Dataset Information

Association of a BMP9 haplotype with ossification of the posterior longitudinal ligament (OPLL) in a Chinese population.

ABSTRACT: Direct or ex vivo BMP9 adenoviral gene therapy can induce massive bone formation at the injection sites and clearly promote spinal fusion. A comprehensive analysis of the osteogenic activity indicated that BMP9 was one of the most potent inducers of osteogenic differentiation both in vitro and in vivo among 14 types of human BMPs. However, genetic variations and whether they correlated with OPLL were not considered. We have sequenced the complete BMP9 gene in 450 patients with OPLL and in 550 matched controls. Analyses were performed on single markers and haplotypes. Single marker tests identified 6 SNPs, among which the minor alleles of rs7923671 (T>C; P=0.0026; OR: 1.33, CI: 1.10-1.60), rs75024165 (C>T, Thr304Met; P<0.001; OR: 1.76, CI: 1.47-2.12) and rs34379100 (A>C; P<0.001; OR: 1.52, CI: 1.27-1.82) were associated with OPLL. Logistic regression analysis showed that the additive model of rs75024165 (TT vs. CT vs. CC; P<0.001; OR: 1.74) and rs34379100 (CC vs. AC vs. AA; P=0.003; OR: 1.95) retained statistical significance when adjusted for clinical and demographic characteristics. Linkage disequilibrium (LD) analysis identified one 3 kb block of intense LD in BMP9 and one specific haplotype, CTCA (P<0.001; OR: 2.37), that contained the OPLL-associated risk alleles and was a risk factor for OPLL. This haplotype is associated with increased severity of OPLL, as shown by the distribution of ossified vertebrae in patients with OPLL (P=0.001). In summary, in the Chinese population studied, SNPs in the BMP9 gene appear to contribute to the risk of OPLL in association with certain clinical and demographic characteristics. The severity of OPLL seems to be mediated predominantly by genetic variations in a 3kb BMP9 locus with the specific haplotype CTCA.

SUBMITTER: Ren Y

PROVIDER: S-EPMC3400650 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Association of a BMP9 haplotype with ossification of the posterior longitudinal ligament (OPLL) in a Chinese population.

Ren Yuan Y Liu Zhi-zhong ZZ Feng Jie J Wan Hong H Li Jun-hua JH Wang Hao H Lin Xin X

PloS one 20120719 7

Direct or ex vivo BMP9 adenoviral gene therapy can induce massive bone formation at the injection sites and clearly promote spinal fusion. A comprehensive analysis of the osteogenic activity indicated that BMP9 was one of the most potent inducers of osteogenic differentiation both in vitro and in vivo among 14 types of human BMPs. However, genetic variations and whether they correlated with OPLL were not considered. We have sequenced the complete BMP9 gene in 450 patients with OPLL and in 550 ma ...[more]

PMID: 22829878

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

Project description:Background:Conventional anterior cervical corpectomy and fusion (ACCF) for cervical ossification of the posterior longitudinal ligament (OPLL) is associated with a high incidence of surgery-related complications. A novel anterior decompression technique [vertebral body sliding osteotomy (VBSO)] has been developed to prevent such complications and achieve effective anterior decompression for severe OPLL patients. The purpose of this study was to describe the procedure of novel surgical technique and to evaluate the long-term surgical outcomes. Methods:Between 2012 and 2014, 24 patients underwent VBSO for treatment of cervical myelopathy caused by severe OPLL. Operation time, estimated blood loss (EBL), neurologic outcomes and perioperative complications were investigated. Various radiographic parameters such as the preoperative canal occupying ratio, postoperative canal widening, and preoperative and postoperative cervical sagittal alignment were also measured. Minimum follow-up was 24 months. Results:The mean Japanese Orthopaedic Association score for cervical myelopathy (C-JOA score) improved from 12.4±2.9 preoperatively to 16.0±1.4 at the final follow-up (P<0.05). The mean recovery rate of the C-JOA score at the final follow-up was 68.65%±17.80%. The mean operating time was 130.7±21.0 minutes and the EBL was 176.3±38.0 mL. There were no perioperative complications. Pseudarthrosis was detected in two cases at 12 months postoperatively. The average spinal canal compromised ratio by OPLL decreased from 64.0%±15.0% preoperatively to 15.5%±12.2% postoperatively (P<0.05), with an average postoperative canal widening of 5.15±1.39 mm. Conclusions:Novel anterior decompression technique termed VBSO may be an effective and safe surgical option for anterior decompression surgery in patients with severe cervical OPLL. Since, VBSO does not involve a direct manipulation of the OPLL mass or dissection of the interspace between the OPLL and dura mater, this may significantly decrease the incidence of surgery-related complications, operation time, and intraoperative blood loss.

Project description:Ossification of the posterior longitudinal ligament (OPLL), a spinal ligament, reduces the range of motion in limbs. No treatment is currently available for OPLL, which is why therapies are urgently needed. OPLL occurs in obesity, is more common in men, and has an onset after 40 years of age. The mechanisms underlying OPLL remain unclear. In this study, we performed a serum proteomic analysis in both OPLL patients and healthy subjects to identify factors potentially involved in the development of OPLL, and found reduced levels of a protein that might underlie the pathology of OPLL. We isolated the protein, determined its amino acid sequence, and identified it as chemokine (C-X-C motif) ligand 7 (CXCL7). Based on these proteomics findings, we generated a CXCL7 knockout mouse model to study the molecular mechanisms underlying OPLL. CXCL7-null mice presented with a phenotype of OPLL, showing motor impairment, heterotopic ossification in the posterior ligament tissue, and osteoporosis in vertebrate tissue. To identify the mechanisms of CXCL7 deficiency in OPLL, we searched for single nucleotide polymorphisms and altered DNA exons, but no abnormalities were found. Although miR-340 levels were found to be high in an miRNA array, they were insufficient to reduce CXCL7 levels. Ubiquitin C-terminal hydrolase1 (UCHL1) was found to be overexpressed in CXCL7-null mice and in the sera of patients with OPLL, and was correlated with OPLL severity. Post-translational modifications of proteins with ubiquitin and ubiquitin-like modifiers, orchestrated by a cascade of specialized ubiquitin activating enzyme (E1), ubiquitin conjugating enzyme (E2), and ubiquitin ligase (E3) enzymes, are thought to control a wide range of cellular processes, and alterations in the ubiquitin-proteasome system have been associated with several degenerative disorders. In addition, the OPLL tissue of CXCL7-null mouse and its primary cells expressed the antibody to ubiquitin (linkage-specific K48). Our data clearly show decreased CXCL7 levels in patients with OPLL, and that OPLL developed in mice lacking CXCL7. Tumor necrosis factor receptor-associated factor (TRAF)6 expression was decreased in CXCL7-null mouse primary cells. Furthermore, K48 polyubiquitination was found in posterior longitudinal ligament ossified tissue and primary cells from CXCL7-null mice. We performed a phosphoproteomics analysis in CXCL7-deficient mice and identified increased phosphorylation of mitogen-activated protein kinase kinase (ME3K)15, ubiquitin protein ligase E3C (UBE3C) and protein kinase C (PKC) alpha, suggesting that ubiquitin-dependent degradation is involved in CXCL7 deficiency. Future studies in the CXCL7-null mouse model are, therefore, warranted to investigate the role of ubiquitination in the onset of OPLL. In conclusion, CXCL7 levels may be useful as a serum marker for the progression of OPLL. This study also suggests that increasing CXCL7 levels in patients can serve as an effective therapeutic strategy for the treatment of OPLL.

Dataset Information

Association of a BMP9 haplotype with ossification of the posterior longitudinal ligament (OPLL) in a Chinese population.

Publications

Association of a BMP9 haplotype with ossification of the posterior longitudinal ligament (OPLL) in a Chinese population.

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