降钙素治疗延缓卵巢切除大鼠腰椎间盘退变

目的:观察降钙素对卵巢切除大鼠腰椎骨量及椎间盘退变的影响。方法:SD大鼠分为基线对照组、假手术组、卵巢切除组及降钙素治疗组,进行腰椎节段骨密度和骨形态计量学分析,观察椎间盘的组织形态学改变。结果:卵巢切除组骨量较对照组和降钙素治疗组显著下降,骨转化指标明显提高。降钙素治疗组的腰椎间盘组织学评分较卵巢切除组显著下降。结论:卵巢切除大鼠椎间盘退变可能是骨量减少引起的脊柱力学改变所致,降钙素治疗可以预防骨量丢失并延缓其腰椎间盘退变。     

脊柱椎间盘退变与高尿酸血症的相关性

背景:高尿酸血症是常见的代谢性疾病,高尿酸血症患者以尿酸结晶形成导致痛风为主要临床表现。既往研究仅报道了尿酸结晶会导致脊柱椎间盘的退变,但关于高尿酸血症与脊柱椎间盘退变的相关性研究较少。目的:回顾性分析高尿酸血症患者脊柱椎间盘的退变特点以及血尿酸浓度与脊柱椎间盘退变的相关性。方法:回顾性分析2021年1月至2022年12月在西南医科大学附属医院骨科就诊并被诊断为脊柱椎间盘退变的所有患者,纳入97例高尿酸血症患者作为高尿酸血症组,然后根据性别、年龄按照1∶2进行匹配,将194例非高尿酸血症患者作为对照组。收集两组患者的血尿酸检验结果,并在全脊柱MRI图像上对两组患者的椎间盘退变程度进行Pfirrmann评分。比较两组患者椎间盘退变程度的差异,分析血尿酸浓度与椎间盘退变程度的相关性。结果与结论:①高尿酸血症组的椎间盘退变程度Pfirrmann评分大于对照组,且高尿酸血症组的椎间盘退变总数大于对照组,差异均有显著性意义(P<0.05);②Spearman相关分析显示,在高尿酸血症组内的多个节段,男性患者的椎间盘退变程度与血尿酸浓度呈正相关(C_(3/4):r=0.317,C_(4/5):r=0.333,C_(5/6):r=0.309,L_(2/3):r=0.443;P<0.05);女性患者的椎间盘退变程度也与血尿酸浓度呈正相关(C_(3/4):r=0.354,C_(4/5):r=0.388,C_(6/7):r=0.312,T_(7/8):r=0.282,T_(9/10):r=0.305,T_(11/12):r=0.277,L_(4/5):r=0.319,L_(5)-S_(1):r=0.367,P<0.05);③在对照组中,男性和女性患者的椎间盘退变程度与血尿酸浓度无明显相关性(P>0.05);④结果提示:在高尿酸血症患者中,血尿酸浓度越高,椎间盘退变程度越严重。因此,高尿酸血症是导致椎间盘退变的危险因素之一。     

Clarifying the nomenclature of intervertebral disc degeneration and displacement: from bench to bedside

As a significant determinant of low back pain, intervertebral disc degeneration (IDD) has attracted more and more attention of both investigators and physicians. Disc herniation, termed as intervertebral disc displacement, is amongst the most prevalent spinal diseases closely linked with IDD. Due to the same origins and similar pathophysiology, the ambiguity regarding the similarity and difference of IDD and intervertebral disc displacement thus remains. The aim of this study was to clarify the nomenclature of IDD and disc herniation in terms of molecular etiology, pathophysiology, nature history and clinical outcomes. Collectively, IDD is a type of multifaceted, progressive spinal disease with or without clinical symptoms as back pain, characterized by extracellular matrix and the integrity of NP and AF lost, fissures formation. Disc herniation (termed as intervertebral disc displacement) is a type of spinal disease based on IDD or not, with local pain and/or sciatica due to mechanical compression and autoimmune cascades upon the corresponding nerve roots. Clarifying the nomenclature of intervertebral disc degeneration and displacement has important implications both for investigators and for physicians.     

人退变椎间盘组织的基因表达谱

目的：研究人类退变椎间盘的基因表达谱,分析人退变椎间盘基因表达水平的变化。方法：按条件优化的一步法抽提人退变及正常椎间盘组织的总RNA各3例,分别用cy3,cy5荧光标记,获得2组椎间盘cDNA的探针,与含有4096条人类全长基因的cDNA表达谱芯片杂交,扫描芯片荧光信号图像,对所获得的基因进行生物信息学分析。结果：在4096条基因中,有差异表达的基因706条,358条基因表达量明显下降,298条基因表达量明显上升。在有差异表达的基因中,细胞凋亡相关类蛋白8条,其中上皮细胞膜蛋白(EMP-1)基因的表达上调明显。结论：退变椎间盘的基因表达发生变化,细胞凋亡增加可能是椎间盘退变发生和发展的因素之一。     

Expression of receptors for putative anabolic growth factors in human intervertebral disc: implications for repair and regeneration of the disc

Low back pain (LBP) is a common, debilitating and economically important disorder. Current evidence implicates loss of intervertebral disc (IVD) matrix consequent upon 'degeneration' as a major cause of LBP. Degeneration of the IVD involves increases in degradative enzymes and decreases in the extracellular matrix (ECM) component in a process that is controlled by a range of cytokines and growth factors. Studies have suggested using anabolic growth factors to regenerate the normal matrix of the IVD, hence restoring disc height and reversing degenerative disc disease. However, for such therapies to be successful it is vital that the target cells (i.e. the disc cells) express the appropriate receptors. This immunohistochemical study has for the first time investigated the expression and localization of four potentially beneficial growth factor receptors (i.e. TGFbetaRII, BMPRII, FGFR3 and IGFRI) in non-degenerate and degenerate human IVDs. Receptor expression was quantified across regions of the normal and degenerate disc and showed that cells of the nucleus pulposus (NP) and inner annulus fibrosus (IAF) expressed significantly higher levels of the four growth factor receptors investigated. There were no significant differences between the four growth factor expression in non-degenerate and degenerate biopsies. However, expression of TGFbetaRII, FGFR3 and IGFRI, but not BMP RII, were observed in the ingrowing blood vessels that characterize part of the disease aetiology. In conclusion, this study has demonstrated the expression of the four growth factor receptors at similar levels in the chondrocyte-like cells of the NP and IAF in both non-degenerate and degenerate discs, implicating a role in normal disc homeostasis and suggesting that the application of these growth factors to the degenerate human IVD would stimulate matrix production. However, the expression of some of the growth factor receptors on ingrowing blood vessels might be problematic in a therapeutic approach.     

A preliminary in vitro study into the use of IL-1Ra gene therapy for the inhibition of intervertebral disc degeneration

Conventional therapies for low back pain (LBP) are purely symptomatic and do not target the cause of LBP, which in approximately 40% of cases is caused by degeneration of the intervertebral disc (DIVD). Targeting therapies to inhibit the process of degeneration would be a potentially valuable treatment for LBP. There is increasing evidence for a role for IL-1 in DIVD. A natural inhibitor of IL-1 exists, IL-1Ra, which would be an ideal molecular target for inhibiting IL-1-mediated effects involved in DIVD and LBP. In this study, the feasibility of ex vivo gene transfer of IL-1Ra to the IVD was investigated. Monolayer and alginate cultures of normal and degenerate human intervertebral disc (IVD) cells were infected with an adenoviral vector carrying the IL-1Ra gene (Ad-IL-1Ra) and protein production measured using an enzyme-linked immunosorbent assay. The ability of these infected cells to inhibit the effects of IL-1 was also investigated. In addition, normal and degenerate IVD cells infected with Ad-IL-1Ra were injected into degenerate disc tissue explants and IL-1Ra production in these discs was assessed. This demonstrated that both nucleus pulposus and annulus fibrosus cells infected with Ad-IL-1Ra produced elevated levels of IL-1Ra for prolonged time periods, and these infected cells were resistant to IL-1. When the infected cells were injected into disc explants, IL-1Ra protein expression was increased which was maintained for 2 weeks of investigation. This in vitro study has shown that the use of ex vivo gene transfer to degenerate disc tissue is a feasible therapy for the inhibition of IL-1-mediated events during disc degeneration.     

丁香苷抑制大鼠椎间盘退变

背景:椎间盘退变是由于椎间盘内部髓核和纤维环组织发生损伤和退化导致的椎间盘结构和功能发生变化,目前尚无有效的治疗药物。目的:探讨丁香苷抑制大鼠椎间盘退变的作用。方法:取10只雄性SD大鼠,将每只大鼠的尾椎Co_(4)/Co_(5)椎间盘设为模型组、Co_(5)/Co_(6)椎间盘设为丁香苷组、Co_(6)/Co_(7)椎间盘设为对照组,对照组不进行任何处理,模型组、丁香苷组采用微型穿刺针进行纤维环全层穿刺建立椎间盘退变模型,造模后即刻,模型组、丁香苷组椎间盘分别注射2.5μL的生理盐水、丁香苷溶液(5μmol/L)。注射4周后取材,采用苏木精-伊红和番红O-固绿染色观察大鼠椎间盘退变程度,免疫组化染色分析大鼠椎间盘组织内Ⅱ型胶原、聚集蛋白聚糖及基质金属蛋白酶3,13的表达。结果与结论:①苏木精-伊红染色显示,模型组椎间盘高度降低,软骨终板变薄且有裂隙出现,纤维环结构紊乱且出现裂隙,髓核消失;丁香苷组椎间盘高度正常或略低于对照组,软骨终板退变程度较模型组轻,纤维环排列较模型组相对规整且无裂隙,髓核部分皱缩。②番红O-固绿染色显示,模型组椎间盘软骨终板出现缺损且软骨钙化层变薄,出现明显退变;丁香苷组椎间盘软骨终板结构形态有一定程度恢复。③免疫组化染色显示,与对照组比较,模型组椎间盘软骨组织内Ⅱ型胶原、聚集蛋白聚糖的表达降低(P<0.0001),基质金属蛋白酶3,13的表达升高(P<0.0001);与模型组比较,丁香苷组椎间盘软骨组织内Ⅱ型胶原、聚集蛋白聚糖的表达升高(P<0.001,P<0.0001),基质金属蛋白酶3,13的表达降低(P<0.001,P<0.0001)。④结果表明,丁香苷可通过抑制基质金属蛋白酶3,13的表达、提高Ⅱ型胶原和聚集蛋白聚糖的表达来改善椎间盘的结构和功能,预防和减缓椎间盘退变过程。     

Intervertebral disc degeneration: evidence for two distinct phenotypes

We review the evidence that there are two types of disc degeneration. ‘Endplate-driven’ disc degeneration involves endplate defects and inwards collapse of the annulus, has a high heritability, mostly affects discs in the upper lumbar and thoracic spine, often starts to develop before age 30 years, usually leads to moderate back pain, and is associated with compressive injuries such as a fall on the buttocks. ‘Annulus-driven’ disc degeneration involves a radial fissure and/or a disc prolapse, has a low heritability, mostly affects discs in the lower lumbar spine, develops progressively after age 30 years, usually leads to severe back pain and sciatica, and is associated with repetitive bending and lifting. The structural defects which initiate the two processes both act to decompress the disc nucleus, making it less likely that the other defect could occur subsequently, and in this sense the two disc degeneration phenotypes can be viewed as distinct.     

Role of growth differentiation factor-5 and bone morphogenetic protein type II receptor in the development of lumbar intervertebral disc degeneration

The present study was designed to evaluate the role of growth differentiation factor-5 (GDF-5) and bone morphogenetic protein type II receptor (BMPR-II) in the development of lumbar intervertebral disc degeneration (IDD). A total of 24 patients with lumbar IDD (experiment group) and 6 patients with lumbar vertebral fracture (control group) were enrolled in the study. Tissue samples of IVD from the experiment group and control group were obtained during lumbar fusion operation, respectively. Fixation and decalcification of IVD tissue were performed, and then HE staining was carried out to observe the morphological changes of the lumbar IVD tissues. The expression of GDF-5 and BMPRII in human lumbar IVD was detected by immunohistochemical staining. HE staining results showed that non- and minimal degeneration was found in 11 cases (score range, 0-3), moderate degeneration in 12 cases (score range, 4-8), and severe degeneration in 7 cases (score range, 9-12). According to the immunohistochemical results, the positive expression rates of GDF-5 and BMPRII in NP were higher than those in AF of the non- and minimal degeneration group, moderate degeneration group and severe degeneration group (all P < 0.05). However, no significant difference in GDF-5 or BMPRII positive expression was observed among the normal, non- and minimal, moderate and severe degeneration groups in neither NP area nor AF area (all P > 0.05). In conclusion, our results showed that GDF-5 and BMPRII expressed both in normal and degenerated IVD tissues, and GDF-5 might have an inhibition effect on degenerated lumbar IVD, suggesting that gene therapy may be a useful approach in producing physiological effects during early- and late-phase of lumbar IDD.     

间充质干细胞治疗椎间盘退行性疾病:基于Web of Science数据库的文献计量及可视化分析

背景:间充质干细胞具有自我更新和多向分化的特性,在治疗椎间盘疾病中具有巨大的潜力和应用前景.目的:针对间充质干细胞治疗椎间盘退行性疾病相关文献进行文献计量学分析,了解该领域的研究热点、发展趋势,为其后续发展提供依据和建议.方法:以间充质干细胞治疗椎间盘退行性疾病为主题,检索2000至2019年Web of Scienc...     

椎间盘退变模型的研究进展

椎间盘退变疾病发病率越来越高,但退变的机制尚不明确.椎间盘退变模型是现今研究椎间盘退变疾病的主要方式,退变模型主要分为体内退变模型和体外退变模型两大类.两种退变模型从不同角度研究椎间盘退变的病理生理过程,为揭示退变机制及预防、治疗椎间盘退变疾病起着重要作用.本文就目前国内外关于两种不同椎间盘退变模型研究的进展作一综述.     

兔椎间盘退变与修复模型的研究现状*

椎间盘退变模型是研究椎间盘退变疾病的基础和关键之一。兔退变椎间盘模型具有操作简单、可重复性好等特点被国内外学者广泛应用。兔椎间盘退变模型包括体内模型、体外模型等。体内模型根据损伤类别包括:机械损伤模型、化学损伤模型、异常应力模型、脊柱不稳模型、脊柱融合模型等;体外模型包括椎间盘细胞模型、椎间盘组织模型等。本文根据近年兔腰椎间盘各种退变模型与修复的研究现状与进展作一综述。     

Visualization of intervertebral disc degeneration in a cadaveric human lumbar spine using microcomputed tomography

Gross features of disc degeneration (DD) that are associated with back pain include tears in the anulus fibrosus, structural changes of the endplates, and a collapse of the anulus. The aim of this study is the detailed visualization and microstructural characterization of DD using microcomputed tomography (μCT) and a dedicated image post-processing pipeline. In detail, we investigate a cadaveric spine that shows both types of DD between L1 and L2 and between L2 and L3, respectively. The lumbar spine was obtained from a male donor aged 74 years. The complete specimen was scanned using μCT with an isometric voxel size of 93 μm. Subsequently, regions of interest (ROI) were prepared featuring each complete intervertebral disc including the adjacent endplates. ROIs were then additionally scanned with a voxel size of 35 μm and by means of magnetic resonance imaging. The collapsed endplate of the superior L2 showed explicit signs of an endplate-driven degeneration, including bony endplate failures. In contrast, the intervertebral disc between L2 and L3 showed indications of an annulus-driven DD including severe disc height loss and concentric tears. Using μCT we were able to visualize and quantify bone and cartilage features in DD. We showed that in both cases a suite of structural changes accompanies cartilage degeneration, including microstructural bony adaptions to counteract changes in the biomechanical loading regimen.     

Toward an understanding of the role of notochordal cells in the adult intervertebral disc: From discord to accord

The goal of this mini‐review is to address the long standing argument that the pathogenesis of disc disease is due to the loss and/or the replacement of the notochordal cells by other cell types. We contend that, although cells of different size and morphology exist, there is no strong evidence to support the view that the nucleus pulposus contains cells of distinct lineages. Based on lineage mapping studies and studies of other notochordal markers, we hypothesize that in all animals, including human, nucleus pulposus retains notochordal cells throughout life. Moreover, all cells including chondrocyte‐like cells are derived from notochordal precursors, and variations in morphology and size are representative of different stages of maturation, and or, function. Thus, the most critical choice for a suitable animal model should relate more to the anatomical and mechanical characteristics of the motion segment than concerns of cell loss and replacement by non‐notochordal cells. Developmental Dynamics 239:2141–2148, 2010. © 2010 Wiley‐Liss, Inc.     

Understanding embryonic development for cell-based therapies of intervertebral disc degeneration: Toward an effort to treat disc degeneration subphenotypes

Chronic low back and neck pain are associated with intervertebral disc degeneration and are major contributors to the global burden of disability. New evidence now suggests that disc degeneration comprises a spectrum of subphenotypes influenced by genetic background, age, and environmental factors, which may be contributing to the mixed outcomes seen in clinical trials of cell-based therapies that aim to treat disc degeneration. This problem is further compounded by the fact that disc degeneration and aging coincide with an exhaustion of endogenous progenitor cells, imposing limitations on the regenerative capacity of the disc. At the bench-side, current work is focused on applying our knowledge of embryonic disc development to direct and refine differentiation of adult and human-induced pluripotent stem cells into notochord-like and nucleus pulposus-like cells for use in novel cell-based therapies. Accordingly, this review presents the salient features of intervertebral disc development, post-natal maintenance, and regeneration, with emphasis on recent advancements. We also discuss how a stratified approach can be undertaken for the development of future cell-based therapies to bring emerging subphenotypes into consideration.     

The interaction between aggrecan gene VNTR polymorphism and cigarette smoking in predicting incident symptomatic intervertebral disc degeneration

An association between the aggrecan variable number of tandem repeat (VNTR) polymorphism and the disc degeneration has been previously reported in Finnish men, and smoking had previously been suspected of causing disc degeneration. However, the interaction between aggrecan gene VNTR polymorphism and smoking in symptomatic intervertebral disc degeneration (IDD) has not been well studied. To examine the interaction between aggrecan gene VNTR and smoking in the susceptibility of symptomatic IDD of Chinese Han in northern China, intervertebral discs of 132 participants were evaluated on magnetic resonance imaging, using decreased signal intensity. After harvesting the blood samples, the aggrecan gene VNTR region was analyzed using polymerase chain reaction (PCR). The data indicated that between the two groups, participants carrying one or two alleles ≤25 repeats who did not smoke showed a 1.102-fold increased risk for symptomatic IDD (p= 0.855; 95% confidence interval 0.389–3.119), and participants carrying two alleles >25 repeats who smoked more than 1 pack-year showed a 1.013-fold higher risk (p = 0.982; 95% confidence interval 0.333–3.084), whereas participants carrying one or two alleles ≤25 repeats who smoked more than 1 pack-year showed a 4.5-fold increased risk for symptomatic IDD (p = 0.005; 95% confidence interval 1.589–12.743). Overall, we observed an underlying additive and multiplicative interaction between the aggrecan gene VNTR polymorphism and smoking in symptomatic IDD.     

兔退变椎间盘中BNIP3的免疫组织化学研究

目的探讨兔退变椎间盘中BNIP3蛋白的表达情况。方法建立兔椎间盘穿刺退变模型,分别培养2、4、8周后对目的椎间盘进行组织HE染色、番红O染色及BNIP3免疫组织化学染色,与正常椎间盘随机对照,检测椎间盘退变程度及BNIP3蛋白表达情况。结果成功建立兔椎间盘退变模型,随椎间盘退变程度加重,BNIP3蛋白在中央髓核组织中的阳性表达逐渐增强。结论兔椎间盘退变过程中,BNIP3蛋白表达增强诱导髓核细胞死亡增加。     

Granulocyte-colony stimulating factor improves intervertebral disc degeneration in experimental adult male rats: A microscopic and radiological study

Intervertebral disc degeneration (IVDD) is a major contributor to low back pain (LBP). Granulocyte-colony stimulating factor (GCSF) is known to mobilize hematopoietic stem cells (HSCs) that may be implicated in intervertebral disc (IVD) regeneration. Rats were divided into the following three groups: (i) control group; (ii) IVDD group—the rats underwent Co5/Co6 and Co7/Co8 IVDD operation; and (iii) GCSF-treated group—the rats received daily GCSF subcutaneous injections starting 6 weeks after the IVDD operation and continued for 5 days. All of the rats were euthanized after 8 weeks, and IVDs were assessed by tail X-ray and histopathological, immunohistochemical, and transmission electron microscopy (TEM) analyses. The X-rays showed disc narrowing in the IVDD group that was significantly widened in the GCSF-treated rats. Histologically, the IVDD group showed disarrangement of the annulus fibrosis lamellae, complete degeneration of the nucleus pulposus, and loss of proteoglycan content. These changes were improved after GCSF treatment. Vertebral endplate thickness and cellularity were significantly decreased with IVDD and significantly increased after GCSF treatment. Stromal cell-derived factor-1α (SDF-1α) immune expression was significantly increased in the IVDD group but decreased in the GCSF-treated group. However, the caspase-3 expression percentage showed no significant difference among the studied groups. TEM showed excessive collagen deposits around the notochordal cells in the IVDD group, which were attenuated in the GCSF-treated group. These results indicate that GCSF improves IVDD and promotes its recovery based on radiological, histological and TEM findings.     

MicroRNA影响椎间盘退变过程的研究进展及可发展空间

文题释义：miRNA：属于一种受内源性非蛋白质编码调控的单链小分子RNA,可以调控人体近1/3的蛋白编码基因参与机体发育与疾病发生,与许多生物进程的调控密切关联,包括生长发育、细胞增殖、凋亡和分化等。其不仅在许多正常人体发育过程中起着关键作用,而且与多种疾病的发生和发展有关。 自噬：是细胞通过溶酶体吞噬和降解自身细胞质和细胞器的过程。自噬在生长、发育、细胞稳定和成熟分化等方面起着重要作用,作为一种独立的Ⅱ型程序性细胞死亡过程,自噬与细胞凋亡存在着密切关联。 背景：在细胞与分子水平上明确MicroRNA(miRNA)在椎间盘退变过程的作用机制,可为早预防或治疗椎间盘退变继发的一系列脊柱疾患提供新的思路。 目的：综述miRNA在椎间盘退变原因和机制中的研究现状。 方法：应用计算机检索PubMed数据库、万方数据库和中国知网数据库,英文检索词为“miRNA、Intervertebral disc degeneration、Extracellular matrix、Apoptosis、Autophagy、Cartilage endplate、Nucleus pulposus、Fibrous ring”,中文检索词为“miRNA、椎间盘退变、细胞外基质、凋亡、自噬、软骨终板、髓核、纤维环”,最终纳入58篇文章进行综述。 结果与结论：miRNA在椎间盘退变过程中的作用已被广泛研究,部分具体机制得到验证;研究多局限于髓核组织,对软骨终板及纤维环报道较少;随着miRNA深入研究,临床方面的研究仍有较大发展空间。 ORCID: 0000-0002-2312-4255(胡宝阳) 中国组织工程研究杂志出版内容重点：人工关节;骨植入物;脊柱;骨折;内固定;数字化骨科;组织工程