Pathogenesis Of Ossification Of The Posterior Longitudinal Ligament Research Articles

“Only Spinal Fixation” as Surgical Treatment of Cervical Myelopathy Related to Ossified Posterior Longitudinal Ligament: Review of 52 Cases

Ossification of the posterior longitudinal ligament (OPLL) is a hyperostotic condition resulting in a progressive narrowing of the spinal canal and subsequent neurologic deficits. Although systemic and local factors in combination with genetic abnormality have been considered in its etiopathogenesis, OPLL remains a poorly understood pathology. Surgical management of OPLL and the choice of the most appropriate treatment are stillcontroversial issues. Here the authors report a series of OPLL-affected patients treated by "only-fixation" technique. Between June 2012 and June 2019, 52 patients having OPLL were treated by a surgical strategy involving only spinal fixation without any form of bone or soft tissue decompression. Facetal fixation for both the atlantoaxial and subaxial spine formed the basis of the surgical treatment. Clinical parameters, analysis of video recordings before and after surgery, and patient self-assessment were included in the analysis of outcome. During the mean follow-up period there was an immediate postoperative and progressive recovery in symptoms in 51 patients. Of 14 patients who were wheelchair bound before surgery, 12 walked independently on follow-up assessment of 6 months. All patients had successful arthrodesis in the surgically treated segments. There were no infective- or implant-related complications. Decision making in the surgical management of cervical OPLL is still controversial. The concept of spinal instability has been shown to be a nodal point in the pathogenesis of OPLL, and "only-spinal fixation" can be considered a rationale for an appropriate surgical treatment.

Integrated miRNA-mRNA network revealing the key molecular characteristics of ossification of the posterior longitudinal ligament

Background:Ossification of the posterior longitudinal ligament (OPLL) refers to an ectopic ossification disease originating from the posterior longitudinal ligament of the spine. Pressing on the spinal cord or nerve roots can cause limb sensory and motor disorders, significantly reducing the patient's quality of life. At present, the pathogenesis of OPLL is still unclear. The purpose of this study is to integrate microRNA (miRNA)-mRNA biological information data to further analyze the important molecules in the pathogenesis of OPLL, so as to provide targets for future OPLL molecular therapy.Methods:miRNA and mRNA expression profiles of GSE69787 were downloaded from Gene Expression Omnibus database and analyzed by edge R package. Funrich software was used to predict the target genes and transcription factors of de-miRNA. Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis of differentially expressed genes (DEGs) were carried out based on CLUEGO plug-in in Cytoscape. Using data collected from a search tool for the retrieval of interacting genes online database, a protein-protein interaction (PPI) network was constructed using Cytoscape. The hub gene selection and module analysis of PPI network were carried out by cytoHubba and molecular complex detection, plug-ins of Cytoscape software respectively.Results:A total of 346 genes, including 247 up-regulated genes and 99 down-regulated genes were selected as DEGs. SP1 was identified as an upstream transcription factor of de-miRNAs. Notably, gene ontology enrichment analysis shows that up- and down-regulated DEGs are mainly involved in BP, such as skeletal structure morphogenesis, skeletal system development, and animal organ morphogenesis. Kyoto Encyclopedia of Genes and Genomes enrichment analysis indicated that only WNT signaling pathway was associated with osteogenic differentiation. Lymphoid enhancer binding factor 1 and wingless-type MMTV integration site family member 2 Wingless-Type MMTV Integration site family member 2 were identified as hub genes, miR-520d-3p, miR-4782-3p, miR-6766-3p, and miR-199b-5p were identified as key miRNAs. In addition, 2 important network modules were obtained from PPI network.Conclusions:In this study, we established a potential miRNA-mRNA regulatory network associated with OPLL, revealing the key molecular mechanism of OPLL and providing targets for future treatment or prevent its occurrence.

Advancements in the pathogenesis of ossification of the posterior longitudinal ligament

Ossification of the posterior longitudinal ligament (OPLL) is a degenerative disease with a series of clinical manifestations caused by compression of the spinal cord and nerve roots. The disease is prevalent in East Asian countries, and the average prevalence rate of Chinese people is 3.08%. Disease progression can lead to paraplegia, but there is no effective preven-tion and cure. The pathogenesis of OPLL is still unclear. Most scholars suggest it may be related to genes, hormones, environment, lifestyle and other factors, but all stay in the stage of hypothesis and theory. In this paper, we searched Pubmed, Embase, CNKI and Wanfang database. According to the included literatures, the pathogenesis of OPLL was divided into the following parts: extra-cellular microenvironment, intracellular cytokines, genetic factors, biomechanical factors, and endocrine and living habits. We summarized and analyzed these literatures. These existing studies independently elucidated the possible mechanisms of OPLL from different angles. Different pathogenic factors promote mesenchymal stem cells to differentiate into osteoblasts through corre-sponding molecular pathways, initiate osteogenesis, and lead to the formation of ectopic ossification. However, none of these stud-ies have clarified the complete pathogenesis of OPLL. Most of the studies focused on the field of genetics. In recent years, a large number of susceptible genes or loci related to the pathogenesis of OPLL have been screened, but they have shortcomings such as insufficient sample size, ethnic regional differences, and poor reproducibility.

Increase of the Serum FGF-23 in Ossification of the Posterior Longitudinal Ligament.

Study Design:Case-control study.Objectives:To determine the possible pathogenesis of ossification of the posterior longitudinal ligament (OPLL) in regard to the serum concentration of fibroblast growth factor 23 (FGF-23).Methods:The study included 95 patients with OPLL and a control group of 73 age- and sex-matched volunteers. The serum concentrations of FGF-23, creatinine (Cre), alkaline phosphatase, calcium (Ca), inorganic phosphate (Pi), and hypersensitive C-reactive protein (hs-CRP) were analyzed from blood samples, and Cre, Ca, Pi, and tubular reabsorption of phosphate were measured using urine samples. We evaluated the severity of ossified spinal lesions in patients with OPLL according to the ossification index (the OP index and the OS index). Data was compared between the OPLL and control group and between the OPLL progression and no progression group.Results:Serum FGF-23 and hs-CRP were higher, and serum Pi was lower in patients with OPLL than in the controls. There was a positive correlation between FGF-23 and hs-CRP and a negative correlation between serum Pi and the OS index; however, the correlations were very weak. Overall, 31.7% of patients had progression of OPLL during follow-up. FGF-23 and hs-CRP were higher in the progression group than in the no progression group.Conclusions:These results might indicate that FGF-23 and hs-CRP are positive markers for OPLL. Phosphate metabolism via FGF-23 might be a target for future study on the pathogenesis of OPLL.

Serum biomarkers in patients with ossification of the posterior longitudinal ligament (OPLL): Inflammation in OPLL.

BackgroudOssification of the posterior longitudinal ligament (OPLL) is characterized by replacement of ligamentous tissue by ectopic new bone formation. OPLL causes narrowing of the spinal canal, resulting in neurological impairment. However, the pathogenesis of OPLL has not been fully elucidated. We investigated whether inflammation occurs in OPLL or not using high-sensitivity CRP (hs-CRP) in a case-control study.Methods and findingsThis study included 103 patients with OPLL in the patient group and 95 age- and sex-matched volunteers with degenerative spinal disease in the control group. Of the 103 OPLL patients, 88 patients who were available for more than 2 years follow-up were checked for OPLL progression. A blood sample was obtained and Hs-CRP, and other routine data, including total protein (TP), albumin (ALB), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), glucose (Glu), calcium (Ca), inorganic phosphate (Pi), white blood cell count (WBC), hemoglobin (Hb) and platelet (PLT), were analyzed. The data were compared between the patients with OPLL and the controls. The severity of the ossified lesions in the whole spine were evaluated by the ossification index (OS index) in patients with OPLL. The data were also compared between the patients with OPLL progression (the progression group) and the patients without OPLL progression (the non-progression group). In the results, the mean hs-CRP in the OPLL group was higher than that in the controls. The Pi in the OPLL group was lower than that in the control group. A negative correlation was found between the Pi and the OS index. The mean hs-CRP in the progression group was higher than that in the non-progression group. There was a positive correlation between the average length of the OPLL progression per year and the hs-CRP.ConclusionsThe results may suggest the occurrence of local inflammation in OPLL and the inflammation might cause OPLL progression. These facts are important for understanding the pathology of OPLL.

Spinal balance failure: A potential cause of spinal ligament ossification

Ossification of the posterior longitudinal ligament (OPLL) and of the ligamentum flavum (OLF), as well as calcification of ligamentum nuchae in the cervical spine and ossification of ligamentum flavum in the thoracic spine, are common types of spinal ligament ossification. As is known, the pathogenesis of OPLL and OLF has been unclear until recently, and mechanical stress assumably plays an important role. In this paper, we try to make a hypothesis that spinal balance failure (characterized by the gravity line, spinal curvature and flexion/extension in the sagittal plane), may play more important roles than any other factors in the development of ligament ossified diseases. Moreover, different stress thresholds and flexion/extension frequency may induce various ossification regions. It is supported by the conclusions that drawn from literature review: (1) OPLL and OLF seldom occur in lumbar spine which is of stiffer and lower-frequency motion than cervical spine, although its range of motion (ROM) was relatively great. (2) Spinal ligament ossification often appears in the cervical spine, which is significantly flexible with a larger motion range. (3) OLF is often seen in the thoracic spine, which is farthest away from the gravity line for thoracic kyphosis. (4) Many OPLL or OLF patients are often found with a local kyphosis or high segmental ROM. (5) The prevalence of ossification is higher in the larger stress regions, as described above, indicating that there may be a stress threshold for the spinal ligaments.

Ossification of the posterior longitudinal ligament: a review

Ossification of the posterior longitudinal ligament (OPLL) is most commonly found in men, the elderly, and Asian patients. There are many diseases associated with OPLL, such as diffuse idiopathic skeletal hyperostosis, ankylosing spondylitis, and other spondyloarthropathies. Several factors have been reported to be associated with OPLL formation and progression, including genetic, hormonal, environmental, and lifestyle factors. However, the pathogenesis of OPLL is still unclear. Most symptomatic patients with OPLL present with neurological deficits such as myelopathy, radiculopathy, and/or bowel and bladder symptoms. There are some reports of asymptomatic OPLL. Both static and dynamic factors are related to the development of myelopathy. Plain radiography, CT, and MR imaging are used to evaluate OPLL extension and the area of spinal cord compression. Management of OPLL continues to be controversial. Each surgical technique has some advantages and disadvantages, and the choice of operation should be made case by case, depending on the patient's condition, level of pathology, type of OPLL, and the surgeon's experience. In this paper, the authors attempt to review the incidence, pathology, pathogenesis, natural history, clinical presentation, classification, radiological evaluation, and management of OPLL.

Association between serum leptin and bone metabolic markers, and the development of heterotopic ossification of the spinal ligament in female patients with ossification of the posterior longitudinal ligament

Obesity is a risk factor for ossification of the posterior longitudinal ligament (OPLL) of the spine, which is characterized by heterotopic bone formation in the posterior longitudinal spinal ligament. Hyperleptinemia is a common feature of obese people and leptin is believed to be an important factor in the pathogenesis of OPLL. However, the association between leptin and bone metabolism and the development of OPLL is not understood fully. The objective of the present study was to determine the association between serum leptin concentration and bone metabolic markers and the extent of heterotopic ossification of the spinal ligament in patients with OPLL. The serum concentrations of leptin, insulin, fructosamine, bone-specific alkaline phosphatase, and carboxyterminal propeptide of type I procollagen, urine deoxypyridinoline levels, and the number of vertebrae with OPLL involvement were measured in 125 (68 males and 57 females) patients with OPLL. The correlation between leptin and these other factors was then examined. Serum leptin and insulin concentrations were increased significantly in OPLL females compared to non-OPLL female controls. In the females with OPLL, serum leptin concentrations corrected for body mass index correlated positively with the number of vertebrae with OPLL involvement. In females, serum leptin levels were significantly higher in patients in whom OPLL extended to the thoracic and/or lumbar spine than in patients in whom OPLL was limited to the cervical spine. Our results suggest that hyperleptinemia, in combination with hyperinsulinemia, may contribute to the development of heterotopic ossification of the spinal ligament in female patients with OPLL.

Association of toll-like receptor 5 gene polymorphism with susceptibility to ossification of the posterior longitudinal ligament of the spine in korean population.

Ossification of the posterior longitudinal ligament (OPLL) has a strong genetic component. Specific gene polymorphisms may be associated with OPLL in several genes which regulate calcification in chondrocytes, change of extracellular collagen matrix and secretions of many growth factors and cytokines controlling bone morphogenesis. Toll-like receptor 5 (TLR5) may play a role in the pathogenesis of OPLL by intermediate nuclear factor-kappa B (NF-κB). The current study focused on coding single nucleotide polymorphisms (SNPs) of TLR5 for a case-control study investigating the relationship between TLR5 and OPLL in a Korean population. A total of 166 patients with OPLL and 231 controls were recruited for a case-control association study investigating the relationship between SNPs of TLR5 gene and OPLL. Four SNPs were genotyped by direct sequencing (rs5744168, rs5744169, rs2072493, and rs5744174). SNP data were analyzed using the SNPStats, SNPAnalyzer, Haploview, and Helixtree programs. Multiple logistic regression analysis with adjustment for age and gender was performed to calculate an odds ratio (OR). None of SNPs were associated with OPLL in three alternative models (codominant, dominant, and recessive models; p > 0.05). A strong linkage disequilibrium block, including all 4 SNPs, was constructed using the Gabriel method. No haplotype was significantly associated with OPLL in three alternative models. These results suggest that Toll-like receptor 5 gene may not be associated with ossification of the posterior longitudinal ligament risk in Korean population.

Ossification of the Posterior Longitudinal Ligament: An Update on Its Biology, Epidemiology, and Natural History

Significant progress has been achieved in basic research during the past decade on the pathogenesis of ossification of the posterior longitudinal ligament (OPLL), a multifactorial disease in which complex genetic and environmental factors interact. A review of the literature was conducted to update recent findings on the biology, epidemiology, natural history, and related diseases of OPLL. Gene analysis studies found specific polymorphisms that may be associated with OPLL in several collagen genes, which encode for extracellular matrix proteins. Polymorphisms in the nucleotide pyrophosphate gene, which is involved in regulation of calcification in chondrocytes, may also be associated with OPLL. However, the results of the gene analysis studies have not always been consistent. Involvement of many growth factors and cytokines, including bone morphogenic proteins and transforming growth factor-beta, has been demonstrated in various histochemical and cytochemical analyses. Several transcription factors involved in cellular differentiation may also have a role. Recent epidemiological studies reaffirmed an earlier finding that diabetes mellitus is a distinct risk factor for OPLL. The long-term follow-up studies of OPLL patients are disclosing the natural history, as well as the frequency and rate of progression, of OPLL after surgical intervention. Further knowledge on the factors responsible for progression of OPLL may predict its behavior in each patient, and treatment may be tailored accordingly. The coexistence of OPLL with other diseases of ectopic ossification of the spine, such as ossification of the ligamentum flavum and diffuse idiopathic skeletal hyperostosis, is not uncommon. Scientific breakthrough in those diseases may, in turn, give insights into the pathogenesis of OPLL.

頚椎後縦靭帯骨化症患者の日常生活における頚椎姿勢の調査

To clarify the role of mechanical factors in the pathogenesis of the ossification of the posterior longitudinal ligament (OPLL), we investigated the cervical posture of 32 patients with OPLL and 18 patients with cervical spondylotic myelopathy (CSM) in their daily life.All patients were examined directly in our hospital.Patients with OPLL maintained their carvical spine in the anterior flexed position significantly longer than patients with CSM.We concluded that mechanical factors are important aspects in the pathogenesis of OPLL.