H4 acetylation in Scn8a promoter in DRG. Importantly, intraperitoneal injection of the TNF-α inhibitor thalidomide reduced the phosphorylation of STAT3 and decreased the recruitment of STAT3 and histone H4 hyperacetylation in the Scn8a promoter, thus subsequently attenuating Nav1.6 upregulation in DRG neurons and mechanical allodynia induced by L5-VRT.ConclusionThese results suggested a new mechanism for Nav1.6 upregulation involving TNF-α/STAT3 pathway activation and subsequent STAT3-mediated histone H4 hyperacetylation in the Scn8a promoter region in DRG, which contributed to L5-VRT-induced neuropathic pain.

PurposeOsteosarcoma is the most common primary malignancy of bone, and typically occurs among children and adolescence. This study aims to evaluate treatment outcomes among children, adolescents and young adults with osteosarcoma over the three decades by the changes in the long‐term relative survival.MethodsOsteosarcoma incidence and relative survival data from Surveillance, Epidemiology, and End Results (SEER) registries during 1984‐2013 were analyzed. The survival differences over three decades, age, sex, race, and socioeconomic status (SES) were assessed by comparing Kaplan‐Meier curves.ResultsThe overall incidence of osteosarcoma kept relatively stable with 0.4 per 100 000 in the three decades with the peak incidence occurring in the aged 10‐19 group. The 10‐year relative survival rate (RSR) increased from 57.7% to 61.0% in the three decades, with the greatest increase in the aged 0‐9 group from 48.2% to 65.7%. The 10‐year RSR improved from 54.1% to 61.5% in males, and from 62.4% to 63.0% in females, respectively, in the three decades. Furthermore, survival dramatically improved from 30% to 60% in the high‐poverty group over the three decades.ConclusionThis study demonstrated that the overall incidence of osteosarcoma remained stable, with an improvement in survival in the three decades. The improved survival was greater in males than in females in the three decades. Furthermore, the survival significantly increased in high‐poverty group, which was attributed to increasing improved health care system and patients with low finance can also have access to receiving effective and consistent treatment without distinction.