Of The Posterior Longitudinal Ligament Research Articles

Integrin αVβ3 antagonist-c(RGDyk) peptide attenuates the progression of ossification of the posterior longitudinal ligament by inhibiting osteogenesis and angiogenesis

BackgroundOssification of the posterior longitudinal ligament (OPLL), an emerging heterotopic ossification disease, causes spinal cord compression, resulting in motor and sensory dysfunction. The etiology of OPLL remains unclear but may involve integrin αVβ3 regulating the process of osteogenesis and angiogenesis. In this study, we focused on the role of integrin αVβ3 in OPLL and explored the underlying mechanism by which the c(RGDyk) peptide acts as a potent and selective integrin αVβ3 inhibitor to inhibit osteogenesis and angiogenesis in OPLL.MethodsOPLL or control ligament samples were collected in surgery. For OPLL samples, RNA-sequencing results revealed activation of the integrin family, particularly integrin αVβ3. Integrin αVβ3 expression was detected by qPCR, Western blotting, and immunohistochemical analysis. Fluorescence microscopy was used to observe the targeted inhibition of integrin αVβ3 by the c(RGDyk) peptide on ligaments fibroblasts (LFs) derived from patients with OPLL and endothelial cells (ECs). The effect of c(RGDyk) peptide on the ossification of pathogenic LFs was detected using qPCR, Western blotting. Alkaline phosphatase staining or alizarin red staining were used to test the osteogenic capability. The effect of the c(RGDyk) peptide on angiogenesis was determined by EC migration and tube formation assays. The effects of the c(RGDyk) peptide on heterotopic bone formation were evaluated by micro-CT, histological, immunohistochemical, and immunofluorescence analysis in vivo.ResultsThe results indicated that after being treated with c(RGDyk), the osteogenic differentiation of LFs was significantly decreased. Moreover, the c(RGDyk) peptide inhibited the migration of ECs and thus prevented the nutritional support required for osteogenesis. Furthermore, the c(RGDyk) peptide inhibited ectopic bone formation in mice. Mechanistic analysis revealed that c(RGDyk) peptide could inhibit osteogenesis and angiogenesis in OPLL by targeting integrin αVβ3 and regulating the FAK/ERK pathway.ConclusionsTherefore, the integrin αVβ3 appears to be an emerging therapeutic target for OPLL, and the c(RGDyk) peptide has dual inhibitory effects that may be valuable for the new therapeutic strategy of OPLL.

Coexisting ossification of the posterior longitudinal ligament, intramedullary hemangioblastoma, and syringomyelia of the cervical spine: illustrative case.

Ossification of the posterior longitudinal ligament (OPLL) is a rare but potentially devastating cause of severe spinal cord compression and degenerative cervical myelopathy. Because OPLL is rarely accompanied by prominent syringomyelia, when both are observed, other causes of syringomyelia should be considered. Simultaneous presentation of OPLL and hemangioblastoma of the cervical spine is a rare encounter and has never been reported in the English-language literature. The authors present a case of a 64-year-old man with muscle weakness of the right upper limb and worsening dysesthesia of the right thumb and index finger. Noncontrast magnetic resonance imaging (MRI) of the cervical spine from another institution revealed OPLL from the C2 to C6 levels with severe spinal cord compression and prominent syringomyelia. Repeated MRI with contrast showed an intramedullary tumor, about 11 mm in diameter, at the right posterior aspect of the C4 level. The authors performed laminectomies from C1 to C6 with posterolateral fusion and removed the C4 tumor. Pathohistological examination of the tumor demonstrated hemangioblastoma. Careful evaluation of the preoperative imaging study is extremely important in surgical decision making. Although rare, concomitant cervical hemangioblastoma should be listed in the differential diagnosis when OPLL is accompanied with prominent syringomyelia.

Exosomal miR-140-5p inhibits osteogenesis by targeting IGF1R and regulating the mTOR pathway in ossification of the posterior longitudinal ligament

BackgroundOssification of the posterior longitudinal ligament (OPLL) is a disabling disease whose pathogenesis is still unclear, and there are no effective cures or prevention methods. Exosomal miRNA plays an important role in the osteogenesis of ectopic bone. Therefore, we focused on the downregulation of miR-140-5p in OPLL cell-derived exosomes to explore the mechanism by which exosomal miR-140-5p inhibits osteogenesis in OPLL.ResultsExosomes were isolated by differential centrifugation and identified by transmission electron microscopy, nanoparticle tracking analysis, and exosomal markers. Exosomal RNA was extracted to perform miRNA sequencing and disclose the differentially expressed miRNAs, among which miR-140-5p was significantly downregulated. Confocal microscopy was used to trace the exosomal miR-140-5p delivered from OPLL cells to human mesenchymal stem cells (hMSCs). In vitro, we verified that exosomal miR-140-5p inhibited the osteoblast differentiation of hMSCs by targeting IGF1R and suppressing the phosphorylation of the IRS1/PI3K/Akt/mTOR pathway. In vivo, we verified that exosomal miR-140-5p inhibited ectopic bone formation in mice as assessed by micro-CT and immunohistochemistry.ConclusionsWe found that exosomal miR-140-5p could inhibit the osteogenic differentiation of hMSCs by targeting IGF1R and regulating the mTOR pathway, prompting a further potential means of drug treatment and a possible target for molecular therapy of OPLL.

High Body Mass Index Is Associated with an Increased Risk of the Onset and Severity of Ossification of Spinal Ligaments.

BackgroundOssification of the posterior longitudinal ligament (OPLL) and that of ligamentum flavum (OLF) are the main types of the ossification of spinal ligaments (OSL) that cause the thoracic myelopathy. Although several studies have investigated the relationship of body mass index (BMI) with the onset or severity of OSL, it remains unverified due to the contradictory results of existing evidence. A systematic review and meta-analysis were performed in this work to determine the relationship of BMI with the onset and severity of OSL.MethodsPubMed, EMBASE, Web of Science, and Cochrane Library were comprehensively searched online for relevant studies focusing on the relationship of BMI with the onset or severity of the OSL. The difference in BMI of OSL (or severe OSL group) and non-OSL (or nonsevere OSL group) groups was evaluated using the mean difference (MD) with a corresponding 95% confidence interval (CI).ResultsFifteen studies were included in this systematic review and meta-analysis. The BMI of the OSL group was significantly higher than that of the non-OSL group (MD = 1.70 kg/m2, 95% CI = 1.02–2.39 kg/m2, and P < 0.01). Similar results were observed in the subgroup analysis of female (P < 0.01), OPLL (P < 0.01), and OLF (P < 0.01) populations. Three studies reported a significant association of BMI with the ossification index of OSL and the standardized regression coefficient ranging from 0.11 to 0.43 (P < 0.05). Moreover, a significantly higher BMI was observed in the severe OSL group compared with that in the nonsevere OSL group (MD = 3.09, 95% CI, 0.22–5.97 kg/m2, and P = 0.04).ConclusionThe significant association of high BMI with the onset and severity of OSL may provide new evidence and insights into the mechanism research and management of OSL.

Small extracellular vesicle-mediated miR-320e transmission promotes osteogenesis in OPLL by targeting TAK1.

Ossification of the posterior longitudinal ligament (OPLL) is an emerging spinal disease caused by heterotopic ossification of the posterior longitudinal ligament. The pathological mechanism is poorly understood, which hinders the development of nonsurgical treatments. Here, we set out to explore the function and mechanism of small extracellular vesicles (sEVs) in OPLL. Global miRNA sequencings are performed on sEVs derived from ligament cells of normal and OPLL patients, and we have showed that miR-320e is abundantly expressed in OPLL-derived sEVs compare to other sEVs. Treatment with either sEVs or miR-320e significantly promote the osteoblastic differentiation of normal longitudinal ligament cells and mesenchymal stem cells and inhibit the osteoclastic differentiation of monocytes. Through a mechanistic study, we find that TAK1 is a downstream target of miR-320e, and we further validate these findings in vivo using OPLL model mice. Together, our data demonstrate that OPLL ligament cells secrete ossification-promoting sEVs that contribute to the development of ossification through the miR-320e/TAK1 axis.

FLUOROSIS SPINE WITH CERVICAL MYELORADICULOPATHY AND OPLL– CASE REPORT

To report case presentations of cervical myelopathy with ossication of the posterior longitudinal ligament (OPLL) due to uorosis. Fluorosis is regularly found in a particular place or among a particular group of people which always goes unnoticed unless otherwise, complication develops. It may be prevented easily if you identify and treat it promptly. The skeletal system is one of the supporting systems of our body that gets affected by uorosis and leads to catastrophic changes. So, it is always necessary to monitor the people living in an endemic area and also people presenting outpatient departments with spine problems.

One-stage posterior surgery with intraoperative ultrasound assistance for thoracic myelopathy with simultaneous ossification of the posterior longitudinal ligament and ligamentum flavum at the same segment: a minimum 5-year follow-up study

BACKGROUND CONTEXTOssification of the posterior longitudinal ligament (OPLL) and ligamentum flavum (OLF) are not uncommon independent causes of thoracic myelopathy (TM); however, concomitant OPLL and OLF at the same segment is rare. The ideal surgical strategy remains controversial, and it is difficult for surgeons to balance sufficient neural decompression while simultaneously reducing the occurrence of postoperative neurological defect after circumferential decompression (CD). Aiming to solve this dilemma, we investigated a CD-based surgery using intraoperative ultrasound (IOU) assistance to evaluate spinal decompression sufficiency. PURPOSEThe aims of this study are to evaluate the surgical outcomes and identify prognostic factors of one-stage posterior surgery with IOU assistance in patients with concomitant OPLL and OLF. STUDY DESIGN/SETTINGRetrospective study of a single-center TM database with long-term follow-up. PATIENT SAMPLETwenty-four patients with TM and concomitant OPLL and OLF. OUTCOME MEASURESJapanese Orthopaedic Association (JOA) score system for TM, recovery rate (RR), complication rate. METHODSTwenty-four patients’ data were retrospectively reviewed. All patients initially underwent en bloc excisions of posterior spinal canal elements, and IOU was then used to evaluate spinal decompression sufficiency. If any compression of OPLL was confirmed in IOU, further CD procedure was performed. The JOA score was used to evaluate health-related quality of life. RR was calculated using the Hirabayashi formula. A RR ≥50% was considered favorable, and a RR <50% was considered unfavorable. The paired t test was performed to statistically compare the preoperative and postoperative JOA scores. The chi-squared test, rank sum test, and logistic regression analyses were performed to find variants associated with unfavorable surgical outcomes The prognostic factors were analyzed by Spearman correlation and Pearson correlation analyses. RESULTSThe invasive CD procedure were avoided in 9 of 28 segments were avoided, with a mean blood loss of 1,458 mL. Seventeen patients experienced cerebrospinal fluid leakage, and 5 experienced immediate postoperative paralysis. The mean JOA score improved from 4.25±2.2 (preoperative) to 8.16±1.9 (final follow-up). The mean RR was 57.7%±29.4%. There was a significant difference (p<.01) between the preoperative and final follow-up JOA score. A comparison between the favorable and the unfavorable groups showed no significant differences in the evaluated factors, but the considerable blood loss was a significant risk factor for poor RR (p=.036, b=−0.43). CONCLUSIONSOne-stage CD-based surgery via a posterior approach with IOU assistance for the treatment of concomitant OPLL and OLF led to significant functional improvement in the majority of patients. Under the premise of sufficient decompression, the postoperative paralysis rate reduced compared to that in previous studies. However, there were still high cerebral spinal fluid leakage rates. Considerable blood loss is a risk factor for poor RR.

Whole-genome sequencing reveals novel genes in ossification of the posterior longitudinal ligament of the thoracic spine in the Chinese population

BackgroundOssification of the posterior longitudinal ligament (OPLL) of the spine is a complex, multifactorial disease. Although several genes that are linked to cervical OPLL susceptibility have been reported, specific genetic studies regarding thoracic OPLL are lacking. Whole-genome sequencing has been considered as an efficient strategy to search for disease-causing genes.MethodsWe analysed whole-genome sequences in a cohort of 25 unrelated patients with thoracic OPLL. Bioinformatics analysis and various algorithms were used to predict deleterious variants. Sanger sequencing was used to confirm the variants.ResultsFour deleterious mutations in three genes (c.2716C>T (p.Arg906Cys) in collagen type VI α6 (COL6A6); c.1946G>C (p.Gly649Ala) in collagen type IX α1 (COL9A1); and c.301T>C (p.Ser101Pro) and c.171A>G (p.Ile57Met) in toll-like receptor 1 (TLR1)) were successfully identified. All the variants were confirmed by Sanger sequencing.ConclusionThe novel deleterious mutations of the three genes may contribute to the development of thoracic OPLL.

Association of miR-146a, miR-149, miR-196a2, and miR-499 Polymorphisms with Ossification of the Posterior Longitudinal Ligament of the Cervical Spine.

BackgroundOssification of the posterior longitudinal ligament (OPLL) of the spine is considered a multifactorial and polygenic disease. We aimed to investigate the association between four single nucleotide polymorphisms (SNPs) of pre-miRNAs [miR-146aC>G (rs2910164), miR-149T>C (rs2292832), miR-196a2T>C (rs11614913), and miR-499A>G (rs3746444)] and the risk of cervical OPLL in the Korean population.MethodsThe genotypic frequencies of these four SNPs were analyzed in 207 OPLL patients and 200 controls by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay.FindingsFor four SNPs in pre-miRNAs, no significant differences were found between OPLL patients and controls. However, subgroup analysis based on OPLL subgroup (continuous: continuous type plus mixed type, segmental: segmental and localized type) showed that miR-499GG genotype was associated with an increased risk of segmental type OPLL (adjusted odds ratio = 4.314 with 95% confidence interval: 1.109–16.78). In addition, some allele combinations (C-T-T-G, G-T-T-A, and G-T-C-G of miR-146a/-149/-196a2/-499) and combined genotypes (miR-149TC/miR-196a2TT) were associated with increased OPLL risk, whereas the G-T-T-G and G-C-C-G allele combinations were associated with decreased OPLL risk.ConclusionThe results indicate that GG genotype of miR-499 is associated with significantly higher risks of OPLL in the segmental OPLL group. The miR-146a/-149/-196a2/-499 allele combinations may be a genetic risk factor for cervical OPLL in the Korean population.

The H2 blocker famotidine suppresses progression of ossification of the posterior longitudinal ligament in a mouse model

BackgroundOssification of the posterior longitudinal ligament (OPLL) of the spine is a common human myelopathy that leads to spinal cord compression. No disease-modifying drug for OPLL has been identified, whereas...

Diagnosis and management of traumatic cervical central spinal cord injury: A review.

Background:The classical clinical presentation, neuroradiographic features, and conservative vs. surgical management of traumatic cervical central spinal cord (CSS) injury remain controversial.Methods:CSS injuries, occurring in approximately 9.2% of all cord injuries, are usually attributed to significant hyperextension trauma combined with congenital/acquired cervical stenosis/spondylosis. Patients typically present with greater motor deficits in the upper vs. lower extremities accompanied by patchy sensory loss. T2-weighted magnetic resonance (MR) scans usually show hyperintense T2 intramedullary signals reflecting acute edema along with ligamentous injury, while noncontrast computed tomography (CT) studies typically show no attendant bony pathology (e.g. no fracture, dislocation).Results:CSS constitute only a small percentage of all traumatic spinal cord injuries. Aarabi et al. found CSS patients averaged 58.3 years of age, 83% were male and 52.4% involved accidents/falls in patients with narrowed spinal canals (average 5.6 mm); their average American Spinal Injury Association (ASIA) motor score was 63.8, and most pathology was at the C3-C4 and C4-C5 levels (71%). Surgery was performed within 24 h (9 patients), 24–48 h (10 patients), or after 48 h (23 patients). In the Brodell et al. study of 16,134 patients with CSS, 39.7% had surgery. In the Gu et al. series, those with CSS and stenosis/ossification of the posterior longitudinal ligament (OPLL) exhibited better outcomes following laminoplasty.Conclusions:Recognizing the unique features of CSS is critical, as the clinical, neuroradiological, and management strategies (e.g. conservative vs. surgical management: early vs. late) differ from those utilized for other spinal cord trauma. Increased T2-weighted MR images best document CSS, while CT studies confirm the absence of fracture/dislocation.

New classification system for ossification of the posterior longitudinal ligament using CT images

BackgroundOssification of the posterior longitudinal ligament (OPLL) is most frequently seen in the cervical spine. The types of cervical OPLL are classified into continuous, mixed, segmental, and other based on plain lateral X-ray. Computed tomography (CT) imaging is often used in clinical practice for evaluating ossified lesions as it can detect their precise location, size, and shape. However, to date, no CT classification of OPLL lesions has been proposed. MethodsOne hundred and forty-four patients diagnosed with cervical OPLL by plain radiograph were included in this study. Sagittal and axial CT images of the cervical spine were obtained. We propose three classification systems: A, B, and axial. Classification A comprises two lesion types: bridge and nonbridge. Classification B requires examiners to describe all vertebral and intervertebral levels where OPLL exits in the cervical spine. Axial classification comprises central and lateral lesions identified on axial CT images. Seven observers evaluated CT images using this classification system, and intra- and interrater reliability were examined. ResultsAveraged Fleiss’ kappa coefficient of interrater agreement was 0.43 ± 0.26 among the seven observers, averaged intrarater reliability for the existence of OPLL was 72.4 ± 8.8 % [95 % confidence interval (CI) 67.5–76.8]. Fifty-four patients (37.5 %) had the bridge type and 90 the nonbridge type according to Classification A; 102 (70.8 %) had central and 42 (29.2 %) lateral OPLL in the axial classification. Four representative cases defined according to the three classification types are reported here. ConclusionSubcommittee members of the Investigation Committee on the Ossification of the Spinal Ligaments of the Japanese Ministry of Public Health and Welfare propose three new classification systems of cervical OPLL based on CT imaging: A, B, and axial.

Single-stage combined decompression for patients with tandem ossification in the cervical and thoracic spine

Retrospective study of clinical outcomes of single-staged combined cervical and thoracic decompression for patients with tandem ossification (TO). To describe primary clinical outcomes of this procedure. TO is introduced to described a double ossification lesion of the posterior longitudinal ligament (OPLL) or the ligament flavum (OLF) at the cervical, thoracic and lumbar spine. In clinical practice, cervical OPLL combined with thoracic OPLL or/and OLF are the most common types of TO. However, little is known about the clinical outcomes of surgical treatment and there is no consensus on the optimal treatment to this combined disorder. Between January 2005 and December 2008, 15 patients of this complicated phenomenon were treated by single-staged combined cervical and thoracic decompression in conditions where patients' general condition allowed and individuals agreed on. Surgical intervention, perioperative complications, and clinical outcomes were reviewed in these 15 TO patients who were followed up for more than 2 years (range 2-5 years). Clinical symptoms were evaluated using the JOA scoring system and activity of daily life was evaluated by Nurick classification before surgery, at 6 months postoperatively, and at final follow-up. Patient satisfaction was determined at final follow-up. The mean blood loss was 1,553.3 ± 735.7 ml (range 700-2,900 ml) and the mean operation time was 280.7 ± 53.6 min (range 220-370 min). The important intraoperative and postoperative complications recorded in medical documents included CSF leakage, hematoma, C5 palsy and neurological deterioration. The JOA score was significantly higher 6 months after surgery (8.1 ± 1.8 points vs. 11.0 ± 1.6 points, p < 0.0001), and there was no significant change between 6 months after surgery and final follow-up (11.0 ± 1.6 points vs. 11.3 ± 2.1, p = 0.5894). The mean Nurick classification significantly improved from grade 3.6 ± 0.7 before surgery to grade 2.5 ± 0.9 at 6 months after surgery (p < 0.001), and well maintained as grade 2.3 ± 1.0 at final follow-up (p = 0.3343). Three patients had satisfaction scores of 3 points, 5 had scores of 2 or 1 point, and 2 had score of 0 point. Pearson correlation analysis showed a significant positive correlation between satisfaction score and JOA score (r = 0.6493, p = 0.0093), and a significant negative correlation between satisfaction score and Nurick classification (r = -0.5941, p = 0.0195). Besides, perioperative complications and progression of tandem ossification which needed revision surgery had significant adverse effect on patients' satisfaction. The results showed that single-staged combined decompression could provide comparable clinical outcomes, and patients' satisfaction was significantly related with postoperative neurological function. In addition, satisfaction score could be decreased by perioperative complications and progression of tandem ossification. Thus, this aggressive surgical strategy should be used more carefully with emphasis on preoperative communication with patients.

Biomechanical study of the spinal cord in thoracic ossification of the posterior longitudinal ligament

BackgroundOssification of the posterior longitudinal ligament (OPLL) in the thoracic spine produces myelopathy. This is often progressive and is not affected by conservative treatment. Therefore, decompressive surgery is usually chosen.ObjectiveTo conduct a stress analysis of the thoracic OPLL.MethodsThe three-dimensional finite element spinal cord model was established. We used local ossification angle (LOA) for the degree of compression of spinal cord. LOA was the medial angle at the intersection between a line from the superior posterior margin at the cranial vertebral body of maximum OPLL to the top of OPLL with beak type, and a line from the lower posterior margin at the caudal vertebral body of the maximum OPLL to the top of OPLL with beak type. LOA 20°, LOA 25°, and LOA 30° compression was applied to the spinal cord in a preoperative model, the posterior decompressive model, and a model for the development of kyphosis.ResultsIn a preoperative model, at more than LOA 20° compression, high stress distributions in the spinal cord were observed. In a posterior decompressive model, the stresses were lower than in the preoperative model. In the model for development of kyphosis, high-stress distributions were observed in the spinal cord at more than LOA 20° compression.ConclusionsPosterior decompression was an effective operative method. However, when the preoperative LOA is more than 20°, it is very likely that symptoms will worsen. If operation is performed at greater than LOA 20°, then correction of kyphosis by fixation of instruments or by forward decompression should be considered.