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IL17RC affects the predisposition to thoracic ossification of the posterior longitudinal ligament.

ABSTRACT: BACKGROUND:Thoracic ossification of the posterior longitudinal ligament (T-OPLL) can cause thoracic spinal stenosis, which results in intractable myelopathy and radiculopathy. The etiology of T-OPLL is unknown and the condition is difficult to treat surgically. Whole-genome sequencing identified a genetic variant at rs199772854 of the interleukin 17 receptor C (IL17RC) gene as a potentially pathogenic locus associated with T-OPLL. We aimed to determine whether the rs199772854A site mutation causes abnormal expression of the IL17RC in Han Chinese patients with T-OPLL and predict the possible pathogenic mechanisms of T-OPLL. Analyses were performed to determine whether IL17RC is involved in the pathogenicity of T-OPLL. METHODS:Peripheral blood and OPLL tissue were collected from a total of 72 patients with T-OPLL disease (36 patients carrying the rs199772854A site mutation in IL17RC and 36 wild-type patients). The expression of IL17RC was analyzed by enzyme-linked immunosorbent assay, reverse transcription-quantitative polymerase chain reaction, immunohistochemistry, and Western blotting. RESULTS:rs199772854A mutation resulted in markedly increased IL17RC gene expression levels in peripheral blood samples and the OPLL tissue obtained following clinical surgery (P?

SUBMITTER: Wang P

PROVIDER: S-EPMC6621948 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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IL17RC affects the predisposition to thoracic ossification of the posterior longitudinal ligament.

Wang Peng P Liu Xiaoguang X Liu Xiao X Kong Chao C Teng Ze Z Ma Yunlong Y Yong Lei L Liang Chen C He Guanping G Lu Shibao S

Journal of orthopaedic surgery and research 20190710 1

<h4>Background</h4>Thoracic ossification of the posterior longitudinal ligament (T-OPLL) can cause thoracic spinal stenosis, which results in intractable myelopathy and radiculopathy. The etiology of T-OPLL is unknown and the condition is difficult to treat surgically. Whole-genome sequencing identified a genetic variant at rs199772854 of the interleukin 17 receptor C (IL17RC) gene as a potentially pathogenic locus associated with T-OPLL. We aimed to determine whether the rs199772854A site mutat ...[more]

PMID: 31291973

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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

IL17RC affects the predisposition to thoracic ossification of the posterior longitudinal ligament.

Publications

IL17RC affects the predisposition to thoracic ossification of the posterior longitudinal ligament.

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