Ossification Of Spinal Ligaments Research Articles

Investigation of the Shared Biomarkers in Heterotopic Ossification Between Ossification of the Ligamentum Flavum and Ankylosing Spondylitis.

Bioinformatics analysis of Gene Expression Omnibus (GEO). Ossification of the ligamentum flavum (OLF) and ankylosing spondylitis (AS) represent intricate conditions marked by the gradual progression of endochondral ossification. This investigation endeavors to unveil common biomarkers associated with heterotopic ossification and explore the potential molecular regulatory mechanisms. Microarray and RNA-sequencing datasets retrieved from the Gene Expression Omnibus (GEO) repository were harnessed to discern differentially expressed genes (DEGs) within the OLF and AS datasets. Subsequently, Weighted Gene Co-expression Network Analysis (WGCNA) was implemented to pinpoint co-expression modules linked to OLF and AS. Common genes were further subjected to an examination of functional pathway enrichment. Moreover, hub intersection genes were identified using the Least Absolute Shrinkage and Selection Operator (LASSO) regression, followed by an evaluation of diagnostic performance in external OLF and AS cohorts. Lastly, an analysis of immune cell infiltration was conducted to scrutinize the correlation of immune cell presence with shared biomarkers in OLF and AS. A total of 1353 and 91 Differentially Expressed Genes (DEGs) were identified in OLF and AS, respectively. Using the Weighted Gene Co-expression Network Analysis (WGCNA), 2 modules were found to be notably significant for OLF and AS. The integrative bioinformatic analysis revealed 3 hub genes (MAB21L2, MEGF10, ISLR) as shared risk biomarkers, with MAB21L2 being the central focus. Receiver Operating Characteristic (ROC) analysis exhibited a strong diagnostic potential for these hub genes. Gene Ontology (GO) analysis indicated their involvement in the positive regulation of myoblast proliferation. Notably, MAB21L2 was singled out as the optimal common biomarker for OLF and AS. Furthermore, an analysis of immune infiltration demonstrated a correlation between MAB21L2 expression and changes in immune cells. Activated CD8 T cells were identified as shared differential immune infiltrating cells significantly linked to MAB21L2 in both OLF and AS. This study represents the first instance of identifying MAB21L2 as a prospective diagnostic marker for patients contending with OLF associated with AS. The research results indicate that the ECM-receptor interaction and the cell-cell adhesion may play a role in both disease processes. This newfound knowledge not only enhances our understanding of the pathogenesis behind spinal ligament ossification but also uncovers potential targets for therapeutic interventions.

Differences in the Demographics and Clinical Characteristics between the Ossification of the Posterior Longitudinal Ligament and Ossification of the Ligamentum Flavum in Patients Who Underwent Thoracic Spinal Surgery for Compressive Myelopathy.

Ossification of the posterior longitudinal ligament (OPLL) and ossification of the ligamentum flavum (OLF) are related diseases associated with the ossification of spinal ligaments that can occasionally lead to thoracic myelopathy. We retrospectively analyzed the clinical data of 34 consecutive patients who underwent thoracic spinal surgeries for OPLL and/or OLF at our hospital between July 2010 and June 2022, and statistically compared data between patients with thoracic OPLL (TOPLL; n = 12) and those with thoracic OLF (TOLF; n = 22). The mean age of the TOPLL group was significantly lower than that of the TOLF group (53.7 vs. 68.4 years). The TOPLL group exhibited a greater female predominance than the TOLF group (58.3% vs. 18.2%). The median body mass index of the TOPLL group was significantly higher than that of the TOLF group (33.0 vs. 26.0 kg/m2). Patients with TOPLL significantly required instrumented fusion and repetitive surgical intervention more than those with TOLF (83.3% vs. 9.1%; 50.0% vs. 0.0%). Although neurological deterioration just after the intervention was more common in patients with TOPLL (41.7% vs. 4.6%), no difference was observed in thoracic Japanese Orthopaedic Association score and recovery rate in the chronic phase between TOPLL and TOLF. The TOPLL group had a younger onset, female dominance, and a greater degree of obesity when compared with the TOLF group. The surgery for TOPLL is challenging, considering that it requires long-range decompression and fusion, subsequent operations, careful management, and long-term follow-up, when compared to TOLF, which necessitates only simple decompression.

Case Report: Skeletal Fluorosis - An Uncommon Cause of Bone Densification

Skeletal fluorosis is an uncommon toxic bone condition marked by the excessive buildup of fluoride in the skeletal structure. The disease manifests as an endemic issue in certain regions of the world and arises from prolonged ingestion or, rarely, inhalation of elevated levels of fluoride. Key imaging features include bilateral patchy bony sclerosis, enthesopathy, ligament, and periosteal bony proliferation, as well as ossification of spinal ligaments. Management of fluorosis generally focuses on symptom treatment.

PTGR1 is involved in cell proliferation in thoracic ossification of the ligamentum flavum.

Thoracic ossification of the ligamentum flavum (TOLF) is a heterotopic ossification of spinal ligaments, leading to serious myelopathy. TOLF underlying mechanisms are not well understood. Our iTRAQ analysis have identified ten inflammatory factors related to TOLF, including l. We found that PTGR1 expressions increased in TOLF by RT-PCR and western blot in this study. Both cell proliferation and differentiation are important for the process of bone formation. In our previous study, we demonstrated that TOLF primary cells grew faster than control cells. It was reported that knockdown of PTGR1 inhibited cell proliferation. We hypothesize that PTGR1 may participate in cell proliferation in TOLF. To test this hypothesis, TOLF primary cells were treated for 24h with PTGR1. We observed that PTGR1 increased cell proliferation. The effect of PTGR1 on cell proliferation related genes was examined in TOLF primary cells. Our results showed that PTGR1 was able to activate expressions of c-Myc and CyclinD1. Moreover, blocking JNK pathway by selective JNK inhibitor SP600125 eliminated the positive effect of PTGR1 on c-Myc expression, indicating that PTGR1 activated the expression of c-Myc via JNK pathway. Our new findings suggest that PTGR1 is involved in cell proliferation of TOLF.

Effect of mechanical stimulation on tissue heterotopic ossification: an in vivo experimental study.

Background: Heterotopic ossification of tendons and ligaments (HOTL) is a common clinical condition characterized by the absence of discernible features and a lack of effective treatment. In vitro experiments have demonstrated that mechanical stimulation can induce cell differentiation toward osteogenesis, thereby promoting heterotopic ossification. Currently, there are few experimental designs aimed at inducing ligament stretching in mice, and the mechanism of heterotopic ossification may not entirely mirror that observed in clinical cases. Therefore, there is an urgent imperative to develop a novel and feasible animal model. Methods: In this study, all the Enpp1 gene deficiency mice (a mouse model with heterotopic ossification of multiple ligaments) were divided into three groups: the control group, the spinal brake group, and the hyperactive group (treadmill training group). An external spinal fixation device was designed to restrict mice's spinal flexion and extension at 6weeks of age. The brace was adjusted weekly according to the changes in the size of the mice. Additionally, treadmill training was used to increase activity in the spinal ligaments and Achilles tendons of the mice. Micro-CT scanning and HE staining were performed at 12, 20, and 28W to evaluate the degree of ossification in the spinal ligament and Achilles tendon. What's more, As one of the mechanical stimulation transduction signals, YAP plays a crucial role in promoting osteogenic differentiation of cells. Immunofluorescence was utilized to assess YAP expression levels for the purpose of determining the extent of mechanical stimulation in tissues. Results: Our findings showed that a few ossification lesions were detected behind the vertebral space of mice at 8weeks of age. Spinal immobilization effectively restricts the flexion and extension of cervical and thoracic vertebrae in mice, delaying spinal ligament ossification and reducing chronic secondary spinal cord injury. Running exercises not only enhance the ossification area of the posterior longitudinal ligament (PLL) and Achilles tendons but also exacerbate secondary spinal cord injury. Further immunofluorescence results revealed a notable increase in YAP expression levels in tissues with severe ossification, suggesting that these tissues may be subjected to higher mechanical stimulation. Conclusion: Mechanical stimulation plays a pivotal role in the process of heterotopic ossification in tissues. Our study provided valid animal models to further explore the pathological mechanism of mechanical stimulation in HOTL development.

High whole-body bone mineral density in ossification of the posterior longitudinal ligament

BACKGROUND CONTEXTRecent studies suggest that ossification of the posterior longitudinal ligament (OPLL) is exacerbated by systemic metabolic disturbances, including obesity. However, although an increase in bone mineral density (BMD) measured at the lumbar spine has been reported in patients with OPLL, no studies have investigated the systemic BMD of patients with OPLL in detail. PURPOSEWe investigated whether patients with OPLL develop increased whole-body BMD. STUDY DESIGNSingle institution cross-sectional study. PATIENT SAMPLEData were collected from Japanese patients with symptomatic OPLL (OPLL [+]; n=99). Control data (OPLL [-]; n=226) without spinal ligament ossification were collected from patients who underwent spinal decompression, spinal fusion, or hip replacement surgery. OUTCOME MEASURESDemographic data, including age, body mass index (BMI), comorbidities, history of treatment for osteoporosis, and history of vertebral and nonvertebral fractures, was obtained from all participants. In addition, whole-body BMD, including the lumbar spine, thoracic spine, femoral neck, skull, ribs, entire upper extremity, entire lower extremity, and pelvis, were measured in all participants using whole-body dual-energy X-ray absorptiometry. METHODSPatient data were collected from 2018 to 2022. All participants were categorized based on sex, age (middle-aged [<70 years] and older adults [≥70 years]), and OPLL type (localized OPLL [OPLL only in the cervical spine], diffuse OPLL [OPLL in regions including the thoracic spine]), and OPLL [-]) and each parameter was compared. The factors associated with whole-body BMD were evaluated via multivariable linear regression analysis. RESULTSCompared with the OPLL (-) group, the OPLL (+) group of older women had significantly higher BMD in all body parts (p<.01), and the OPLL (+) group of older men had significantly higher BMD in all body parts except the ribs, forearm, and skull (p<.01). The factors associated with increased BMD of both the femoral neck (load-bearing bone) and skull (nonload-bearing bone) were age, BMI, and coexisting diffuse OPLL in women and BMI and coexisting localized OPLL in men. CONCLUSIONSPatients with OPLL have increased whole-body BMD regardless of sex, indicating that it is not simply due to load-bearing from obesity. These findings suggested that OPLL is associated with a systemic pathology.

Dyslipidemia as a novel risk for the development of symptomatic ossification of the posterior longitudinal ligament

BACKGROUND CONTEXTObesity and visceral fat have been implicated as potential factors in the pathogenesis of the ossification of the posterior longitudinal ligament (OPLL); the details of the factors involved in OPLL remain unclear. PURPOSEWe aimed to determine the association between dyslipidemia and symptomatic OPLL. STUDY DESIGNSingle institution cross-sectional study. PATIENT SAMPLEData were collected from Japanese patients with OPLL (n=92) who underwent whole-spine computed tomography scanning. Control data (n=246) without any spinal ligament ossification were collected from 627 Japanese participants who underwent physical examination. OUTCOME MEASURESBaseline information and lipid parameters, including triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) from fasting blood samples were collected to assess the comorbidity of dyslipidemia. METHODSPatient data were collected from 2020 to 2022. Patients with dyslipidemia were defined as those who were taking medication for dyslipidemia and who met one of the following criteria: TG ≥150 mg/dL, LDL-C ≥140 mg/dL, and/or HDL-C <40 mg/dL. The factors associated with OPLL development were evaluated using multivariate logistic regression analysis. RESULTSThe comorbidity of dyslipidemia in the OPLL group was more than twice that in the control group (71.7% and 35.4%, respectively). The mean body mass index (BMI) of the OPLL group was significantly higher than that of the control group (27.2 kg/m2 and 23.0 kg/m2). Multivariate logistic regression analysis revealed that dyslipidemia was associated with the development of OPLL (regression coefficient, 0.80; 95% confidence interval, 0.11–1.50). Additional risk factors included age, BMI, and diabetes mellitus. CONCLUSIONSWe demonstrated a novel association between dyslipidemia and symptomatic OPLL development using serum data. This suggests that visceral fat obesity or abnormal lipid metabolism are associated with the mechanisms of onset and exacerbation of OPLL as well as focal mechanical irritation due to being overweight.

Review of Basic Research about Ossification of the Spinal Ligaments Focusing on Animal Models

Ossification of the posterior longitudinal ligament (OPLL) is a heterotopic ossification that may cause spinal cord compression. With the recent development of computed tomography (CT) imaging, it is known that patients with OPLL often have complications related to ossification of other spinal ligaments, and OPLL is now considered part of ossification of the spinal ligaments (OSL). OSL is known to be a multifactorial disease with associated genetic and environmental factors, but its pathophysiology has not been clearly elucidated. To elucidate the pathophysiology of OSL and develop novel therapeutic strategies, clinically relevant and validated animal models are needed. In this review, we focus on animal models that have been reported to date and discuss their pathophysiology and clinical relevance. The purpose of this review is to summarize the usefulness and problems of existing animal models and to help further the development of basic research on OSL.

Comparison of radiological characteristics between diffuse idiopathic skeletal hyperostosis and ankylosing spondylitis: a multicenter study

To evaluate the radiological differences between diffuse idiopathic skeletal hyperostosis (DISH) and ankylosing spondylitis (AS) using whole spine computed tomography (CT), including the spine and sacroiliac joint (SIJ). The ossification and bridging of spinal ligament and fusion of the facet joint and SIJ were evaluated in 111 patients who were diagnosed with DISH and 27 patients with AS on the whole spine CT. The number of anterior bridging and shape of bridging (candle-wax-type/ smooth-type) were also evaluated. We further evaluated patients with DISH and AS by matching their age and sex. Complete SIJ fusion was more common in AS, whereas anterior and posterior bony bridging around SIJ was more common in DISH. However, 63% of patients with DISH had a partial or complete fusion. In spinal anterior bony bridging, the majority of patients with AS had the smooth-type, whereas those with DISH had the candle-wax-type. However, some of the patients with DISH (11%) had smooth-type. Intervertebral facet joint fusion is more common in AS. The number of anterior spinal bony bridging was greater in AS than in DISH, especially in the lumbar spine. These results are useful in differentiating DISH from AS and should therefore be considered when making a diagnosis.

Lumbar ossification of the ligamentum flavum reflects a strong ossification tendency of the entire spinal ligament

Patients with ossification of the ligamentum flavum (OLF) in the lumbar spine may be at high risk of developing concomitant ossification of the entire spinal ligament, but the etiology remains unclear. We investigated the propensity for spinal ligament ossification in asymptomatic subjects with lumbar OLF using the data of 595 Japanese individuals receiving medical check-ups, including computed tomography (CT) scanning. The severity of OLF (total number of intervertebral segments with OLF) of the entire spine on CT was quantified using an OLF index. Subjects with OLF were grouped according to this index: localized OLF (n = 138), intermediate OLF (n = 70), and extensive OLF (n = 31). The proportion of subjects with lumbar OLF increased with increasing OLF index (localized 13.7%, intermediate 41.4%, and extensive 70.9%). Multiple regression analysis found that lumbar OLF index was associated with thoracic OLF index, and co-existence of ossification of the posterior longitudinal ligament (OPLL) of the thoracic and lumbar spine. This study showed that subjects with more multilevel lumbar OLF were more likely to develop multilevel thoracic OLF and to have coexisting OPLL. Patients with lumbar OLF may be a distinctive subgroup with a strong tendency to ossification of the entire spinal ligament.

Association of Inflammation, Ectopic Bone Formation, and Sacroiliac Joint Variation in Ossification of the Posterior Longitudinal Ligament

Ossification of the posterior longitudinal ligament (OPLL) is considered a multifactorial condition characterized by ectopic new bone formation in the spinal ligament. Recently, its connections with inflammation as well as sacroiliac (SI) joint ankylosis have been discussed. Nevertheless, whether inflammation, spinal ligament ossification, and SI joint changes are linked in OPLL has never been investigated. In this study, whole-spinal computed tomography and serum high-sensitive C-reactive protein (hs-CRP) levels were obtained in 162 patients with cervical OPLL. Ossification lesions were categorized as plateau and hill shapes. Accordingly, patients were divided into plateau-shaped (51 males and 33 females; mean age: 67.7 years) and hill-shaped (50 males and 28 females; mean age: 67.2 years) groups. SI joint changes were classified into four types and three subtypes, as previously described. Interactions among ossification shapes, hs-CRP levels, and morphological changes in the SI joint were investigated. The plateau shape was more common in the vertebral segments (59.5%), compared to the hill shape, which was predominant in the intervertebral regions (65.4%). Serum hs-CRP levels in the plateau-shaped group (0.11 ± 0.10 mg/dL) were significantly higher than those in the hill-shaped group (0.07 ± 0.08 mg/dL). SI joint intra-articular fusion was the main finding in the plateau-shaped group and showed significantly higher hs-CRP levels compared to the anterior para-articular bridging, which more frequently occurred in the hill-shaped group. Our findings suggested a possible inflammation mechanism that might contribute to the new bone formation in OPLL, particularly the plateau shape.

Strong relationship between dyslipidemia and the ectopic ossification of the spinal ligaments

Obesity and metabolic disturbances are prevalent in ossification of the posterior longitudinal ligament (OPLL) and ossification of the ligamentum flavum (OLF); however, the involvement of dyslipidemia (DL) in OPLL/OLF remains uncertain. We investigated the association between dyslipidemia and OPLL/OLF using a dataset of 458 individuals receiving health screening tests, including computed tomography. Subjects were grouped according to the presence or location of OPLL/OLF: controls (no OPLL/OLF, n = 230), OLF (n = 167), cervical OPLL (n = 28), and thoracic OPLL (n = 33). They were also grouped according to the presence of dyslipidemia (DL[+], n = 215; DL[−], n = 243). The proportion of dyslipidemia in the OLF and OPLL groups was 1.6–2.2 times higher than that in the control group. The proportion of OLF and OPLL in the DL(+) group was significantly higher than that in the DL(−) group (OLF, 43% vs. 29%; cervical OPLL, 14.4% vs. 3.2%; thoracic OPLL, 11.1% vs. 3.7%). Multivariate logistic regression analysis showed an association between all ossification types and dyslipidemia. This study demonstrated an association of dyslipidemia with OPLL/OLF; further investigation on the causal relationship between dyslipidemia and ectopic spinal ligament ossification is warranted to develop a therapeutic intervention for OPLL/OLF.

Clinical features and outcomes of spine surgery in patients with ankylosing spondylitis.

The study aimed to comprehend the clinical features and outcomes of surgical treatments for spinal disorders in patients with ankylosing spondylitis (AS). This retrospective study enrolled patients with AS who underwent spine surgery between 2000 and 2019 in our facility. Thirteen patients with AS underwent spine surgeries. The mean age was 56.2 years, and the mean disease duration was 25.1 years at the time of surgery. Nine patients had vertebral fracture, two had kyphotic deformity, and two had myelopathy due to the spinal ligament ossification. Fracture cases included five patients with secondary pseudarthrosis/delayed palsy due to conservative treatment failure. Spinal fixation was performed in all patients. Pedicle subtraction osteotomy for kyphosis and laminectomy for myelopathy were also conducted. All patients improved after surgeries. One patient with kyphotic deformity underwent additional surgery of bilateral hip prosthesis, which resulted in better spine alignment. Four cases of perioperative complications were observed. Myelopathy was newly found as the aetiology requiring surgery in patients with AS. This summarized case series could help physicians to identify patients with surgically treatable spinal disorders among patients with AS.

Incidence of ossification of the spinal ligaments in acromegaly patients

Some previous case reports have implied a relationship between acromegaly and ossification of the spinal ligaments. However, there have been no reports of a case series exploring the incidence of ossification of the spinal ligaments in patients with acromegaly. To this end, computed tomography (CT) of the spine in 10 consecutive patients with acromegaly was examined in this study. Five out of 10 patients had ossification of the spinal ligaments. Among them, two patients had ossification of the posterior longitudinal ligament (OPLL), which was noticeably higher than the prevalence of OPLL in the general adult population (1.9–4.3 %). Body mass index was significantly higher in the group with spinal ligament ossification (p = 0.03), but there were no significant differences in age, sex, serum phosphate, albumin-adjusted calcium, growth hormone (GH), standard deviation of insulin-like growth factor-1 (IGF-1), or the incidence of diabetes mellitus between the groups with or without ossification of the spinal ligaments. The ossification index (OS index) was used to determine the severity of spinal ligament ossification, and there were no significant correlations between the OS index and GH or IGF-1 (p = 0.51 and 0.75, respectively). This study was the first to report a high prevalence of spinal ossification in patients with acromegaly. In conclusion, this study suggested a possible association between acromegaly and ossification of the spinal ligaments, although the number of patients was insufficient to draw a conclusion. Acromegaly patients should be tested to confirm, or rule out, spinal ossification, and further studies to clarify the underlying mechanism of spinal ossification in acromegaly patients are warranted.

Evidence for a genetic contribution to the ossification of spinal ligaments in Ossification of Posterior Longitudinal Ligament and Diffuse idiopathic skeletal hyperostosis: A narrative review

Diffuse Idiopathic Skeletal Hyperostosis (DISH) and Ossification of the Posterior Longitudinal Ligament (OPLL) are common disorders characterized by the ossification of spinal ligaments. The cause for this ossification is currently unknown but a genetic contribution has been hypothesized. Over the last decade, many studies on the genetics of ectopic calcification disorders have been performed, mainly on OPLL. Most of these studies were based on linkage analysis and case control association studies. Animal models have provided some clues but so far, the involvement of the identified genes has not been confirmed in human cases. In the last few years, many common variants in several genes have been associated with OPLL. However, these associations have not been at definitive levels of significance and evidence of functional significance is generally modest. The current evidence suggests a multifactorial aetiopathogenesis for DISH and OPLL with a subset of cases showing a stronger genetic component.

Significance of body mass index on thoracic ossification of the ligamentum flavum in Chinese population.

To investigate the risk factors for thoracic ossification of the ligamentum flavum (TOLF), especially the relationship between BMI and TOLF. A total of 856 individuals consisting of 326 controls without ossification of spinal ligaments and 530 TOLF inpatients who underwent thoracic spine decompression surgery at our hospital between January 2013 and September 2020 were included. All subjects were classified into 4 grades: Grade 0) control; Grade 1) single-segment TOLF; Grade 2) multi-segment TOLF; and Grade 3) TOLF combined thoracic ossification of the posterior longitudinal ligament (T-OPLL). Logistic regression analysis was performed to identify the risk factors for TOLF. The TOLF index was calculated to assess the severity of TOLF, and its relationship with BMI was investigated by correlation analysis. Overall, TOLF patients are most numerous in the 50-59 age group. Age and gender were considered as independent risk factors for Grades 1 and 2. BMI was identified as an independent risk factor for TOLF. Furthermore, BMI was significantly higher in Grade 1 (26.1 VS 24.5kg/m2, P = 0.0001), Grade 2 (28.2 VS 24.5kg/m2, P < 0.0001), and Grade 3 (29.1 VS 24.5kg/m2, P < 0.0001) than Grade 0. Notably, in TOLF patients without combined T-OPLL, BMI was positively correlated with TOLF index, while BMI was negatively correlated with age in younger individuals. BMI is a crucial risk factor for TOLF. It highlights the necessity of close follow-up of asymptomatic TOLF patients with high BMI to detect and treat their TOLF progression promptly.

Current understanding of tandem spinal stenosis: epidemiology, diagnosis, and surgical strategy.

Tandem spinal stenosis (TSS) is defined as the concomitant occurrence of stenosis in at least two or more distinct regions (cervical, thoracic, or lumbar) of the spine and may present with a constellation of signs and symptoms. It has four subtypes, including cervico-lumbar, cervico-thoracic, thoraco-lumbar, and cervico-thoraco-lumbar TSS. The prevalence of TSS varies depending on the different subtypes and cohorts.The main aetiologies of TSS are spinal degenerative changes and heterotopic ossification, and patients with developmental spinal stenosis, ligament ossification, and spinal stenosis at any region are at an increased risk of developing TSS.The diagnosis of TSS is challenging. The clinical presentation of TSS could be complex, concealed, or severe, and these features may be confusing to clinicians, resulting in an incomplete or delayed diagnosis. Additionally, a consolidated diagnostic criterion for TSS is urgently required to improve consistency across studies and form a basis for establishing treatment guidelines.The optimal treatment option for TSS is still under debate; areas of controversies include choice of the decompression range, choice between simultaneous or staged surgical patterns, and the order of the surgeries.The present study reviews publications on TSS, consolidates current awareness on prevalence, aetiologies, potential risk factors, diagnostic dilemmas and criteria, and surgical strategies based on TSS subtypes. This is the first review to include thoracic spinal stenosis as a candidate disorder in TSS and aims at providing the readers with a comprehensive overview of TSS.

IL-6 is involved in thoracic ossification of the ligamentum flavum.

Thoracic ossification of the ligamentum flavum (TOLF) is a heterotopic ossification of spinal ligaments. TOLF is the major cause of thoracic spinal canal stenosis and myelopathy, and its underlying mechanisms are not clear. Bone formation is a complex developmental process involving the differentiation of mesenchymal stem cells to osteoblasts, and regulated by BMP2, RUNX2, Osterix (OSX), etc. In this study, we continue to further characterize properties of TOLF. Our immunohistochemistry experiments showed that expressions of osteoblastic factors such as BMP2 and RUNX2 increased in TOLF. According to flow cytometry analysis the proportion of S phase of cell cycle in primary TOLF cells was 9% higher than the control. Alizarin red staining and ALP staining observations were consistent with immunohistochemistry results. It was also observed that inflammatory cytokine IL-6 level dramatically increased in the culture supernatant of primary TOLF cells. We propose the hypothesis that IL-6 is involved in TOLF. To testify the hypothesis, we examined the effect of IL-6. Our results showed that IL-6 was able to activate expressions of osteoblastic factors such as BMP2, RUNX2, OSX, OCN and ALP, and that expressions of cell proliferation factors cyclin D1 and cyclin C increased in the presence of IL-6. Moreover, IL-6-induced BMP2 expression was inhibited by p38 inhibitor SB203580, indicating that IL-6 regulated the osteogenic BMP2 activation through p38 MAPK pathway. These data suggest that IL-6 is involved in TOLF.

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.

Progression of Spinal Ligament Ossification in Patients with Thoracic Myelopathy

ObjectiveTo evaluate the rate of increase in thickness and cross‐section area (CSA) of the ossification in thoracic myelopathy with or without cervical and lumbar spinal ligament ossification.MethodsA total of 24 patients with 170 segments (47 ligamentum flavum [OLF] and 123 cases of ossification of the posterior longitudinal ligament [OPLL]) of spinal ligament ossification between January 2012 and March 2019 at a single institution were retrospectively reviewed. Demographic data, classification of OPLL, Sato classification of OLF, pre‐ and postoperative neurological function and complications were recorded. The thickness and CSA at the segment of maximum compression were measured with Image J software on the axial CT image.ResultsTwelve female and 12 male patients with thoracic myelopathy and spinal ligament ossification were enrolled in the study. The mean age of the patients was 54.0 ± 11.9 years with an average follow‐up of 22.2 ± 23.5 months. Overall, the mean rate of progression in thickness and CSA was 1.2 ± 1.6 and 18.4 ± 50.6 mm2/year, respectively. Being female, aging (≥45 years), and lower BMI (<28 kg/m2) predisposed patients to have faster ossification growth in thickness and CSA. The difference between the rate of OPLL and OLF progression in thickness and CSA was not significant. However, the rate of OPLL progression in the thoracic spine was significantly higher than that in the cervical spine regarding thickness (1.4 ± 1.9 vs. 0.6 ± 0.7 mm/year) and CSA (27.7 ± 72.0 vs. 7.3 ± 10.3 mm2/year).ConclusionThis is the first study to investigate ligament ossification progression in patients with thoracic myelopathy. The difference between the rate of OPLL and OLF progression in thickness and CSA was not significant. However, the rate of thoracic OPLL progression in thickness and CSA was significantly higher than that in the cervical spine.