Piezo1 activates the NLRP3 inflammasome in nucleus pulposus cell-mediated by Ca2+/NF-κB pathway

Studying and understanding the mechanism of inflammation in nucleus pulposus is the key to understand and prevent intervertebral disc degeneration. We propose a model of mechanical sensitive ion channel Piezo1 mediated inflammation of nucleus pulposus cells. Piezo1 can up-regulate the level of interleukin-1β (IL-1β) in nucleus pulposus cells once it is activated. It is suggested that Piezo1 may mediate inflammation by activating Nod-like receptor protein 3 (NLRP3) inflammasome to accelerate the production and maturation of IL-1β. The primary objective of this study was to explore whether Piezo1 activates NLRP3 inflammasome in nucleus pulposus cells. Piezo1 sensitization was induced by mechanical stretch following which we analyzed the priming and assembly of NLRP3 inflammasome and also studied if the downstream Ca²⁺/NF-κB pathway mediated this activation in nucleus pulposus cells. The expression of Piezo1 and NLRP3 inflammasome increased in a time-dependent manner upon mechanical stretch. Piezo1 activation promoted NLRP3 inflammasome assembly, which was demonstrated by the upregulation of caspase-1 activation and IL-1β production. Transfection of Piezo1-siRNA reversed this process. The inhibition of Ca²⁺/NF-κB pathway reduced Piezo1-dependent activation of NLRP3 inflammasome. Thus, we propose that activation of NLRP3 inflammasome in nucleus pulposus cells mediated by Piezo1 through the Ca²⁺/NF-κB pathway is a novel pathogenesis for the progress of intervertebral disc degeneration. As per our knowledge this is the first study which has provided evidence linking Piezo1-mediated inflammation in nucleus pulposus cells with the production of NLRP3 inflammasome.     

Upregulation of Sirt1 by tyrosol suppresses apoptosis and inflammation and modulates extracellular matrix remodeling in interleukin-1β-stimulated human nucleus pulposus cells through activation of PI3K/Akt pathway

Intervertebral disc degeneration (IDD) is the major pathogenesis of lower back pain. Tyrosol is a polyphenolic compound that exhibits anti-oxidant, anti-apoptotic, and anti-inflammatory effects. Herein, we explored the effects and mechanisms of tyrosol on IDD progression in interleukin (IL)-1β-stimulated human nucleus pulposus cells (HNPCs). Cell viability and apoptosis were detected by CCK-8 and flow cytometry analysis, respectively. The production of tumor necrosis factor-α (TNF-α), IL-6, nitric oxide (NO), and prostaglandin E2 (PGE2) was examined to evaluate inflammation. The mRNA expression of matrix metalloproteinases (MMPs) (MMP-3/9/13), collagen type II, SRY-related high mobility group box 9 (SOX-9), and aggrecan was measured by qRT-PCR. Protein levels of silent information regulator 2 homolog 1 (Sirt1), phosphorylated protein kinase B (p-Akt), Akt, collagen type II, SOX-9, and aggrecan were determined by western blot. Results showed that tyrosol attenuated IL-1β-induced viability reduction, apoptosis, and caspase-3/7 activity in HNPCs. The increase in the production of TNF-α, IL-6, NO, and PGE2 in IL-1β-treated HNPCs was abolished by tyrosol treatment. Tyrosol treatment reversed IL-1β-induced upregulation of MMP-3, MMP-9, and MMP-13, and downregulation of collagen II, SOX-9, and aggrecan in HNPCs. Additionally, tyrosol treatment activated the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in IL-1β-stimulated HNPCs. Sirt1 was upregulated by tyrosol, and Sirt1 silencing inhibited Akt phosphorylation in HNPCs. Sirt1 knockdown attenuated the effects of tyrosol on IL-1β-induced apoptosis, inflammation, and ECM remodeling in HNPCs. In summary, upregulation of Sirt1 by tyrosol suppressed apoptosis and inflammation and regulated ECM remodeling in IL-1β-stimulated HNPCs through activation of PI3K/Akt pathway.     

Growth Factors in Intervertebral Disc Homeostasis

Intervertebral disc degeneration is a complex age-related pathology associated with back pain. Research on the growth factors that regulate disc homeostasis is of critical importance for understanding the basis of the disease. Here we summarize the data on the expression and function of various growth factors in the disc from in vivo and in vitro studies, as well as on their alterations during degeneration and ageing. Such studies are becoming more crucial in the prospect of clinical application of growth factors for the treatment of disc degeneration.     

Inflamación en la hernia del disco intervertebral

Up until fairly recently, it was thought that sciatic pain in the lumbar herniated disc was caused by compression on the nerve root. However, the lumbar herniated disc shows mixed pictures which are difficult to explain by simple mechanical compromise. In recent years various immunology, immunohistochemistry and molecular biology studies have shown that the herniated tissue is not an inert material, but rather it Is biologically very active with the capability of expressing a series of inflammatory mediators: cytokines such as interleukin-1, interleukin-6, interleuquin-8 and tumor necrosis factor being the ones which stand out. The inflammation is not only induced by the chemical irritation of the bioactive substances released by the nucleus pulposus but also by an autoimmune response against itself. Thus, in addition to the mechanical factor, the biomechanical mediation plays an important role in the pathophysiology of sciatic pain and of radiculopathy. Through a review of a wide range of literature, we researched the cellular molecular mediators involved in this inflammatory process around the lumbar herniated disc and its involvement in sciatic pain.     

非线性模型在椎间盘黏弹性特性分析中的应用

目的 构建变参数非线性模型,研究人体椎间盘在循环应变状态下的应力松弛特性。方法 采用变参数非线性模型结合椎间盘应力松弛和蠕变反应的实验数据,研究循环应变状态下椎间盘的应力松弛特性,比较线性与非线性模型在循环状态下椎间盘黏弹性特性的差异。结果 采用变参数非线性模型得出的循环模量和松弛系数在0.01Hz循环状态下与实验模型非常接近,得出的循环模量在0.1和1 Hz下也与实验值相近,但是得出的松弛系数在0.1和1 Hz下失真严重。结论 在压缩应变作用下椎间盘经历的是一个非线性的应力行为,非线性变参数模型更符合研究在循环应变下椎间盘应力松弛反应的需要。     

关节盘移位对颞下颌关节内应力分布的影响

目的 通过对不同关节盘移位的数值模拟,探究各种移位情况下颞下颌关节（temporomandibular joint,TMJ）内各结构的应力分布规律。方法 依据CT图像,建立包含下颌骨、全牙列、关节盘和关节软骨的正常TMJ三维有限元模型;参考关节盘前、后、外、内移位的临床特征,建立对应的4个模型。关节盘与关节软骨间考虑接触,用缆索元模拟下颌韧带和关节盘附着,施加正中咬合荷载。结果 前移位将导致关节盘中带产生过高的压应力,达到3.23 MPa;后、内、外移位时关节盘的整体应力水平比前移位和正常TMJ高;各种移位都使关节结节后斜面的应力值大幅度增加,但对髁突关节面的影响却不大。结论 各种移位都将导致关节盘和关节结节后斜面产生过高的应力,且后、内、外移位更为危险,更容易造成关节结构和功能的损伤。     

Long-term follow-up of intersegmental displacement after orthognathic surgery using cone-beam computed tomographic superimposition

ObjectivesTo evaluate intersegmental displacement during long-term follow-up after bilateral sagittal split osteotomy (BSSO) by mandibular body area superimposition.Materials and MethodsCone-beam computed tomography (CBCT) images of 23 patients ages 18−37 years with class III malocclusion before orthognathic surgery were obtained. A three-dimensional (3D) CBCT examination was performed at four stages: surgery (T0), 6 months after surgery (T1), 1 year after surgery (T2), and long-term follow-up (6.1 ± 2.1 years, T3). The CBCT datasets were superimposed on the symphyseal area and the lower part of the distal segment of the mandible between T0 and the other time points (T1, T2, and T3). The reference points (both condyle, coronoid, and sigmoid) were estimated by the CBCT analyzed program.ResultsThe coronoid, condylion, and sigmoid showed changes within 6 months after surgery, but there was no significant change in the intersegmental displacement between 6 months and 6 years after surgery. The distances between the left and right coronoid, condylion, and sigmoid from T0 to T3 were noted.ConclusionsThe change in intersegmental displacement between T0 and T3 affecting relapse after orthognathic surgery was not significantly different. This suggests that the mandible itself may have a stable morphology during the follow-up period.     

Association between hypoplastic condyles and temporomandibular joint disc displacements: a cone beam computed tomography and magnetic resonance imaging metrical analysis

This study investigated the association between hypoplastic condyles and disc displacements without reduction (DDw/oR). Consecutive patients with non-syndromic unilateral condylar hypoplasia were recruited and clinical, cone beam computed tomography (CBCT) and magnetic resonance imaging (MRI) data were acquired. Linear measurements including condylar head width, depth, height and condyle length were determined with CBCT while MRI was used to assess disc position, morphology and displacement. A total of 43 patients were enrolled of which 93.02% had a history of temporomandibular disorders (TMDs) and 83.72% presented with TMD signs and symptoms. Depth and height of the condylar head along with condyle length of hypoplastic joints (6.68 ± 1.67 mm, 4.97 ± 1.25 mm and 14.49 ± 3.02 mm, respectively) were significantly lesser than normal joints (7.77 ± 1.26 mm, 6.35 ± 1.45 mm and 18.20 ± 3.18 mm) (P < 0.001). The prevalence of DDw/oR was significantly higher in hypoplastic joints (79.07% versus 13.95%) (P < 0.001). Joints with hypoplastic condyles had shorter disc lengths (6.99 ± 2.16 mm vs, 8.45 ± 2.26 mm) (P = 0.007). Furthermore, disc displacements were significantly more advanced (8.52 ± 2.84 mm) and severe (76.74% with severe translations) when compared to the contralateral side (4.77 ± 2.97 mm and 32.56%) (P < 0.05). A significant association was observed between condylar hypoplasia and temporomandibular joint DDw/oR with hypoplastic joints exhibiting more severely displaced and deformed discs. DDw/oR coupled with repaired degenerative joint disease may mimic condylar hypoplasia radiographically.     

Clinical protocol for managing acute disc displacement without reduction: a magnetic resonance imaging evaluation

This study investigated the efficacy of a sequential combination of arthrocentesis, mandibular manipulation, and anterior repositioning splint (ARS) in the management of acute temporomandibular joint (TMJ) disc displacement without reduction (DDwoR). Twenty-one consecutive patients diagnosed with acute DDwoR by Diagnostic Criteria for Temporomandibular Disorders and magnetic resonance imaging (MRI) were recruited and managed with this method. Clinical and MRI data were obtained before and at 1 week after treatment. The disc–condyle relationship was determined by disc–condyle angle measurement. Condyle/disc positions were described as x–y coordinates with the summit of the articular fossa as the coordinate origin. Statistical analyses including independent/paired samples t-tests were conducted; significance was set at P < 0.05. Clinical success was observed in 95.2% of patients (20/21) with 22 joints affected by acute DDwoR. After combined treatment and ARS insertion, TMJs with DDwoR showed (a) normal disc–condyle relationships with substantial forward and downward condyle movement and significant disc reduction in closed position, and (b) discs with an intermediate zone located between the condylar head and articular eminence in open position. The combined approach was highly effective in ‘unlocking’ acute TMJ DDwoR and achieving spatial full disc reduction and a normal disc–condyle relationship. The duration of acute DDwoR appears to be critical for success.