CDC5L promotes early chondrocyte differentiation and proliferation by modulating pre-mRNA splicing of SOX9, COL2A1, and WEE1.

Ossification of the posterior longitudinal ligament (OPLL) of the spine is a common pathological condition that causes intractable myelopathy and radiculopathy, mainly the result of an endochondral ossification-like process. Our previous genome-wide association study identified six susceptibility loci for OPLL, including the cell division cycle 5-like (CDC5L) gene region. Here, we found CDC5L to be expressed in type II collagen-producing chondrocyte-like fibroblasts in human OPLL specimens, as well as in differentiating ATDC5 chondrocytes. Cdc5l siRNA transfection in murine chondrocytes decreased the expression of the early chondrogenic genes Sox9 and Col2a1, diminished the cartilage matrix production, and enhanced the expression of parathyroid-hormone-related protein (a resting chondrocyte marker). We also showed that Cdc5l shRNA suppressed the growth of cultured murine embryonal metatarsal cartilage rudiments and that Cdc5l knockdown suppressed the growth of ATDC5 cells. Fluorescence-activated cell sorting analysis revealed that the G2/M cell cycle transition was blocked; our data showed that Cdc5l siRNA transfection enhanced expression of Wee1, an inhibitor of the G2/M transition. Cdc5l siRNA also decreased the pre-mRNA splicing efficiency of Sox9 and Col2a1 genes in both ATDC5 cells and primary chondrocytes; conversely, loss of Cdc5l resulted in enhanced splicing of Wee1 pre-mRNA. Finally, an RNA-binding protein immunoprecipitation assay revealed that Cdc5l bound directly to these target gene transcripts. Overall, we conclude that Cdc5l promotes both early chondrogenesis and cartilage growth and may play a role in the etiology of OPLL, at least in part by fine-tuning the pre-mRNA splicing of chondrogenic genes and Wee1, thus initiating the endochondral ossification process.

Usefulness of digital tomosynthesis in diagnosing cervical ossification of the posterior longitudinal ligament: a comparative study with other imaging modalities.

PURPOSE: The diagnosis and classification of ossification of the posterior longitudinal ligament (OPLL) can be difficult with radiography alone; therefore, computed tomography (CT) is also usually performed. There are many reports on the usefulness of digital tomosynthesis (DTS) for image analysis in orthopedics. This study aimed to compare the accuracy of DTS with radiography and CT for the diagnosis and classification of cervical OPLL (C-OPLL). MATERIALS AND METHODS: We included 31 patients with OPLL and 30 with cervical spondylotic myelopathy. The patients' cervical spine radiography, DTS, and CT images were each evaluated twice by three specialists and three residents. RESULTS: In the intra-observer reliability study, there was one observer with a fair level of kappa values for radiography and DTS among three residents. The kappa values for CT were the best for all observers. In the inter-observer reliability study, the interclass correlation coefficient (ICC) values were high for both diagnosis and classification by specialists at the almost perfect level for all three imaging modalities. On the other hand, the ICC values for both diagnosis and classification for radiography by the residents were lower than those for DTS and CT. CONCLUSIONS: This study revealed that DTS may be an alternative to CT for the diagnosis and classification of C-OPLL by specialists. Caution should be exercised in diagnosing and classifying C-OPLL using radiography and DTS by residents, and the use of CT is recommended.

Bone strength of the proximal femur in healthy subjects with ossification of the posterior longitudinal ligament.

We compared the bone strength measured via quantitative computed tomography-based finite element method (QCT/FEM) between healthy adults with and without ossification of the posterior longitudinal ligament (OPLL). No statistically significant difference was observed in the bone strength between healthy adults with and without OPLL. Hyperostosis of the posterior longitudinal ligament in OPLL may not be associated with the systemic bone strength. INTRODUCTION: Although patients with OPLL have been reportedly associated with increased level of bone mineral density (BMD) using dual-energy X-ray absorptiometry (DXA), little is known about the bone strength in OPLL subjects. The aim of this study is to investigate the bone strength measured via QCT/FEM in healthy subjects with OPLL using the medical check-up data, including whole-body CT scans. METHODS: We examined 796 participants (529 men and 267 women) who underwent CT scans in a single health center between January 2008 and May 2009. We identified OPLL in whole spine and divided the subjects into two groups: non-OPLL and OPLL groups. We calculated the predicted bone strength (PBS) of the proximal femur using QCT/FEM and examined the bone mineral status of the calcaneus using quantitative ultrasound (QUS). We compared the PBS and the QUS parameters between the non-OPLL and OPLL groups. RESULTS: Seventy-four subjects (9.3%; 57 men and 17 women) were diagnosed with OPLL in the whole spine. The OPLL group was significantly older than the non-OPLL group. No statistically significant difference was observed in the PBS and the QUS parameters between the non-OPLL and OPLL groups in both sexes. Furthermore, no statistically significant difference was noted in the PBS and the QUS parameters between two groups in age- and gender-matched analysis. CONCLUSIONS: Our results suggest that hyperostosis of the posterior longitudinal ligament in OPLL may not be associated with bone strength and bone mineral status at the extremities.

Long Non-coding RNA XIST May Influence Cervical Ossification of the Posterior Longitudinal Ligament Through Regulation of miR-17-5P/AHNAK/BMP2 Signaling Pathway.

Long non-coding RNAs (lncRNAs) play an important role in the development of bone-related diseases. This study was conducted to investigate the role and mechanism of lncRNA X inactive specific transcript (XIST) in the occurrence of cervical ossification of the posterior longitudinal ligament (OPLL). Here, primary human ligament fibroblasts cells (LFCs) were isolated from 30 cases of OPLL and 30 normal cervical posterior longitudinal ligament (non-OPLL) tissues to perform the qPCR and Western blot assay. We found that the mRNA level of lncRNA XIST was significantly increased in OPLL LFCs compared to non-OPLL LFCs. By bioinformatics analysis, we found that lncRNA XIST has four binding sites for miR-17-5p and found that the mRNA level of miR-17-5p was also significantly decreased in OPLL LFCs compared to non-OPLL LFCs. Since AHNAK is the target gene of miR-17-5p, we further found that the expression of AHNAK was significantly reduced in non-OPLL LFCs after being transfected with miR-17-5p mimic. The qPCR results showed that the mRNA expressions of BMP2 and Runx2 were significantly decreased. After being transfected with lncRNA XIST siRNA in the non-OPLL LFCs, the mRNA levels of lncRNA XIST, AHNAK, BMP2, and Runx2 were significantly decreased and the phosphorylated protein of Smad1/5/8 was reduced. After being cultured by mechanical vibration, the mRNA levels of lncRNA XIST, AHNAK, BMP2, Runx2, COL1, OC, OPN, and Phospho1 were significantly increased, but the mRNA expression of miR-17-5p was significantly decreased. The expression of phosphorylated Smad1/5/8 protein was also significantly increased. Together, this study was the first to determine that XIST gene inhibition plays an important role in the occurrence of cervical OPLL, through the mechanism of regulation of miR-17-5P/AHNAK/BMP2 signaling pathway. Thus, XIST may be a potential target that could be modulated for the treatment of cervical OPLL.

Risk assessment of vertebral artery injury in anterior controllable antedisplacement and fusion (ACAF) surgery: a cadaveric and radiologic study.

PURPOSE: We have introduced a novel surgery technique named anterior controllable antedisplacement and fusion (ACAF) for the treatment of ossification of the posterior longitudinal ligament. As reported, the satisfactory postoperative outcome can be attributed to the larger decompression width. However, it may associate with high prevalence of vertebral artery injury (VAI) theoretically. Thus, assessment of the vulnerability of vertebral artery in ACAF is of great importance. METHODS: Computed tomographic scan data of 28 patients were retrospectively studied. Seven radiographic parameters were evaluated: uncinate process (UP) tips distance, transverse foramen (TF)-UP tips distance, TF-LWL (the ipsilateral limited wedging line) distance, the limited distance of lateral decompression, the maximum oblique angle of LWL, TF-LWG (the lateral wall of groove) distance, and width of groove. Eleven fresh cadaveric spines undergoing ACAF surgery were also studied. Two anatomic parameters were evaluated: width of groove and LWG-TF distance. RESULTS: The UP tips distance increased from C3 to C6 and tended to be larger in males. The UP tip-TF distance and LWL-TF distance were smallest at C4, but both were larger than 2 mm. Maximum oblique angle decreased from C3 to C6. Postoperatively, both radiographic and cadaveric measurements showed the width of groove was larger than UP tips distance, but LWG-TF distance was larger than 2 mm in all levels. CONCLUSION: UP can be used as anatomical landmarks to avoid VAI during ACAF surgery. Radiographic and cadaveric measurements verified the safety of ACAF surgery, even for those cases with wedging and lateral slotting.

Anterior controllable antedisplacement fusion as a choice for 28 patients of cervical ossification of the posterior longitudinal ligament with dura ossification: the risk of cerebrospinal fluid leakage compared with anterior cervical corpectomy and fusion.

PURPOSE: To compare the incidence rate of cerebrospinal fluid (CSF) leakage between anterior controllable antedisplacement fusion (ACAF) and anterior cervical corpectomy and fusion (ACCF) in the treatment of ossification of the posterior longitudinal ligament (OPLL) with dura ossification (DO). METHODS: In the period from June 2015 to June 2017, ACAF and ACCF were performed on patients with OPLL with DO. Double-layer sign was observed on axial bone window of CT images. The operation duration, blood loss, and hospital stay were measured. Radiologic assessment included occupying rate, type and extent of OPLL, decompression width, postoperative area of the spinal canal, and anteroposterior diameter of the spinal cord. The JOA scoring system was used to evaluate the neurological status. Surgery-related complications such as CSF leakage and spinal cord or nerve injury were all recorded. RESULTS: There were 28 patients in ACAF group and 31 in ACCF group. On cross-sectional CT, decompression width and postoperative spinal canal area were both significantly larger in the ACAF group than that in the ACCF group (P < 0.01). The anteroposterior diameter of the spinal cord was significantly larger in the ACAF group (P < 0.05). Mean JOA score was better in the ACAF group (P < 0.05). In the ACCF group, seven (22.6%) patients had CSF leakage. However, only one (3.6%) presented with CSF leakage in the ACAF group. The difference of incidence rate of CSF leakage was significant (P < 0.01). CONCLUSIONS: ACAF, which can significantly reduce CSF leakage and achieve good neurological recovery, is a good option to treat cervical OPLL with DO. These slides can be retrieved under Electronic Supplementary Material.

Skip corpectomy and fusion (SCF) versus anterior controllable antedisplacement and fusion (ACAF): which is better for patients with multilevel cervical OPLL?

BACKGROUND: The aim of this study was to compare the clinical efficacy and radiological outcomes of skip corpectomy and fusion (SCF) with anterior controllable antedisplacement and fusion (ACAF) for treating multilevel ossification of the posterior longitudinal ligament (OPLL). METHODS: 62 patients with multilevel OPLL who had undergone SCF or ACAF were analyzed retrospectively. Types of OPLL, occupying ratio (OR), Japanese Orthopaedic Association (JOA) score, Recovery Rate (RR), Neck Disability Index (NDI) score, Cobb's angles of C2-C7, operation time, blood loss, hospital stay, ratings for fusion assessment and complications were recorded and assessed. RESULTS: Postoperative C2-C7 Cobb's angle (11.1 ± 3.2° vs. 13.7 ± 2.5°; P < 0.05), NDI scores at final follow-up (14.3 ± 1.6 vs. 13.3 ± 1.3; P < 0.05), and rate of cerebral fluid (CSF) leakage (5, 16.7% vs. 0,0%; P < 0.05) were significantly better in the ACAF group. At 6 months, bone graft fusion rate was significantly greater in the ACAF group (24.75% vs. 15.50%; P < 0.05). CONCLUSIONS: Surgical treatment of multilevel OPLL by SCF or ACAF showed no significant differences in clinical outcomes, with the exception of better NDI scores at final follow-up in ACAF. In addition, ACAF is better than SCF in terms of early bone graft fusion rate, lordotic curvature improvement, risk of CSF leakage.

A retrospective imaging study of surgical outcomes and range of motion in patients with cervical ossification of the posterior longitudinal ligament.

PURPOSE: The K line was introduced in a previous study, but did not include the cervical range of motion (ROM) as a parameter for evaluating surgical outcomes for patients with cervical ossification of the posterior longitudinal ligament (OPLL), and few reports have used both the K line and X-ray evaluations of the cervical ROM to describe the surgical outcomes in such patients. METHODS: Double-door C2-C7 or C3-C7 laminoplasty was performed in 100 patients with cervical OPLL who were classified according to the K line [86 patients, K line (+) and 14 patients, K line (-)]. Preoperative and 1-year postoperative Japanese Orthopedic Association (JOA) scores were used to evaluate recovery rates. Preoperative and postoperative C2-C7 lordotic angles were measured using the Cobb method. In addition, preoperative and postoperative sagittal alignments in flexion and extension were studied, and the flexion values were calculated by subtracting the preoperative and postoperative flexion ROM from extension ROM. RESULTS: The mean JOA scores recovery rate were 57.3% in the K line (+) and 37.7% in the K line (-) groups (p < 0.05), and the respective corresponding mean postoperative C2-C7 lordotic angles were 9.1° and -3.4° (p < 0.001). In the K line (+) group, the JOA score recovery rate for a postoperative flexion value >0 was significantly lower than that for a postoperative flexion value ≤0 (p < 0.01), and the mean JOA score recovery rate worsened with an increased signal intensity on 1-year postoperative magnetic resonance imaging. CONCLUSIONS: K line (+) patients exhibited sufficient neurological improvement after laminoplasty. However, even patients in this group had a low JOA score recovery rate if the postoperative flexion value was >0 and the 1-year postoperative increased signal intensity grade was 2 or 3.

Assessing Range of Motion Gap in Circumferential Surgery for Cervical Myelopathy due to Ossification of the Posterior Longitudinal Ligament.

OBJECTIVE: Only a few studies have investigated the gap range of motion (gROM) in cervical myelopathy or deformity caused by ossification of the posterior longitudinal ligament (OPLL). The aim of this study is to investigate the correlation between the individual gROM and the postoperative clinical outcomes of patients with OPLL. METHODS: Consecutive patients of cervical myelopathy caused by OPLL were analyzed retrospectively. The clinical outcomes were evaluated using Visual Analogue Scale scores of the neck and arm pain and the Japanese Orthopaedic Association scores. Radiologic measurements included flexion ROM (fROM), which was defined as the difference of cervical lordosis in flexion and neutral positions, extension ROM (eROM), defined as the difference between neutral and extension positions, and gROM, defined as the difference between fROM and eROM. Patients were grouped by the values of gROM, and comparisons of all outcomes were made between the groups. RESULTS: A total of 42 patients underwent surgery. The patients with greater gROM did not differ from those with smaller gROM by demographic characteristics. During follow-up (mean 45.8 months), both groups had similar improvements, but the C5 palsy rates were higher in the greater gROM group than in the smaller gROM group (71% and 22%, P < 0.05). CONCLUSIONS: Simultaneous circumferential decompression and fixation is an effective surgical option for patients with cervical myelopathy caused by OPLL. A higher rate of postoperative C5 palsy was observed in the patients with greater gROMs after surgery, although all patients presented with similar clinical improvements.

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.

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 6 weeks 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 28 W 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 8 weeks 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.

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

BACKGROUND CONTEXT: Obesity 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. PURPOSE: We aimed to determine the association between dyslipidemia and symptomatic OPLL. STUDY DESIGN: Single institution cross-sectional study. PATIENT SAMPLE: Data 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 MEASURES: Baseline 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. METHODS: Patient 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. RESULTS: The 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. CONCLUSIONS: We 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.

Risk factors for C5 palsy following the posterior spinal process-splitting laminoplasty for cervical ossification of the posterior longitudinal ligament: a case control study.

Background: Postoperative C5 palsy is a common complication of laminoplasty for cervical ossification of the posterior longitudinal ligament (C-OPLL), although there are several hypotheses regarding its etiology, the exact pathomechanism for this undesirable event remain unclear. The aim of this study was to review clinical and imaging findings in patients with C5 palsy and to propose potential risk factors for this complication. Methods: A total of 220 consecutive patients who had undergone posterior spinal process-splitting laminoplasty (pSPSL) for C-OPLL between January 2018 and December 2019 were included in this study. Postoperative C5 palsy was defined as deltoid muscle weakness of a grade ≤3 in manual muscle test (MMT). These patients were divided into two groups based on the postoperative development of C5 palsy: patients with C5 palsy (group A) and those without C5 palsy (group B). The clinical and imaging covariates evaluated were age, sex, OPLL type, K-line, foraminal stenosis, gutter malposition, and preoperative spinal cord signal change. Logistic regression was used to analyze the independent risk factors for C5 palsy. Results: In total, 211 patients (18 in group A and 193 in group B) were enrolled in this study, and the incidence of C5 palsy was 8.53%. Sixteen patients had a MMT of grade 3 and two had an MMT of grade ≤2. During the follow-up period (mean duration: 25.10±6.67 months), the MMT grade rose to 5 in 16 patients, 4 in one patient, and 3 in one patient. Multivariate analysis revealed that malposition of the bony gutter [odds ratio (OR) 11.073, 95% confidence interval (CI): 3.411, 35.948; P<0.001] and C4/5 intervertebral foramen stenosis (OR 8.455, 95% CI: 2.559, 27.936; P<0.001) were independent risk factors for C5 palsy. Conclusions: The incidence of C5 palsy was 8.53% among patients undergoing pSPSL for C-OPLL. Gutter malposition and C4/5 intervertebral foramen stenosis were identified as risk factors for this complication.

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.

Degenerative Cervical Myelopathy: Development and Natural History [AO Spine RECODE-DCM Research Priority Number 2].

STUDY DESIGN: Narrative review. OBJECTIVES: To discuss the current understanding of the natural history of degenerative cervical myelopathy (DCM). METHODS: Literature review summarizing current evidence pertaining to the natural history and risk factors of DCM. RESULTS: DCM is a common condition in which progressive arthritic disease of the cervical spine leads to spinal cord compression resulting in a constellation of neurological symptoms, in particular upper extremity dysfunction and gait impairment. Anatomical factors including cord-canal mismatch, congenitally fused vertebrae and genetic factors may increase individuals' risk for DCM development. Non-myelopathic spinal cord compression (NMSCC) is a common phenomenon with a prevalence of 24.2% in the healthy population, and 35.3% among individuals >60 years of age. Clinical radiculopathy and/or electrophysiological signs of cervical cord dysfunction appear to be risk factors for myelopathy development. Radiological progression of incidental Ossification of the Posterior Longitudinal Ligament (OPLL) is estimated at 18.3% over 81-months and development of myelopathy ranges between 0-61.5% (follow-up ranging from 40 to 124 months between studies) among studies. In patients with symptomatic DCM undergoing non-operative treatment, 20-62% will experience neurological deterioration within 3-6 years. CONCLUSION: Current estimates surrounding the natural history of DCM, particularly those individuals with mild or minimal impairment, lack precision. Clear predictors of clinical deterioration for those treated with non-operative care are yet to be identified. Future studies are needed on this topic to help improve treatment counseling and clinical prognostication.

Modified axial computed tomography classification of cervical ossification of the posterior longitudinal ligament: selecting the optimal operating procedure and enhancing the accuracy of prognosis.

BACKGROUND: Cervical ossification of the posterior longitudinal ligament (OPLL) causes spinal cord compression, which can lead to myelopathy or radiculopathy. Non-surgical treatments have little effect on this condition. Current OPLL classification systems offer little guidance on the selection of an appropriate operating procedure. In this study, we developed a modified axial computed tomography classification (MACTC) scheme. We then examined the usefulness of the MACTC scheme and two other existing classification schemes in guiding OPLL operation choice. METHODS: Following screening in which a defined exclusion criteria was used, a total of 91 patients with OPLL participated in the study. Patients' follow-up data for at least 2 years were obtained. The recovery rate of the Japanese Orthopaedic Association (JOA) scores was compared to two other classification schemes. RESULTS: According to the MACTC, central-sharp-type OPLL had a lower recovery rate of the JOA score than that of central-gentle-type OPLL (36.05±32.38 vs. 83.90±23.52, P≤0.05). The recovery rate of the JOA scores in the ipsilateral open-door OPLL group was significantly lower than that in the contralateral group of the lateral-steep type (36.67±41.5 vs. 88.89±17.21, P=0.04), but not of that in the lateral-gentle type. There was no significant difference in the recovery rates of the JOA scores between groups when using either existing classification scheme (P>0.05). CONCLUSIONS: The MACTC scheme can assist surgeons to choose the most appropriate operating procedure, and provide an accurate prognosis. If operations on central-sharp-type OPLL are not performed using both the posterior and anterior approaches, prognosis will be poor. The contralateral side should be the first choice for door opening in laminoplasty, especially for patients with lateral-steep-type OPLL. Severe OPLL may not be an absolute contraindication for the posterior approach.

Epidemiology of symptomatic ossification of the posterior longitudinal ligament: a nationwide registry survey.

BACKGROUND: Ossification of the posterior longitudinal ligament (OPLL) is radiographically detectable in 3-6% of Asian individuals, although not all detectable OPLL cases lead to myelopathy. To date, it is unknown how many patients suffer from neurological symptoms due to OPLL. The purpose of this study was to investigate the epidemiology of symptomatic OPLL using Japan's national registry database. METHODS: We examined the registry data of patients with OPLL who held a certificate of medical subsidy from the Japanese Ministry of Health, Labor and Welfare. The study period was from January 1, 2011 to December 31, 2012. RESULTS: Registry data revealed that the incidence and the period prevalence of symptomatic OPLL were 0.005% (5 per 100,000 population) and 0.027% (27 per 100,000 population), respectively. OPLL occurred twice as often in men as in women. The peak age for onset of symptoms was 60-69 years. The mean Japanese Orthopedic Association (JOA) score was 9 points. Ninety percent of OPLL patients underwent surgery, and 90% of these surgeries were performed with a posterior approach. The most common indication for surgery was a JOA score of 11 points. CONCLUSIONS: According to registry data, the prevalence of symptomatic OPLL was less than one-hundredth of that of radiographically detected OPLL. This indicates that most cases of radiographically detectable OPLL may be asymptomatic.

Anterior Controllable Antedisplacement and Fusion (ACAF) vs Posterior Laminoplasty for Multilevel Severe Cervical Ossification of the Posterior Longitudinal Ligament: Retrospective Study Based on a Two-Year Follow-up.

OBJECTIVES: To compare the clinical outcomes of anterior controllable antedisplacement fusion (ACAF), a new surgical technique, with laminoplasty for the treatment of multilevel severe cervical ossification of the posterior longitudinal ligament (OPLL) based on a 2-year follow-up. METHODS: Clinical data of 53 patients (21 by ACAF and 32 by laminoplasty) who have accepted surgery for treatment of cervical myelopathy caused by multilevel severe OPLL (occupying rate ≥ 50%) from March 2015 to March 2017 were retrospectively reviewed and compared between ACAF group and laminoplasty group. Operative time, blood loss, and complications of the two groups were recorded. Radiographic parameters were evaluated pre- and postoperatively: cervical lordosis on X-ray, space available for the cord (SAC) and the occupying ratio (OR) on computed tomography (CT), and the anteroposterior (AP) diameter of the spinal cord at the narrowest level and the spinal cord curvature on magnetic resonance imaging (MRI). Japanese Orthopaedic Association (JOA) scoring was used to evaluate neurologic recovery. Statistical analysis was conducted to analyze the differences between two groups. The Mann-Whitney U test and chi square test were used to compare categorical variables. unpaired t test was used to compare continuous data. RESULTS: All patients were followed up for at least 24 months. The operative time was longer in ACAF group (286.5 vs 178.2 min, P < 0.05). The blood loss showed no significant difference (291.6 vs 318.3 mL, P > 0.05). Less complications were observed in ACAF group than in laminoplasty group (one case [4.7%] of C5 palsy and one case [4.7%] of cerebrospinal fluid [CSF] leakage in ACAF group; four cases [12.5%] of C5 palsy, two cases [6.3%] of CSF leakage, and four cases [12.5%] of axial symptoms in laminoplasty group). The mean JOA score at last follow-up (14.6 vs 12.8, P < 0.05) and the improvement rate (IR) (63.8% vs 47.8%, P < 0.05) in ACAF group were superior to those in laminoplasty group significantly. The postoperative OR (16.7% vs 40.9%, P < 0.05), SAC (150.8 vs 110.5 mm2 , P < 0.05), AP spinal cord diameter (5.5 vs 4.2 mm, P < 0.05), and cervical lordosis (12.7° vs 4.7°, P < 0.05) were improved more considerably in ACAF group, with significant differences between two groups. Notably, the spinal cord on MRI showed a better curvature in ACAF group. CONCLUSIONS: This study showed that ACAF is considered superior to laminoplasty for the treatment of multilevel severe OPLL as anterior direct decompression and better curvature of the spinal cord led to satisfactory neurologic outcomes and low complication rate.

Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire as an outcome measure for ossification of posterior longitudinal ligament patients in East Asia: an investigation of reliability, validity, and responsiveness.

BACKGROUND: The surgical outcomes of individual patient with ossification of the posterior longitudinal ligament (OPLL) can vary depending on various patient-related factors. Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire (JOACMEQ) is a well-developed tool for outcome measurement and considers both disease-specific and general health aspects. This study aimed to investigate the reliability, validity, and responsiveness of the JOACMEQ in patients with OPLL in mainland China and to compare post-operative outcomes of OPLL patients between mainland China and Japan. METHODS: This multicenter trial was performed between July 2009 and June 2019. The procedure for the JOACMEQ translation followed Beaton's guidelines. All patients enrolled were diagnosed with OPLL and had completed the JOACMEQ, the modified Japanese Orthopaedic Association (mJOA) scale, and the 36-Item Short Form Health Survey (SF-36) before and after surgery. The reliability (Cronbach's α and Pearson's correlation), construct validity (factor analysis), concurrent validity (Spearman's correlation with SF-36) and responsiveness (effect sizes) of JOACMEQ were evaluated. A mixed-model analytic approach was used to analyze differences in postoperative outcomes between the 2 countries. RESULTS: Ninety-one patients from mainland China and ninety-one patients from Japan were recruited. JOACMEQ showed satisfactory internal consistency (Cronbach's α=0.75). In test-retest reliability evaluation, except for the bladder function domain, the JOACMEQ domains had good test-retest reliability (0.89-0.96). In factor analysis, most of the items (19/24) were well clustered. Regarding clinical validity, all 5 domains were found to have moderate correlations with the physical component summary (PCS) of SF-36 (r=0.25-0.50), and the bladder function and quality of life domains also had moderate correlations (r=0.25-0.50) with the mental component summary (MCS) of SF-36. JOACMEQ showed a variable responsiveness in different domains (effect size =0.17-0.84; standardized response means =0.15-0.85). Regarding postoperative improvements in the JOACMEQ score, mixed-model analysis revealed a significant difference in the quality of life domain between Chinese and Japanese patients (16.0±18.7 vs. 7.8±17.7, P<0.05). CONCLUSIONS: JOACMEQ generally shows good reliability, good validity and mild responsiveness, and can identify the post-operative improvements in patients with OPLL in mainland China. Chinese OPLL patients showed a significantly larger improvement in postoperative quality of life compared to their Japanese counterparts.

Genetic pathways disrupted by ENPP1 deficiency provide insight into mechanisms of osteoporosis, osteomalacia, and paradoxical mineralization.

Ectonucleotide phosphatase/phosphodiesterase 1 (ENPP1) deficiency results in either lethal arterial calcifications ('Generalized Arterial Calcification of Infancy' - GACI), phosphate wasting rickets ('Autosomal Recessive Hypophosphatemic Rickets type 2' - ARHR2), early onset osteoporosis, or progressive spinal rigidity ('Ossification of the Posterior Longitudinal Ligament' - OPLL). As ENPP1 generates a strong endogenous mineralization inhibitor - extracellular pyrophosphate (PPi) - ENPP1 deficiency should not result in reduced bone volume, and therefore the mechanism ENPP1 associated osteoporosis is not apparent given current understanding of the enzyme's function. To investigate genetic pathways driving the skeletal phenotype of ENPP1 deficiency we compared gene expression in Enpp1asj/asj mice and WT sibling pairs by RNAseq and qPCR in whole bones, and in the liver and kidney by qPCR, directly correlating gene expression with measures of bone microarchitectural and biomechanical phenotypes. Unbiased analysis of the differentially expressed genes compared to relevant human disease phenotypes revealed that Enpp1asj/asj mice exhibit strong signatures of osteoporosis, ARHR2 and OPLL. We found that ENPP1 deficient mice exhibited reduced gene transcription of Wnt ligands in whole bone and increased transcription of soluble Wnt inhibitors in the liver and kidney, suggestive of multiorgan inhibition of Wnt activity. Consistent with Wnt suppression in bone, Collagen gene pathways in bone were significantly decreased and Fgf23 was significantly increased, all of which directly correlated with bone microarchitectural defects and fracture risk in Enpp1asj/asj mice. Moreover, the bone findings in 10-week old mice correlated with Enpp1 transcript counts but not plasma [PPi], suggesting that the skeletal phenotype at 10 weeks is driven by catalytically independent ENPP1 function. In contrast, the bone findings in 23-week Enpp1asj/asj mice strongly correlated with plasma PPi, suggesting that chronically low PPi drives the skeletal phenotype in older mice. Finally, correlation between Enpp1 and Fgf23 transcription suggested ENPP1 regulation of Fgf23, which we confirmed by dosing Enpp1asj/asj mice with soluble ENPP1-Fc and observing suppression of intact plasma FGF23 and ALP. In summary, our findings suggest that osteoporosis associated with ENPP1 deficiency involves the suppression of Wnt via catalytically independent Enpp1 pathways, and validates Enpp1asj/asj mice as tools to better understand OPLL and Paradoxical Mineralization Disorders.