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Petrosyan E, Fares J, Ahuja CS, Lesniak MS, Koski TR, Dahdaleh NS, El Tecle NE. Genetics and pathogenesis of scoliosis. NORTH AMERICAN SPINE SOCIETY JOURNAL 2024; 20:100556. [PMID: 39399722 PMCID: PMC11470263 DOI: 10.1016/j.xnsj.2024.100556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 09/02/2024] [Accepted: 09/03/2024] [Indexed: 10/15/2024]
Abstract
Background Scoliosis is defined as a lateral spine curvature of at least 10° with vertebral rotation, as seen on a posterior-anterior radiograph, often accompanied by reduced thoracic kyphosis. Scoliosis affects all age groups: idiopathic scoliosis is the most common spinal disorder in children and adolescents, while adult degenerative scoliosis typically affects individuals over fifty. In the United States, approximately 3 million new cases of scoliosis are diagnosed annually, with a predicted increase in part due to global aging. Despite its prevalence, the etiopathogenesis of scoliosis remains unclear. Methods This comprehensive review analyzes the literature on the etiopathogenetic evidence for both idiopathic and adult degenerative scoliosis. PubMed and Google Scholar databases were searched for studies on the genetic factors and etiopathogenetic mechanisms of scoliosis development and progression, with the search limited to articles in English. Results For idiopathic scoliosis, genetic factors are categorized into three groups: genes associated with susceptibility, disease progression, and both. We identify gene groups related to different biological processes and explore multifaceted pathogenesis of idiopathic scoliosis, including evolutionary adaptations to bipedalism and developmental and homeostatic spinal aberrations. For adult degenerative scoliosis, we segregate genetic and pathogenic evidence into categories of angiogenesis and inflammation, extracellular matrix degradation, neural associations, and hormonal influences. Finally, we compare findings in idiopathic scoliosis and adult degenerative scoliosis, discuss current limitations in scoliosis research, propose a new model for scoliosis etiopathogenesis, and highlight promising areas for future studies. Conclusions Scoliosis is a complex, multifaceted disease with largely enigmatic origins and mechanisms of progression, keeping it under continuous scientific scrutiny.
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Affiliation(s)
- Edgar Petrosyan
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Jawad Fares
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Christopher S. Ahuja
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Maciej S. Lesniak
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Tyler R. Koski
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Nader S. Dahdaleh
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Najib E. El Tecle
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
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Piqueras-Toharias M, Ibáñez-Vera AJ, Peinado-Rubia AB, Rodríguez-Almagro D, Lomas-Vega R, Sedeño-Vidal A. Effects of High-Velocity Spinal Manipulation on Quality of Life, Pain and Spinal Curvature in Children with Idiopathic Scoliosis: A Systematic Review. CHILDREN (BASEL, SWITZERLAND) 2024; 11:1167. [PMID: 39457132 PMCID: PMC11506289 DOI: 10.3390/children11101167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 09/02/2024] [Accepted: 09/20/2024] [Indexed: 10/28/2024]
Abstract
BACKGROUND/OBJECTIVES Scoliosis is a condition that involves deformation of the spine in the coronal plane and commonly appears in childhood or adolescence, significantly limiting a person's life. The cause is multifactorial, and treatment aims to improve the spinal curvature, prevent major pathologies, and enhance aesthetics. The objective of this review was to determine whether high-velocity low-amplitude (HVLA) spinal manipulation is more effective than other treatments for children with idiopathic scoliosis (IS). METHODS The PubMed, Web of Science, Scopus and PEDro databases were searched for both clinical trials and cohort studies. Methodological quality was assessed via the PEDro scale (for clinical trials) and the Newcastle-Ottawa scale (for observational studies). The protocol of this systematic review was registered in PROSPERO (CRD42024532442). RESULTS Five studies were selected for review. The results indicated moderate improvements in pain and the Cobb angle and limited improvements in quality of life. CONCLUSIONS HVLA spinal manipulation does not seem to have significant effects on reducing spinal deformity in IS patients, nor does it significantly impact quality of life. However, this therapy may have significant effects on reducing pain in these patients.
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Affiliation(s)
- Mario Piqueras-Toharias
- Department of Health Sciences, Campus las Lagunillas, Universidad de Jaén, 23071 Jaén, Spain; (M.P.-T.); (A.S.-V.)
| | - Alfonso Javier Ibáñez-Vera
- Department of Health Sciences, Campus las Lagunillas, Universidad de Jaén, 23071 Jaén, Spain; (M.P.-T.); (A.S.-V.)
| | | | - Daniel Rodríguez-Almagro
- Department of Nursing, Physiotherapy and Medicine, University of Almería, La Cañada de San Urbano, 04120 Almería, Spain;
| | - Rafael Lomas-Vega
- Department of Health Sciences, Campus las Lagunillas, Universidad de Jaén, 23071 Jaén, Spain; (M.P.-T.); (A.S.-V.)
| | - Ana Sedeño-Vidal
- Department of Health Sciences, Campus las Lagunillas, Universidad de Jaén, 23071 Jaén, Spain; (M.P.-T.); (A.S.-V.)
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Gallego-Siles JR, Siles-Fuentes MJ, Ibáñez-Vera AJ, Cortés-Pérez I, Obrero-Gaitán E, Lomas-Vega R. Idiopathic scoliosis in subjects with eye diseases: A systematic review with meta-analysis. Ann N Y Acad Sci 2024; 1533:81-88. [PMID: 38327125 DOI: 10.1111/nyas.15102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2024]
Abstract
Our aim was to find the best evidence on the prevalence of idiopathic scoliosis (IS) in subjects with eye diseases (EDs) and to determine the most common visual alterations that are present. Following the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), a bibliographic search up to June 2023 in the PubMed, PsycINFO, SCOPUS, and CINAHL Complete databases was performed. Observational studies were selected and the results were analyzed with prevalence odds ratio (OR). A total of six studies, including 18,396 subjects, were selected. The group of subjects with EDs was made up of 6048 individuals, of whom 655 (10.83%) had IS. The group of subjects without EDs was made up of 12,348 individuals of whom 444 (3.60%) presented with IS with an OR = 2.91, CI (95%) = [1.75, 4.83]. Blindness was assessed in a single study with an OR = 7.83, CI (95%) = [1.66, 36.90]; all three studies in the refractive error subgroup yielded an OR = 2.24, CI (95%) = [1.10, 4.58]; and the two studies that included subjects with strabismus showed an OR = 3.09, CI (95%) = [1.38, 7.00]. EDs were associated with an almost three times greater odds of having IS. We recommend the inclusion of vision testing in children with IS.
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Mórocz M, Qorri E, Pekker E, Tick G, Haracska L. Exploring RAD18-dependent replication of damaged DNA and discontinuities: A collection of advanced tools. J Biotechnol 2024; 380:1-19. [PMID: 38072328 DOI: 10.1016/j.jbiotec.2023.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 12/01/2023] [Accepted: 12/03/2023] [Indexed: 12/21/2023]
Abstract
DNA damage tolerance (DDT) pathways mitigate the effects of DNA damage during replication by rescuing the replication fork stalled at a DNA lesion or other barriers and also repair discontinuities left in the newly replicated DNA. From yeast to mammalian cells, RAD18-regulated translesion synthesis (TLS) and template switching (TS) represent the dominant pathways of DDT. Monoubiquitylation of the polymerase sliding clamp PCNA by HRAD6A-B/RAD18, an E2/E3 protein pair, enables the recruitment of specialized TLS polymerases that can insert nucleotides opposite damaged template bases. Alternatively, the subsequent polyubiquitylation of monoubiquitin-PCNA by Ubc13-Mms2 (E2) and HLTF or SHPRH (E3) can lead to the switching of the synthesis from the damaged template to the undamaged newly synthesized sister strand to facilitate synthesis past the lesion. When immediate TLS or TS cannot occur, gaps may remain in the newly synthesized strand, partly due to the repriming activity of the PRIMPOL primase, which can be filled during the later phases of the cell cycle. The first part of this review will summarize the current knowledge about RAD18-dependent DDT pathways, while the second part will offer a molecular toolkit for the identification and characterization of the cellular functions of a DDT protein. In particular, we will focus on advanced techniques that can reveal single-stranded and double-stranded DNA gaps and their repair at the single-cell level as well as monitor the progression of single replication forks, such as the specific versions of the DNA fiber and comet assays. This collection of methods may serve as a powerful molecular toolkit to monitor the metabolism of gaps, detect the contribution of relevant pathways and molecular players, as well as characterize the effectiveness of potential inhibitors.
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Affiliation(s)
- Mónika Mórocz
- HCEMM-HUN-REN BRC Mutagenesis and Carcinogenesis Research Group, HUN-REN Biological Research Centre, Szeged H-6726, Hungary.
| | - Erda Qorri
- HCEMM-HUN-REN BRC Mutagenesis and Carcinogenesis Research Group, HUN-REN Biological Research Centre, Szeged H-6726, Hungary; Faculty of Science and Informatics, Doctoral School of Biology, University of Szeged, Szeged H-6720, Hungary.
| | - Emese Pekker
- HCEMM-HUN-REN BRC Mutagenesis and Carcinogenesis Research Group, HUN-REN Biological Research Centre, Szeged H-6726, Hungary; Doctoral School of Interdisciplinary Medicine, University of Szeged, Korányi fasor 10, 6720 Szeged, Hungary.
| | - Gabriella Tick
- Mutagenesis and Carcinogenesis Research Group, HUN-REN Biological Research Centre, Szeged H-6726, Hungary.
| | - Lajos Haracska
- HCEMM-HUN-REN BRC Mutagenesis and Carcinogenesis Research Group, HUN-REN Biological Research Centre, Szeged H-6726, Hungary; National Laboratory for Drug Research and Development, Magyar tudósok krt. 2. H-1117 Budapest, Hungary.
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Jiang X, Liu F, Zhang M, Hu W, Zhao Y, Xia B, Xu K. Advances in genetic factors of adolescent idiopathic scoliosis: a bibliometric analysis. Front Pediatr 2024; 11:1301137. [PMID: 38322243 PMCID: PMC10845672 DOI: 10.3389/fped.2023.1301137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Accepted: 12/11/2023] [Indexed: 02/08/2024] Open
Abstract
Objective This study offers a bibliometric analysis of the current situation, hotspots, and cutting-edge domains of genetic factors of adolescent idiopathic scoliosis (AIS). Methods All publications related to genetic factors of AIS from January 1, 1992, to February 28, 2023, were searched from the Web of Science. CiteSpace software was employed for bibliometric analysis, collecting information about countries, institutions, authors, journals, and keywords of each article. Results A cumulative number of 308 articles have been ascertained. Since 2006, publications relating to genetic factors of AIS have significantly increased. China leads in both productivity and influence in this area, with the Chinese Academy of Medical Sciences being the most productive institution. The most prolific scholars in this field are Y. Qiu and Z. Z. Zhu. The publications that contributed the most were from Spine and European Spine Journal. The most prominent keywords in the genetic factors of AIS were "fibrillin gene", "menarche", "calmodulin", "estrogen receptor gene", "linkage analysis", "disc degeneration", "bone mineral density", "melatonin signaling dysfunction", "collagen gene", "mesenchymal stem cell", "LBX1", "promoter polymorphism", "Bone formation", "cerebrospinal fluid flow" and "extracellular matrix". Conclusion This analysis provides the frontiers and trends of genetic factors in AIS, including relevant research, partners, institutions and countries.
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Affiliation(s)
| | - Fuyun Liu
- Department of Orthopedics, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
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Li Q, Huo A, Li M, Wang J, Yin Q, Chen L, Chu X, Qin Y, Qi Y, Li Y, Cui H, Cong Q. Structure, ligands, and roles of GPR126/ADGRG6 in the development and diseases. Genes Dis 2024; 11:294-305. [PMID: 37588228 PMCID: PMC10425801 DOI: 10.1016/j.gendis.2023.02.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 12/24/2022] [Accepted: 02/05/2023] [Indexed: 03/29/2023] Open
Abstract
Adhesion G protein-coupled receptors (aGPCRs) are the second largest diverse group within the GPCR superfamily, which play critical roles in many physiological and pathological processes through cell-cell and cell-extracellular matrix interactions. The adhesion GPCR Adgrg6, also known as GPR126, is one of the better-characterized aGPCRs. GPR126 was previously found to have critical developmental roles in Schwann cell maturation and its mediated myelination in the peripheral nervous system in both zebrafish and mammals. Current studies have extended our understanding of GPR126-mediated roles during development and in human diseases. In this review, we highlighted these recent advances in GPR126 in expression profile, molecular structure, ligand-receptor interactions, and associated physiological and pathological functions in development and diseases.
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Affiliation(s)
- Qi Li
- Institute of Neuroscience and Jiangsu Key Laboratory of Neuropsychiatric Diseases, Soochow University, Suzhou, Jiangsu 215123, China
| | - Anran Huo
- Institute of Neuroscience and Jiangsu Key Laboratory of Neuropsychiatric Diseases, Soochow University, Suzhou, Jiangsu 215123, China
| | - Mengqi Li
- Institute of Neuroscience and Jiangsu Key Laboratory of Neuropsychiatric Diseases, Soochow University, Suzhou, Jiangsu 215123, China
| | - Jiali Wang
- Institute of Neuroscience and Jiangsu Key Laboratory of Neuropsychiatric Diseases, Soochow University, Suzhou, Jiangsu 215123, China
| | - Qiao Yin
- Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China
| | - Lumiao Chen
- Department of Nephrology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China
| | - Xin Chu
- Department of Emergency Center, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, China
| | - Yuan Qin
- Institute of Neuroscience and Jiangsu Key Laboratory of Neuropsychiatric Diseases, Soochow University, Suzhou, Jiangsu 215123, China
| | - Yuwan Qi
- Institute of Neuroscience and Jiangsu Key Laboratory of Neuropsychiatric Diseases, Soochow University, Suzhou, Jiangsu 215123, China
| | - Yang Li
- Department of Neurology, Huzhou Central Hospital, The Affiliated Huzhou Hospital, Zhejiang University School of Medicine, Huzhou, Zhejiang 313000, China
| | - Hengxiang Cui
- Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Qifei Cong
- Institute of Neuroscience and Jiangsu Key Laboratory of Neuropsychiatric Diseases, Soochow University, Suzhou, Jiangsu 215123, China
- Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China
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Ru L, Zheng H, Lian W, Zhao S, Fan Q. Knowledge mapping of idiopathic scoliosis genes and research hotspots (2002-2022): a bibliometric analysis. Front Pediatr 2023; 11:1177983. [PMID: 38111628 PMCID: PMC10725947 DOI: 10.3389/fped.2023.1177983] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 11/06/2023] [Indexed: 12/20/2023] Open
Abstract
Background The etiology of idiopathic scoliosis (IS) remains unclear. Gene-based studies on genetic etiology and molecular mechanisms have improved our understanding of IS and guided treatment and diagnosis. Therefore, it is imperative to explicate and demarcate the preponderant areas of inquiry, key scholars, and their aggregate scholarly output, in addition to the collaborative associations amongst publications or researchers. Methods Documents were retrieved from the Web of Science Core Collection (WoSCC) with the following criteria: TS = ("idiopathic scoliosis" AND gene) refined by search operators (genomic OR "hereditary substance" OR "germ plasm" OR Cistrons OR genetics OR genetic OR genes OR Polygenic OR genotype OR genome OR allele OR polygenes OR Polygene) AND DOCUMENT TYPES (ARTICLE OR REVIEW), and the timespan of 2002-01-01 to 2022-11-26. The online bibliometric analysis platform (bibliometric), bibliographic item co-occurrence matrix builder (BICOMB), CiteSpace 6.1. R6 and VOS viewer were used to evaluate articles for publications, nations, institutions, journals, references, knowledge bases, keywords, and research hotspots. Results A total of 479 documents were retrieved from WoSCC. Fourty-four countries published relevant articles. The country with the most significant number of articles was China, and the institution with the most significant number of articles was Nanjing University. Citation analysis formed eight meaningful clusters and 16 high-frequency keywords. (2) The citation knowledge map included single nucleotide polymorphisms, whole exome sequencing, axonal dynamin, drug development, mesenchymal stem cells, dietary intake, curve progression, zebrafish development model, extracellular matrix, and rare variants were the current research hotspots and frontiers. Conclusions Recent research has focused on IS-related genes, whereas the extracellular matrix and unusual variants are research frontiers and hotspots. Functional analysis of susceptibility genes will prove to be valuable for identifying this disease.
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Affiliation(s)
- Like Ru
- School of Pediatrics, Henan University of Chinese Medicine, Zhengzhou, China
| | - Hong Zheng
- The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China
- School of Pediatrics, Henan University of Chinese Medicine, Zhengzhou, China
| | - Wenjun Lian
- The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China
| | - Shuying Zhao
- The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China
| | - Qimeng Fan
- The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China
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AlMekkawi AK, Caruso JP, El Ahmadieh TY, Palmisciano P, Aljardali MW, Derian AG, Al Tamimi M, Bagley CA, Aoun SG. Single Nucleotide Polymorphisms and Adolescent Idiopathic Scoliosis: A Systematic Review and Meta-Analysis of the Literature. Spine (Phila Pa 1976) 2023; 48:695-701. [PMID: 36940245 DOI: 10.1097/brs.0000000000004623] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 02/25/2023] [Indexed: 03/22/2023]
Abstract
STUDY DESIGN Meta-analysis. OBJECTIVE To determine the single nucleotide polymorphisms (SNPs) that are related to adult idiopathic scoliosis. SUMMARY AND BACKGROUND DATA Adolescent idiopathic scoliosis (AIS) is considered one of the most prevalent spinal diseases. Even though the cause of AIS is yet to be determined, family history and sex have shown conclusive associations. Multiple studies have indicated that AIS is more prevalent in families where at least one other first-degree relative is similarly affected, indicating a possible genetic etiology to AIS. MATERIALS AND METHODS Articles were collected from 3 different search engines and then processed in 2 stages for final article selection for quantitative analysis. Five different genetic models were represented to show the association between the different SNPs and AIS. The Hardy-Weinberg equilibrium was examined using Fisher exact test, with significance set at P <0.05. The final analysis paper's quality was evaluated using the Newcastle Ottawa Scale. Kappa interrater agreement was calculated to evaluate the agreement between authors. RESULTS The final analysis comprised 43 publications, 19412 cases, 22005 controls, and 25 distinct genes. LBX1 rs11190870 T>C and MATN-1 SNPs were associated with an increased risk of AIS in one or all of the 5 genetic models. IGF-1 , estrogen receptor alfa, and MTNR1B , SNPs were not associated with AIS in all 5 genetic models. Newcastle Ottawa Scale showed good quality for the selected articles. Cohen k = 0.741 and Kappa interrater agreement of 84% showed that the writers were in strong agreement. CONCLUSIONS There seem to be associations between AIS and genetic SNP. Further larger studies should be conducted to validate the results.
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Affiliation(s)
- Ahmad K AlMekkawi
- Department of Neurosurgery, The University of Texas Southwestern, Dallas, TX
| | - James P Caruso
- Department of Neurosurgery, The University of Texas Southwestern, Dallas, TX
| | - Tarek Y El Ahmadieh
- Department of Neurosurgery, Loma Linda University, Anderson St., Loma Linda, CA
| | - Paolo Palmisciano
- Department of Neurosurgery, University of Cincinnati, Cincinnati, OH
| | - Marwa W Aljardali
- The LAU Gilbert and Rose-Marie Chagoury School of Medicine; Beirut, Lebanon
| | | | - Mazin Al Tamimi
- Department of Neurosurgery, The University of Texas Southwestern, Dallas, TX
| | - Carlos A Bagley
- Department of Neurosurgery, The University of Texas Southwestern, Dallas, TX
| | - Salah G Aoun
- Department of Neurosurgery, The University of Texas Southwestern, Dallas, TX
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Wang W, Chen T, Liu Y, Wang S, Yang N, Luo M. Predictive value of single-nucleotide polymorphisms in curve progression of adolescent idiopathic scoliosis. EUROPEAN SPINE JOURNAL : OFFICIAL PUBLICATION OF THE EUROPEAN SPINE SOCIETY, THE EUROPEAN SPINAL DEFORMITY SOCIETY, AND THE EUROPEAN SECTION OF THE CERVICAL SPINE RESEARCH SOCIETY 2022; 31:2311-2325. [PMID: 35434775 DOI: 10.1007/s00586-022-07213-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 03/24/2022] [Accepted: 04/06/2022] [Indexed: 12/18/2022]
Abstract
PURPOSE Genetic diagnosis is a promising approach because several single-nucleotide polymorphisms (SNPs) associated with adolescent idiopathic scoliosis (AIS) progression have been reported. We review the predictive value of SNPs in curve progression of adolescent idiopathic scoliosis. METHODS We reviewed DNA-based prognostic testing to predict curve progression. Then, the multiple polymorphisms in loci related to AIS progression were also reviewed, and we elucidated the predictive value of SNPs from four functional perspectives, including endocrine metabolism, neuromuscular system, cartilage and extracellular matrix, enzymes, and cytokines. RESULTS The ScoliScores were less successful predictors than expected, and the weak power of predictive SNPs might account for its failure. Susceptibility loci in ESR1, ESR2, GPER, and IGF1, which related to endocrine metabolism, have been reported to predict AIS progression. Neuromuscular imbalance might be a potential mechanism of scoliosis, and SNPs in LBX1, NTF3, and SOCS3 have been reported to predict the curve progression of AIS. Susceptibility loci in SOX9, MATN1, AJAP1, MMP9, and TIMP2, which are related to cartilage and extracellular matrix, are also potentially related to AIS progression. Enzymes and cytokines play essential roles in regulating bone metabolism and embryonic development. SNPs in BNC2, SLC39A8, TGFB1, IL-6, IL-17RC, and CHD7 were suggested as predictive loci for AIS curve progression. CONCLUSIONS Many promising SNPs have been identified to predict the curve progression of AIS. However, conflicting results from replication studies and different ethnic groups hamper their reliability. Convincing SNPs from multiethnic populations and functional verification are needed.
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Affiliation(s)
- Wengang Wang
- Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, Henan, People's Republic of China
| | - Tailong Chen
- Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, Henan, People's Republic of China
| | - Yibin Liu
- Department of Emergency, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, Henan, People's Republic of China
| | - Songsong Wang
- Department of Emergency, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, Henan, People's Republic of China
| | - Ningning Yang
- Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, Henan, People's Republic of China. .,Department of Emergency, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, Henan, People's Republic of China.
| | - Ming Luo
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, People's Republic of China.
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Liu J, Li W, Liu B, Dai A, Wang Y, She L, Zhang P, Zheng W, Dai Q, Yang M. Melatonin Receptor 1B Genetic Variants on Susceptibility to Gestational Diabetes Mellitus: A Hospital-Based Case-Control Study in Wuhan, Central China. Diabetes Metab Syndr Obes 2022; 15:1207-1216. [PMID: 35480849 PMCID: PMC9035465 DOI: 10.2147/dmso.s345036] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 04/01/2022] [Indexed: 11/23/2022] Open
Abstract
PURPOSE The aim of the study was to find out the associations of Melatonin receptor 1B (MTNR1B) genetic variants with gestational diabetes mellitus (GDM) in Wuhan of central China. PATIENTS AND METHODS A hospital-based case-control study that included 1679 women was carried out to explore the associations of MTNR1B single nucleotide polymorphisms (SNPs) with GDM risk, which were analyzed through logistic regression analysis by adjusting age, pre-pregnancy BMI and family history of diabetes. Multifactor dimensionality reduction was applied to determine gene-gene interactions between SNPs. RESULTS MTNR1B SNPs rs10830962, rs10830963, rs1387153, rs7936247 and rs4753426 were significantly associated with GDM risk (P<0.05). The rs10830962/G, rs10830963/G, rs1387153/T, and rs7936247/T were risk variants, whereas rs4753426/T was protective variant for GDM development. Fasting plasma glucose (FPG) and 1h-plasma glucose (PG) were significantly different among genotypes at rs10830962 and rs10830963, whereas 2h-PG levels were not. Gene-gene interactions were not found among the five SNPs on GDM risk. CONCLUSION MTNR1B genetic variants have significant associations but no gene-gene interactions with GDM risk in central Chinese population. Furthermore, MTNR1B SNPs have significant relationships with glycemic traits.
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Affiliation(s)
- Jianqiong Liu
- Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, People's Republic of China
| | - Wei Li
- Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, People's Republic of China
| | - Bei Liu
- Technical Guidance Institute, Jinan Family Planning Service Center, Jinan, Shandong Province, People's Republic of China
| | - Anna Dai
- School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, People's Republic of China
| | - Yanqin Wang
- Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, People's Republic of China
| | - Lu She
- School of Medicine, Wuhan University of Science and Technology, Wuhan, Hubei Province, People's Republic of China
- Research Center for Health Promotion in Women, Youth and Children, Wuhan University of Science and Technology, Wuhan, Hubei Province, People's Republic of China
| | - Pei Zhang
- School of Medicine, Wuhan University of Science and Technology, Wuhan, Hubei Province, People's Republic of China
- Research Center for Health Promotion in Women, Youth and Children, Wuhan University of Science and Technology, Wuhan, Hubei Province, People's Republic of China
| | - Wenpei Zheng
- Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, People's Republic of China
| | - Qiong Dai
- Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, People's Republic of China
| | - Mei Yang
- School of Medicine, Wuhan University of Science and Technology, Wuhan, Hubei Province, People's Republic of China
- Research Center for Health Promotion in Women, Youth and Children, Wuhan University of Science and Technology, Wuhan, Hubei Province, People's Republic of China
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11
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Lee CC, Kuo YC, Hu JM, Chang PK, Sun CA, Yang T, Li CW, Chen CY, Lin FH, Hsu CH, Chou YC. MTNR1B polymorphisms with CDKN2A and MGMT methylation status are associated with poor prognosis of colorectal cancer in Taiwan. World J Gastroenterol 2021; 27:5737-5752. [PMID: 34629798 PMCID: PMC8473598 DOI: 10.3748/wjg.v27.i34.5737] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 06/30/2021] [Accepted: 08/23/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Identifying novel colorectal cancer (CRC) prognostic biomarkers is crucial to helping clinicians make appropriate therapy decisions. Melatonin plays a major role in managing the circadian rhythm and exerts oncostatic effects on different kinds of tumours.
AIM To explore the relationship between MTNR1B single-nucleotide polymorphism (SNPs) combined with gene hypermethylation and CRC prognosis.
METHODS A total of 94 CRC tumour tissues were investigated. Genotyping for the four MTNR1B SNPs (rs1387153, rs2166706, rs10830963, and rs1447352) was performed using multiplex polymerase chain reaction. The relationships between the MTNR1B SNPs and CRC 5-year overall survival (OS) was assessed by calculating hazard ratios with 95%CIs.
RESULTS All SNPs (rs1387153, rs2166706, rs10830963, and rs1447352) were correlated with decreased 5-year OS. In stratified analysis, rs1387153, rs10830963, and rs1447352 risk genotype combined with CDKN2A and MGMT methylation status were associated with 5-year OS. A strong cumulative effect of the four polymorphisms on CRC prognosis was observed. Four haplotypes of MTNR1B SNPs were also associated with the 5-year OS. MTNR1B SNPs combined with CDKN2A and MGMT gene methylation status could be used to predict shorter CRC survival.
CONCLUSION The novel genetic biomarkers combined with epigenetic biomarkers may be predictive tool for CRC prognosis and thus could be used to individualise treatment for patients with CRC.
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Affiliation(s)
- Chia-Cheng Lee
- Division of Colorectal Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
- Medical Informatics Office, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
| | - Yu-Cheng Kuo
- School of Public Health, National Defense Medical Center, Taipei 114, Taiwan
| | - Je-Ming Hu
- Division of Colorectal Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
| | - Pi-Kai Chang
- Division of Colorectal Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
| | - Chien-An Sun
- Department of Public Health, College of Medicine, Fu-Jen Catholic University, New Taipei City 24205, Taiwan
- Big Data Research Center, College of Medicine, Fu-Jen Catholic University, New Taipei City 24205, Taiwan
| | - Tsan Yang
- Department of Health Business Administration, Meiho University, Pingtung 91202, Taiwan
| | - Chuan-Wang Li
- Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei 114, Taiwan
- Institute of Preventive Medicine, National Defense Medical Center, New Taipei City 237, Taiwan
| | - Chao-Yang Chen
- Division of Colorectal Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
| | - Fu-Huang Lin
- School of Public Health, National Defense Medical Center, Taipei 114, Taiwan
| | - Chih-Hsiung Hsu
- School of Public Health, National Defense Medical Center, Taipei 114, Taiwan
| | - Yu-Ching Chou
- School of Public Health, National Defense Medical Center, Taipei 114, Taiwan
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12
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Liang ZT, Guo CF, Li J, Zhang HQ. The role of endocrine hormones in the pathogenesis of adolescent idiopathic scoliosis. FASEB J 2021; 35:e21839. [PMID: 34387890 DOI: 10.1096/fj.202100759r] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 07/21/2021] [Accepted: 07/21/2021] [Indexed: 11/11/2022]
Abstract
Adolescent idiopathic scoliosis (AIS) is a common spinal deformity characterized by changes in the three-dimensional structure of the spine. It usually initiates during puberty, the peak period of human growth when the secretion of numerous hormones is changing, and it is more common in females than in males. Accumulating evidence shows that the abnormal levels of many hormones including estrogen, melatonin, growth hormone, leptin, adiponectin and ghrelin, may be related to the occurrence and development of AIS. The purpose of this review is to provide a summary and critique of the research published on each hormone over the past 20 years, and to highlight areas for future study. It is hoped that the presentation will help provide a better understanding of the role of endocrine hormones in the pathogenesis of AIS.
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Affiliation(s)
- Zhuo-Tao Liang
- Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Chao-Feng Guo
- Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Jiong Li
- Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Hong-Qi Zhang
- Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
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13
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Zaydman AM, Strokova EL, Pahomova NY, Gusev AF, Mikhaylovskiy MV, Shevchenko AI, Zaidman MN, Shilo AR, Subbotin VM. Etiopathogenesis of adolescent idiopathic scoliosis: Review of the literature and new epigenetic hypothesis on altered neural crest cells migration in early embryogenesis as the key event. Med Hypotheses 2021; 151:110585. [PMID: 33932710 DOI: 10.1016/j.mehy.2021.110585] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 02/28/2021] [Accepted: 03/24/2021] [Indexed: 12/17/2022]
Abstract
Adolescent idiopathic scoliosis (AIS) affects 2-3% of children. Numerous hypotheses on etiologic/causal factors of AIS were investigated, but all failed to identify therapeutic targets and hence failed to offer a cure. Therefore, currently there are only two options to minimize morbidity of the patients suffering AIS: bracing and spinal surgery. From the beginning of 1960th, spinal surgery, both fusion and rod placement, became the standard of management for progressive adolescent idiopathic spine deformity. However, spinal surgery is often associated with complications. These circumstances motivate AIS scientific community to continue the search for new etiologic and causal factors of AIS. While the role of the genetic factors in AIS pathogenesis was investigated intensively and universally recognized, these studies failed to nominate mutation of a particular gene or genes combination responsible for AIS development. More recently epigenetic factors were suggested to play causal role in AIS pathogenesis. Sharing this new approach, we investigated scoliotic vertebral growth plates removed during vertebral fusion (anterior surgery) for AIS correction. In recent publications we showed that cells from the convex side of human scoliotic deformities undergo normal chondrogenic/osteogenic differentiation, while cells from the concave side acquire a neuronal phenotype. Based on these facts we hypothesized that altered neural crest cell migration in early embryogenesis can be the etiological factor of AIS. In particular, we suggested that neural crest cells failed to migrate through the anterior half of somites and became deposited in sclerotome, which in turn produced chondrogenic/osteogenic-insufficient vertebral growth plates. To test this hypothesis we conducted experiments on chicken embryos with arrest neural crest cell migration by inhibiting expression of Paired-box 3 (Pax3) gene, a known enhancer and promoter of neural crest cells migration and differentiation. The results showed that chicken embryos treated with Pax3 siRNA (microinjection into the neural tube, 44 h post-fertilization) progressively developed scoliotic deformity during maturation. Therefore, this analysis suggests that although adolescent idiopathic scoliosis manifests in children around puberty, the real onset of the disease is of epigenetic nature and takes place in early embryogenesis and involves altered neural crest cells migration. If these results confirmed and further elaborated, the hypothesis may shed new light on the etiology and pathogenesis of AIS.
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Affiliation(s)
- Alla M Zaydman
- Novosibirsk Research Institute of Traumatology and Orthopaedics named after Ya.L. Tsivyan, Novosibirsk, Russia
| | - Elena L Strokova
- Novosibirsk Research Institute of Traumatology and Orthopaedics named after Ya.L. Tsivyan, Novosibirsk, Russia
| | - Nataliya Y Pahomova
- Novosibirsk Research Institute of Traumatology and Orthopaedics named after Ya.L. Tsivyan, Novosibirsk, Russia
| | - Arkady F Gusev
- Novosibirsk Research Institute of Traumatology and Orthopaedics named after Ya.L. Tsivyan, Novosibirsk, Russia
| | - Mikhail V Mikhaylovskiy
- Novosibirsk Research Institute of Traumatology and Orthopaedics named after Ya.L. Tsivyan, Novosibirsk, Russia
| | - Alexander I Shevchenko
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences", Novosibirsk, Russia
| | | | - Andrey R Shilo
- Novosibirsk Zoo named after R.A. Shilo, Novosibirsk, Russia
| | - Vladimir M Subbotin
- Arrowhead Pharmaceuticals Inc., Madison WI, USA; University of Pittsburgh, Pittsburgh PA, USA; University of Wisconsin, Madison WI, USA.
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14
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Ko DS, Kim YH, Goh TS, Lee JS. Altered physiology of mesenchymal stem cells in the pathogenesis of adolescent idiopathic scoliosis. World J Clin Cases 2020; 8:2102-2110. [PMID: 32548139 PMCID: PMC7281031 DOI: 10.12998/wjcc.v8.i11.2102] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 05/13/2020] [Accepted: 05/23/2020] [Indexed: 02/05/2023] Open
Abstract
Adolescent idiopathic scoliosis is the most common spinal deformity during puberty, especially in females. It is characterized by aberrant skeletal growth and generalized reduced bone density, which is associated with impaired bone mineral metabolism. Despite recent progress in multidisciplinary research to support various hypotheses, the pathogenesis of Adolescent idiopathic scoliosis is still not clearly understood. One of the hypothesis is to study the role of mesenchymal stem cells due to its involvement in the above-mentioned bone metabolic abnormalities. In this review, we will summarize reported literatures on the role of mesenchymal stem cells, particularly in the pathogenesis of Adolescent idiopathic scoliosis. In addition, we will describe the research on mesenchymal stem cells of Adolescent idiopathic scoliosis performed using bioinformatics tools.
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Affiliation(s)
- Dai Sik Ko
- Division of Vascular Surgery, Department of Surgery, Gachon University Gil Medical Center, Incheoz 21565, South Korea
| | - Yun Hak Kim
- Department of Anatomy and Department of Biomedical Informatics, School of Medicine, Pusan National University, Yangsan 50612, South Korea
| | - Tae Sik Goh
- Department of Orthopaedic Surgery and Biomedical Research Institute, Pusan National University Hospital, Busan 49241, South Korea
| | - Jung Sub Lee
- Department of Orthopaedic Surgery and Biomedical Research Institute, Pusan National University Hospital, Busan 49241, South Korea
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15
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Quantitation Analysis of PCDH10 Methylation in Adolescent Idiopathic Scoliosis Using Pyrosequencing Study. Spine (Phila Pa 1976) 2020; 45:E373-E378. [PMID: 31651684 DOI: 10.1097/brs.0000000000003292] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
STUDY DESIGN A retrospective and comparative study. OBJECTIVE To evaluate the difference of DNA methylation in protocadherin10 (PCDH10) genes between adolescent idiopathic scoliosis (AIS) and normal controls, and to assess the association between DNA methylation and the etiology of AIS. SUMMARY OF BACKGROUND DATA The PCDH10 gene showed abnormal expression in AIS. However, the mechanism was still unclear. DNA methylation was an important epigenetic mechanism at the interface between genetics and environmental phenotype, seeming to be a suitable epigenetic mark for the abnormal expression of PCDH10 in AIS. METHODS There were 50 AIS patients and 50 healthy controls included in the study. The peripheral blood sample of each participant was taken. The pyrosequencing assay was used to assess the methylation status of PCDH10 promoter and real time PCR (RT-PCR) was used to detect the PCDH10 gene expression. The comparison analysis was performed using independent t test and 2-tailed Pearson coefficients was calculated for the correlation analysis. RESULTS The average methylation level was 4.32 ± 0.73 in AIS patients and 3.14 ± 0.97 in healthy controls (P < 0.001). The PCDH10 gene expression was 0.23 ± 0.04 in AIS patients and 0.36 ± 0.08 in normal controls (P < 0.0001). Statistically significant linear correlation was found between PCDH10 gene methylation level and Cobb angle of major curve (P < 0.001). Besides, a significant negative correlation between PCDH10 methylation and PCDH10 gene expression was found (P < 0.001). CONCLUSION AIS patients were associated with high DNA methylation level and low gene expression of PCDH10 gene rather than normal controls. The high methylation level indicated high Cobb angle of major curves in AIS. The abnormal DNA methylation may widely exist and serve as a potential mechanism for AIS. LEVEL OF EVIDENCE 3.
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16
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Li J, Li N, Chen Y, Hui S, Fan J, Ye B, Fan Z, Zhang J, Zhao RC, Zhuang Q. SPRY4 is responsible for pathogenesis of adolescent idiopathic scoliosis by contributing to osteogenic differentiation and melatonin response of bone marrow-derived mesenchymal stem cells. Cell Death Dis 2019; 10:805. [PMID: 31645544 PMCID: PMC6811559 DOI: 10.1038/s41419-019-1949-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 08/16/2019] [Accepted: 08/26/2019] [Indexed: 12/18/2022]
Abstract
Adolescent idiopathic scoliosis (AIS) is a complex, three-dimensional deformity of the spine that commonly occurs in pubescent girls. Decreased osteogenic differentiation and aberrant melatonin signalling have been demonstrated in mesenchymal stem cells (MSCs) from AIS patients and are implicated in the pathogenesis of AIS. However, the molecular mechanisms underlying these abnormal cellular features remain largely unknown. Our previous work comparing gene expression profiles between MSCs from AIS patients and healthy controls identified 1027 differentially expressed genes. In the present study, we focused on one of the most downregulated genes, SPRY4, in the MAPK signalling pathway and examined its role in osteogenic differentiation. We found that SPRY4 is markedly downregulated in AIS MSCs. Knockdown of SPRY4 impaired differentiation of healthy MSCs to osteoblasts, while SPRY4 overexpression in AIS MSCs enhanced osteogenic differentiation. Furthermore, melatonin treatment boosted osteogenic differentiation, whereas SPRY4 ablation ablated the promotional effects of melatonin. Moreover, SPRY4 was upregulated by melatonin exposure and contributed to osteogenic differentiation and melatonin response in a MEK-ERK1/2 dependent manner. Thus, loss of SPRY4 in bone marrow derived-MSCs results in reduced osteogenic differentiation, and these defects are further aggravated under the influence of melatonin. Our findings provide new insights for understanding the role of melatonin in AIS aetiology and highlight the importance of MSCs in AIS pathogenesis.
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Affiliation(s)
- Jing Li
- Center of Excellence in Tissue Engineering, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Key Laboratory of New Drug Development and Clinical Trial of Stem Cell Therapy, Beijing, P.R. China
| | - Na Li
- Center of Excellence in Tissue Engineering, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Key Laboratory of New Drug Development and Clinical Trial of Stem Cell Therapy, Beijing, P.R. China
| | - Yunfei Chen
- Center of Excellence in Tissue Engineering, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Key Laboratory of New Drug Development and Clinical Trial of Stem Cell Therapy, Beijing, P.R. China
| | - Shangyi Hui
- Department of Anesthesiology, Peking Union Medical College Hospital, Beijing, P.R. China
| | - Junfen Fan
- Center of Excellence in Tissue Engineering, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Key Laboratory of New Drug Development and Clinical Trial of Stem Cell Therapy, Beijing, P.R. China
| | - Buqing Ye
- CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Zusen Fan
- CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Jianguo Zhang
- Department of Orthopedics, Peking Union Medical College Hospital, Beijing, P.R. China.
| | - Robert Chunhua Zhao
- Center of Excellence in Tissue Engineering, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Key Laboratory of New Drug Development and Clinical Trial of Stem Cell Therapy, Beijing, P.R. China.
| | - Qianyu Zhuang
- Department of Orthopedics, Peking Union Medical College Hospital, Beijing, P.R. China.
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Replication Study for the Association of GWAS-associated Loci With Adolescent Idiopathic Scoliosis Susceptibility and Curve Progression in a Chinese Population. Spine (Phila Pa 1976) 2019; 44:464-471. [PMID: 30234802 DOI: 10.1097/brs.0000000000002866] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
STUDY DESIGN A genetic association (replication) study. OBJECTIVE The aim of this study was to replicate and further evaluate the association among seven genome-wide association studies (GWAS)-identified single nucleotide polymorphisms (SNPs) in Chinese girls with adolescent idiopathic scoliosis (AIS) with disease onset, curve types, and progression. SUMMARY OF BACKGROUND DATA AIS is the most common pediatric spinal deformity with a strong genetic predisposition. Recent GWAS identified 10 new disease predisposition loci for AIS. METHODS Three hundred nineteen female AIS patients with Cobb angle ≥ 10 and 201 healthy controls were studied for the association with disease onset. Seven GWAS-identified SNPs (rs11190870 in LBX1, rs12946942 in SOX9/KCNJ2, rs13398147 in PAX3/EPH4, rs241215 in AJAP1, rs3904778 in BNC2, rs6570507 in GPR126, and rs678741 in LBX1-AS1) were analyzed. In subgroup analysis, AIS patients were subdivided by curve types and disease progression to examine for genotype association. RESULTS We replicated the association with disease onset in four common SNPs rs11190870, rs3904778, rs6570507, and rs678741. In addition, rs1190870 and rs678741 remained significantly associated in the right thoracic curves only subgroup. However, no significant difference was observed with both clinical curve progression or Cobb angle. CONCLUSION This study replicated the associations of four GWAS-associated SNPs with occurrence of AIS in our Chinese population. However, none of these SNPs was associated with curve severity and progression. The results suggest that curve progression may be determined by environmental (nongenetic) factor, but further study with a larger sample size is required to address this issue. LEVEL OF EVIDENCE 4.
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A Genetic Variant in GPR126 Causing a Decreased Inclusion of Exon 6 Is Associated with Cartilage Development in Adolescent Idiopathic Scoliosis Population. BIOMED RESEARCH INTERNATIONAL 2019; 2019:4678969. [PMID: 30886859 PMCID: PMC6388357 DOI: 10.1155/2019/4678969] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Accepted: 01/30/2019] [Indexed: 12/24/2022]
Abstract
Adolescent idiopathic scoliosis (AIS) is the most common spinal deformity disease in adolescents but its etiology and pathogenesis are still unclear. The current study aims to identify the relationship between single nucleotide polymorphisms (SNPs) of G protein-coupled receptor 126 (GPR126) gene and AIS predisposition. GPR126 contains 26 exons and alternative splicing of exon 6 and exon 25 produces 4 protein-coding transcripts. We genotyped SNPs of GPR126 gene around exon 6 and exon 25 in 131 Chinese AIS patients and 132 healthy controls and provided evidence that SNP rs41289839 G>A is strongly associated with AIS susceptibility. Linkage disequilibrium analysis suggests that rs41289839 and other AIS-related SNPs were in strong LD. Next, we demonstrated that rs41289839 G>A inhibits the inclusion of exon 6 during alternative splicing, resulting in a decreased expression level of exon 6-included transcript (GPR126-exon6in) relative to the exon 6 excluded transcript (GPR126-exon6ex) by minigene assay. Chondrogenic differentiation experiment showed that GPR126-exon6in has a high expression level relative to GPR126-exon6ex during chondrogenic differentiation of hMSCs. Our findings indicate that newly discovered SNP is related to cartilage development and may provide valuable insights into the etiology and pathogenesis of adolescent idiopathic scoliosis.
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Li C, Zhou Y, Qiao B, Xu L, Li Y, Li C. Association Between a Melatonin Receptor 1B Genetic Polymorphism and Its Protein Expression in Gestational Diabetes Mellitus. Reprod Sci 2018; 26:1382-1388. [PMID: 29656698 DOI: 10.1177/1933719118765983] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
AIMS This study was conducted to investigate the relationship between a genetic polymorphism and the expression of melatonin receptor 1B (MTNR1B) in the placenta of Han Chinese women with gestational diabetes mellitus (GDM). METHODS In this study, 215 patients with GDM and 243 healthy controls were genotyped using direct sequencing for the MTNR1B single-nucleotide polymorphism rs10830963. The expression of MTNR1B in placenta was detected by immunohistochemistry and Western blotting. The association of rs10830963 with the expression of MTNR1B, plasma glucose, and insulin levels as well as blood lipid levels was investigated. RESULTS The genotype and allele frequencies of rs10830963 were significantly different between women with GDM and controls (P < .05). Fasting blood glucose, fasting insulin, and homeostasis model assessment for insulin resistance in women with GDM with the GG and GC genotypes were significantly higher than those with the CC genotype (P < .05). The expression level of MTNR1B in placenta was significantly higher in the GDM group than in the control group (P < .05). The expression of MTNR1B was significantly higher in all participants with the GG and GC genotypes (1.31 [0.74]) than in pregnant women with the CC genotype (0.92 [0.52], P < .05). CONCLUSIONS The genetic polymorphism rs10830963 in MTNR1B and its protein expression levels in placenta are associated with an increased risk of developing GDM. Furthermore, rs10830963 may tag a molecular mechanism leading to insulin resistance in Han Chinese women with GDM.
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Affiliation(s)
- Chao Li
- Department of Obstetrics, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yubin Zhou
- Department of medicine, Qingdao University, Qingdao, China
| | - Binglong Qiao
- Department of Radiology, Qingdao Municipal Hospital, Qingdao, China
| | - Lin Xu
- Department of Radiology, Qingdao Municipal Hospital, Qingdao, China
| | - Yan Li
- Department of Radiology, Qingdao Municipal Hospital, Qingdao, China
| | - Can Li
- Department of Obstetrics, The Affiliated Hospital of Qingdao University, Qingdao, China
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Li X, Lu J, Teng W, Zhao C, Ye X. Quantitative Evaluation of MMP-9 and TIMP-1 Promoter Methylation in Chronic Periodontitis. DNA Cell Biol 2018; 37:168-173. [PMID: 29298087 DOI: 10.1089/dna.2017.3948] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
In this study, we investigated the promoter DNA methylation (DNAm) status of the MMP-9 and TIMP-1 genes in patients with chronic periodontitis to evaluate disease progression. Using pyrosequencing technology, DNAm levels of MMP-9 and TIMP-1 CpG islands were measured in 88 chronic periodontitis patients and 15 healthy controls. We found a positive correlation between methylation levels of MMP-9 CpG islands and the severity of chronic periodontitis. Methylated CpG islands were also closely associated with the duration of chronic periodontitis. Moreover, female patients exhibited lower methylation levels of MMP-9 but higher methylation levels of TIMP-1 compared with male patients, and the methylation levels of TIMP-1 gradually decreased with age. The findings of gender disparity in the DNAm of MMP-9 and TIMP-1 genes provide novel insights into chronic periodontitis.
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Affiliation(s)
- Xiting Li
- 1 Department of Periodontology, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-Sen University , Guangzhou, People's Republic of China .,2 Department of Regenerative Medicine, Guangdong Provincial Key Laboratory of Stomatology , Guangzhou, People's Republic of China
| | - Jiaxuan Lu
- 1 Department of Periodontology, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-Sen University , Guangzhou, People's Republic of China .,2 Department of Regenerative Medicine, Guangdong Provincial Key Laboratory of Stomatology , Guangzhou, People's Republic of China
| | - Wei Teng
- 1 Department of Periodontology, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-Sen University , Guangzhou, People's Republic of China .,2 Department of Regenerative Medicine, Guangdong Provincial Key Laboratory of Stomatology , Guangzhou, People's Republic of China
| | - Chuanjiang Zhao
- 1 Department of Periodontology, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-Sen University , Guangzhou, People's Republic of China .,2 Department of Regenerative Medicine, Guangdong Provincial Key Laboratory of Stomatology , Guangzhou, People's Republic of China
| | - Xiaolei Ye
- 3 Department of Pharmacology, Ningbo Institute of Medical Sciences, Ningbo University , Ningbo, People's Republic of China
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Fadzan M, Bettany-Saltikov J. Etiological Theories of Adolescent Idiopathic Scoliosis: Past and Present. Open Orthop J 2017; 11:1466-1489. [PMID: 29399224 PMCID: PMC5759107 DOI: 10.2174/1874325001711011466] [Citation(s) in RCA: 78] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Revised: 09/01/2017] [Accepted: 09/11/2017] [Indexed: 12/11/2022] Open
Abstract
Adolescent idiopathic scoliosis is one of the most common spinal deformities, yet its cause is unknown. Various theories look to biomechanical, neuromuscular, genetic, and environmental origins, yet our understanding of scoliosis etiology is still limited. Determining the cause of a disease is crucial to developing the most effective treatment. Associations made with scoliosis do not necessarily point to causality, and it is difficult to determine whether said associations are primary (playing a role in development) or secondary (develop as a result of scoliosis). Scoliosis is a complex condition with highly variable expression, even among family members, and likely has many causes. These causes could be similar among homogenous groups of AIS patients, or they could be individual. Here, we review the most prevalent theories of scoliosis etiology and recent trends in research.
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Affiliation(s)
- Maja Fadzan
- Scoliosis 3DC, 3 Baldwin Green Common, Suite 204, Woburn, MA 01801, USA
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Genetic Polymorphism of NUCKS1 Is Associated With the Susceptibility of Adolescent Idiopathic Scoliosis. Spine (Phila Pa 1976) 2017; 42:1629-1634. [PMID: 28338576 DOI: 10.1097/brs.0000000000002167] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
STUDY DESIGN A genetic association study. OBJECTIVE The aim of this study was to investigate whether NUCKS1 is a susceptible gene of adolescent idiopathic scoliosis (AIS) in Chinese population and to further narrate its association with the clinical phenotypes. SUMMARY OF BACKGROUND DATA AIS is characterized by late onset of menarche and disturbed growth rhythm. Previous studies showed that NUCKS1 is associated with age at menarche and pubertal height growth. METHODS Single-nucleotide polymorphism rs951366 of NUCKS1 was genotyped in 972 patients and 1454 healthy controls. The differences of genotype and allele distributions between AIS patients and healthy controls were evaluated using the χ test. One-way analysis of variance test was used to compare the relationship between different genotypes and clinical features including tissue expression of NUCKS1, age at menarche, and curve magnitude. RESULTS Patients were found to have a significantly lower frequency of CC than the controls (5.9% vs. 10.6%, P < 0.001). Besides, the frequency of allele C was found to be remarkably lower in the patients than the controls (26.4% vs. 30.9%, P < 0.001), with an odds ratio of 0.80 (95% confidential interval = 0.71-0.91). Patients with genotype CC had a remarkably lower age at menarche than patients with genotype TT (12.1 ± 1.7 vs. 12.8 ± 2.4 years, P = 0.02). Patients with genotype TT had a remarkably lower expression level of NUCKS1 than patients with genotype CC (2.8 ± 1.9 vs. 4.3 ± 2.2, P = 0.03). As for curve magnitude, no significant difference was found among patients with different genotypes. CONCLUSION Patients with allele T of rs951366 can be more vulnerable to the incidence of AIS as well as a late onset of menarche. Further functional analysis is warranted for a comprehensive knowledge on the contribution of this variant to the development of AIS. LEVEL OF EVIDENCE 4.
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Quantitative evaluation of the relationship between COMP promoter methylation and the susceptibility and curve progression of adolescent idiopathic scoliosis. EUROPEAN SPINE JOURNAL : OFFICIAL PUBLICATION OF THE EUROPEAN SPINE SOCIETY, THE EUROPEAN SPINAL DEFORMITY SOCIETY, AND THE EUROPEAN SECTION OF THE CERVICAL SPINE RESEARCH SOCIETY 2017; 27:272-277. [DOI: 10.1007/s00586-017-5309-y] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Revised: 08/12/2017] [Accepted: 09/20/2017] [Indexed: 01/26/2023]
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Association of IL-6 and MMP-3 gene polymorphisms with susceptibility to adolescent idiopathic scoliosis: a meta-analysis. J Genet 2017; 95:573-9. [PMID: 27659327 DOI: 10.1007/s12041-016-0665-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Recently, several institutions have investigated the associations of MMP-3-1171 5A/6A and IL-6-174-G/C gene polymorphisms with adolescent idiopathic scoliosis (AIS), while reports from different institutions are not consistent. Therefore, we, comprehensively and systematically performed this meta-analysis to detect whether the two gene polymorphisms are correlated with AIS. From January 1994 to October 2015, all case-control studies focussed on the relationship between the two aforementioned gene polymorphisms and the susceptibility to AIS were retrieved from bibliographic databases. A total of 16 articles were found, of which five consisted of 944 cases and 1177 controls, were finally included after being assessed by two reviewers. We calculated the pooled odds ratio (OR) with 95% confidence interval (95% CI) to assess the associations. The pooled data analyses were based on allele contrast, homozygote, heterozygote, dominant and recessive models. Overall, there was no significant association of IL-6-174-G/C gene polymorphism with AIS risk. Significant association was observed in homozygote model of MMP-3-1171-5A/6A gene polymorphism (5A5A versus 6A6A: OR = 1.69, 95% CI = 1.11-2.58, P = 0.02). When stratified into Caucasian and Asian populations, positive association was found in Caucasian population (5A versus 6A: OR = 1.43, 95% CI = 1.11-1.84, P = 0.006; 5A5A versus 6A6A: OR = 1.90, 95% CI = 1.13-3.19, P = 0.015); however, there was no significant association in Asian population. The present study concluded that 5A5A genotype of MMP-3-1171 5A/6A gene polymorphism was associated with AIS, especially in Caucasian population. However, no significant association was detected between IL-6-174-G/C gene polymorphism and AIS.
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Liu Y, Ni C, Li Z, Yang N, Zhou Y, Rong X, Qian M, Chui D, Guo X. Prophylactic Melatonin Attenuates Isoflurane‐Induced Cognitive Impairment in Aged Rats through Hippocampal Melatonin Receptor 2 – cAMP Response Element Binding Signalling. Basic Clin Pharmacol Toxicol 2017; 120:219-226. [PMID: 27515785 DOI: 10.1111/bcpt.12652] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Accepted: 08/03/2016] [Indexed: 11/29/2022]
Affiliation(s)
- Yajie Liu
- Department of Anesthesiology Peking University Third Hospital Beijing China
| | - Cheng Ni
- Department of Anesthesiology Peking University Third Hospital Beijing China
| | - Zhengqian Li
- Department of Anesthesiology Peking University Third Hospital Beijing China
| | - Ning Yang
- Department of Anesthesiology Peking University Third Hospital Beijing China
| | - Yang Zhou
- Department of Anesthesiology Peking University Third Hospital Beijing China
| | - Xiaoying Rong
- Department of Anesthesiology Peking University Third Hospital Beijing China
| | - Min Qian
- Department of Anesthesiology Peking University Third Hospital Beijing China
| | - Dehua Chui
- Neuroscience Research Institute & Department of Neurobiology Peking University Beijing China
| | - Xiangyang Guo
- Department of Anesthesiology Peking University Third Hospital Beijing China
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Zamecnik J, Krskova L, Hacek J, Stetkarova I, Krbec M. Etiopathogenesis of adolescent idiopathic scoliosis: Expression of melatonin receptors 1A/1B, calmodulin and estrogen receptor 2 in deep paravertebral muscles revisited. Mol Med Rep 2016; 14:5719-5724. [DOI: 10.3892/mmr.2016.5927] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Accepted: 10/11/2016] [Indexed: 11/05/2022] Open
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Nikolova ST, Yablanski VT, Vlaev EN, Savov AS, Kremensky IM. Investigation of Predictive Potential of TPH1 Common Polymorphism in Idiopathic Scoliosis. JOURNAL OF CLINICAL AND EXPERIMENTAL INVESTIGATIONS 2016. [DOI: 10.5799/jcei.328607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
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Samaan MC, Missiuna P, Peterson D, Thabane L. Understanding the role of the immune system in adolescent idiopathic scoliosis: Immunometabolic CONnections to Scoliosis (ICONS) study protocol. BMJ Open 2016; 6:e011812. [PMID: 27401365 PMCID: PMC4947809 DOI: 10.1136/bmjopen-2016-011812] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
INTRODUCTION Adolescent idiopathic scoliosis (AIS) affects up to 3% of children around the world. There is limited knowledge of AIS aetiopathogenesis, and this evidence is needed to develop new management strategies. Paraspinal muscle in AIS demonstrates evidence of differential fibrosis based on curve sidedness. Fibrosis is the hallmark of macrophage-driven inflammation and tissue remodelling, yet the mechanisms of fibrosis in paraspinal muscle in AIS are poorly understood. OBJECTIVES The primary objective of this study is to determine the influence of curve sidedness on paraspinal muscle inflammation. Secondary objectives include defining the mechanisms of macrophage homing to muscle, and determining muscle-macrophage crosstalk in muscle fibrosis in AIS. METHODS AND ANALYSIS This is a cross-sectional study conducted in a tertiary paediatric centre in Hamilton, Ontario, Canada. We will recruit boys and girls, 10-17 years of age, who are having surgery to correct AIS. We will exclude children who have an active infection or are on immunosuppressive therapies within 2 weeks of surgery, smokers and pregnant girls. Paraspinal muscle biopsies will be obtained at the start of surgery. Also, blood and urine samples will be collected from participants, who will fill questionnaires about their lifestyle. Anthropometric measures will also be collected including height, weight, waist and hip circumferences. ETHICS AND DISSEMINATION This study has received ethics authorisation by the institutional review board. This work will be published in peer-reviewed journals and will be presented in oral and poster formats at scientific meetings. DISCUSSION This study will explore the mechanisms of paraspinal muscle inflammation, remodelling and fibrosis in AIS. This will help identify pathways and molecules as potential therapeutic targets to treat and prevent AIS. It may also yield markers that predict scoliosis progression and response to treatment in these children.
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Affiliation(s)
- M Constantine Samaan
- Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada
- Division of Pediatric Endocrinology, McMaster Children's Hospital, Hamilton, Ontario, Canada
- Department of Clinical Epidemiology & Biostatistics, McMaster University, Hamilton, Ontario, Canada
| | - Paul Missiuna
- Division of Orthopedics, Department of Surgery, McMaster University, Hamilton, Ontario, Canada
| | - Devin Peterson
- Division of Orthopedics, Department of Surgery, McMaster University, Hamilton, Ontario, Canada
| | - Lehana Thabane
- Department of Clinical Epidemiology & Biostatistics, McMaster University, Hamilton, Ontario, Canada
- Department of Anesthesia, McMaster University, Hamilton, Ontario, Canada
- Centre for Evaluation of Medicines, Hamilton, Ontario, Canada
- Biostatistics unit, St Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada
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Chen C, Xu C, Zhou T, Gao B, Zhou H, Chen C, Zhang C, Huang D, Su P. Abnormal osteogenic and chondrogenic differentiation of human mesenchymal stem cells from patients with adolescent idiopathic scoliosis in response to melatonin. Mol Med Rep 2016; 14:1201-9. [PMID: 27314307 PMCID: PMC4940077 DOI: 10.3892/mmr.2016.5384] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2015] [Accepted: 05/31/2016] [Indexed: 12/11/2022] Open
Abstract
Abnormalities of membranous and endochondral ossification in patients with adolescent idiopathic scoliosis (AIS) remain incompletely understood. To investigate abnormalities in the melatonin signaling pathway and cellular response to melatonin in AIS, a case-control study of osteogenic and chondrogenic differentiation was performed using human mesenchymal stem cells (hMSCs). AIS was diagnosed by physical and radiographic examination. hMSCs were isolated from the bone marrow of patients with AIS and control subjects (n=12 each), and purified by density gradient centrifugation. The expression levels of melatonin receptors (MTs) 1 and 2 were detected by western blotting. Osteogenic and chondrogenic differentiation was induced by culturing hMSCs in osteogenic and chondrogenic media containing vehicle or 50 nM melatonin. Alkaline phosphatase (ALP) activity assays, quantitative glycosaminoglycan (GAG) analysis, and reverse transcription-quantitative polymerase chain reaction analysis were performed. Compared with controls, MT2 demonstrated low expression in the AIS group. Melatonin increased ALP activity, GAG synthesis and upregulated the expression of genes involved in osteogenic and chondrogenic differentiation including, ALP, osteopontin, osteocalcin, runt-related transcription factor 2, collagen type II, collagen type X, aggrecan and sex-determining region Y-box 9 in the normal control hMSCs, but did not affect the AIS groups. Thus, AIS hMSCs exhibit abnormal cellular responses to melatonin during osteogenic and chondrogenic differentiation, which may be associated with abnormal membranous and endochondral ossification, and skeletal growth. These results indicate a potential modulating role of melatonin via the MT2 receptor on abnormal osteogenic and chondrogenic differentiaation in patients with AIS.
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Affiliation(s)
- Chong Chen
- Department of Spine Surgery, The First Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Caixia Xu
- Research Center of Translational Medicine, The First Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Taifeng Zhou
- Department of Spine Surgery, The First Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Bo Gao
- Department of Orthopedic Surgery, Sun Yat‑sen Memorial Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510120, P.R. China
| | - Hang Zhou
- Department of Spine Surgery, The First Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Changhua Chen
- Department of Zoology, School of Life Sciences, Sun Yat‑sen University, Guangzhou, Guangdong 510275, P.R. China
| | - Changli Zhang
- Department of Zoology, School of Life Sciences, Sun Yat‑sen University, Guangzhou, Guangdong 510275, P.R. China
| | - Dongsheng Huang
- Department of Orthopedic Surgery, Sun Yat‑sen Memorial Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510120, P.R. China
| | - Peiqiang Su
- Department of Spine Surgery, The First Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
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Association Study between Promoter Polymorphism of TPH1 and Progression of Idiopathic Scoliosis. J Biomark 2016; 2016:5318239. [PMID: 27293961 PMCID: PMC4884859 DOI: 10.1155/2016/5318239] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2016] [Revised: 04/10/2016] [Accepted: 05/03/2016] [Indexed: 12/02/2022] Open
Abstract
The concept of disease-modifier genes as an element of genetic heterogeneity has been widely accepted and reported. The aim of the current study is to investigate the association between the promoter polymorphism TPH1 (rs10488682) and progression of idiopathic scoliosis (IS) in Eastern European population sample. A total of 105 patients and 210 healthy gender-matched controls were enrolled in this study. The TPH1 promoter polymorphism was genotyped by amplification followed by restriction. The statistical analysis was performed by Fisher's Exact Test. The results indicated that the genotypes and alleles of TPH1 (rs10488682) are not correlated with curve severity, curve pattern, or bracing. Therefore, the examined polymorphic variant could not be considered as a genetic factor with modifying effect of IS. In conclusion, this case-control study revealed no statistically significant association between TPH1 (rs10488682) and progression of IS in Eastern European population sample. These preliminary results should be replicated in extended population studies including larger sample sizes. The identification of molecular markers for IS could be useful for a more accurate prognosis of the risk for a rapid progression of the curve. That would permit early stage treatment of the patient with the least invasive procedures.
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Adolescent idiopathic scoliosis: evidence for intrinsic factors driving aetiology and progression. INTERNATIONAL ORTHOPAEDICS 2016; 40:2075-2080. [PMID: 26961194 DOI: 10.1007/s00264-016-3132-4] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/18/2016] [Accepted: 02/08/2016] [Indexed: 12/22/2022]
Abstract
Adolescent idiopathic scoliosis (AIS) is now considered to be a multifactorial heterogeneous disease, with recent genomic studies supporting the role of intrinsic factors in contributing to the onset of disease pathology and curve progression. Understanding the key molecular signalling pathways by which these intrinsic factors mediate AIS pathology may facilitate the development of pharmacological therapeutics and the identification of predictive markers of progression. The heterogenic nature of AIS has implicated multiple tissue types in the disease pathophysiology, including spinal bone, intervertebral disc and paraspinal muscles. In this review, we highlight some of the mechanisms and intrinsic molecular regulators within these different tissue types and review the evidence for their involvement in AIS pathology.
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Xu L, Sun W, Qin X, Qiu Y, Zhu Z. The TGFB1 gene is associated with curve severity but not with the development of adolescent idiopathic scoliosis: a replication study in the Chinese population. BMC Musculoskelet Disord 2016; 17:15. [PMID: 26758901 PMCID: PMC4711171 DOI: 10.1186/s12891-016-0863-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2015] [Accepted: 01/05/2016] [Indexed: 11/24/2022] Open
Abstract
Background The transforming growth factor beta-1 (TGFB1) gene was recently reported to be a new susceptible gene of adolescent idiopathic scoliosis (AIS) in Russian population. This study aimed to replicate the relationship between the TGFB1 gene and the susceptibility of AIS in a Chinese population, and to further describe its association with the curve severity. Methods A total of 1251 female AIS patients and 994 age-matched healthy controls were included in this study. The rs1800469 of TGFB1 gene was genotyped for all participants using the PCR-based Invader assay. The differences of genotype and allele distributions between AIS patients and healthy controls were assessed using the Chi-square test. One-way ANOVA test was used to compare the mean Cobb angles among patients with different genotypes. Results There was no significant difference in terms of the genotype and the allele frequency between the patients and the controls. The mean Cobb angle was 34.7 ± 11.9° (range 25–61°). Case-only analysis showed that rs1800469 was significantly associated with the curve severity. Patients with genotype TT had remarkably higher curve magnitude (39.1 ± 12.8°) than those with genotype CT (34.8 ± 11.1°) or CC (32.1 ± 10.6°). Conclusions The TGFB1 gene may not be a predisposition gene of AIS in the Chinese population. However, it can play a role in the curve progression of AIS. Replication studies in other ethnic groups are warranted to understand the implication of TGFB1 gene in AIS.
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Affiliation(s)
- Leilei Xu
- Department of Spine Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Zhongshan Road 321, Nanjing, 210008, China
| | - Weixiang Sun
- Department of Spine Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Zhongshan Road 321, Nanjing, 210008, China
| | - Xiaodong Qin
- Department of Spine Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Zhongshan Road 321, Nanjing, 210008, China
| | - Yong Qiu
- Department of Spine Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Zhongshan Road 321, Nanjing, 210008, China
| | - Zezhang Zhu
- Department of Spine Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Zhongshan Road 321, Nanjing, 210008, China.
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Xu L, Huang S, Qin X, Mao S, Qiao J, Qian BP, Qiu Y, Zhu Z. Investigation of the 53 Markers in a DNA-Based Prognostic Test Revealing New Predisposition Genes for Adolescent Idiopathic Scoliosis. Spine (Phila Pa 1976) 2015; 40:1086-1091. [PMID: 25811265 DOI: 10.1097/brs.0000000000000900] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
STUDY DESIGN A genetic association study of 53 single nucleotide polymorphisms (SNPs) with adolescent idiopathic scoliosis (AIS). OBJECTIVE To explore new predisposition genes of AIS in Chinese Han population SUMMARY OF BACKGROUND DATA.: A panel of 53 SNPs were reported to be associated with curve severity of AIS. However, there is still a lack of knowledge concerning the association of these SNPs with the susceptibility of AIS in the Chinese Han population. METHODS A gene-based association study was conducted by genotyping the 53 SNPs of a prognostic test. DNA samples of 990 female patients with AIS and 1188 age-matched healthy controls were analyzed using the polymerase chain reaction-based Invader assay. The χ test was carried out to compare the differences of genotype and allele distributions between patients with AIS and healthy controls. RESULTS A total of 4 SNPs were found to present significant differences in allele or genotype frequencies between the 2 groups. Compared with normal controls, patients were found to have significantly higher allele G of rs12618119 and allele A of rs9945359. Besides, patients were found to have significantly lower allele T of rs4661748 and allele C of rs4782809 than the normal controls. BIN1, CDH13, SETBP1, and SPATA21 genes could be associated with the susceptibility of AIS. CONCLUSION Four new predisposition genes of AIS were identified on the basis of a large-scale case-control study. Putting all these findings together, it suggests that AIS is a multifactorial disease possibly involving different pathways such as development of central neural system and bone formation. Further studies exploring more predisposition gene are essential to illustrate the etiology of AIS and to guide the prevention or prognosis of the disease. LEVEL OF EVIDENCE 3.
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Affiliation(s)
- Leilei Xu
- *Department of Spine Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China; and †Department of Internal Medicine, Affiliated Hospital of Nantong University, Nantong, China
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Yang M, Wei X, Yang W, Li Y, Ni H, Zhao Y, Chen Z, Bai Y, Li M. The polymorphisms of melatonin receptor 1B gene (MTNR1B) (rs4753426 and rs10830963) and susceptibility to adolescent idiopathic scoliosis: a meta-analysis. J Orthop Sci 2015; 20:593-600. [PMID: 25898821 DOI: 10.1007/s00776-015-0725-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2014] [Accepted: 04/03/2015] [Indexed: 12/20/2022]
Abstract
OBJECTIVE To determine whether MTNR1B rs4753426 and rs10830963 polymorphisms are correlated with AIS. Adolescent idiopathic scoliosis (AIS) is the most common form of spinal deformity, while its etiology remains uncertain. Melatonin receptor 1B (MTNR1B) gene polymorphisms have been found to be significantly associated with AIS risk; however, some of these results are controversial. METHODS An systematic online search was performed using PubMed, EMBASE, Web of Science and the Cochrane Library to identify case-control studies investigating the relationship between MTNR1B rs4753426 and rs10830963 polymorphisms and the susceptibility of AIS. The pooled odds ratio (OR) with 95 % confidence interval (95 % CI) was calculated to assess the associations, and subgroup meta-analyses were performed according to the ethnicity of the study populations. RESULTS A total of five studies involving 2395 cases and 3645 controls met the inclusion criteria after assessment by two reviewers. Overall, no significant associations were found between MTNR1B rs4753426 polymorphism and AIS risk (C vs. T: OR = 1.11, 95 % CI 0.94-1.30, P = 0.21; CC vs. TT: OR = 1.15, 95 % CI 0.97-1.36, P = 0.12; CT vs. TT: OR = 1.14, 95 % CI 0.97-1.35, P = 0.10; CC/CT vs. TT: OR = 1.14, 95 % CI 0.98-1.33, P = 0.09; CC vs. CT/TT OR = 1.10, 95 % CI 0.84-1.45, P = 0.48), as well as the MTNR1B rs10830963 polymorphism (G vs. C: OR = 0.99, 95 % CI 0.88-1.12, P = 0.91; GG vs. CC: OR = 0.99, 95 % CI 0.74-1.33, P = 0.96; CG vs. CC: OR = 1.00, 95 % CI 0.84-1.18, P = 0.88; GG/CG vs. CC: OR = 0.99, 95 % CI 0.84-1.17, P = 0.93; GG vs. CG/CC OR = 0.99, 95 % CI 0.75-1.30, P = 0.92). When stratified by ethnicity, there were no significant associations between MTNR1B rs4753426 and MTNR1B rs10830963 polymorphisms and AIS risk in either Asian or Caucasian populations. CONCLUSION MTNR1B rs4753426 and MTNR1B rs10830963 polymorphisms are not obviously associated with risk of AIS in either Asian populations or Caucasian populations.
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Affiliation(s)
- Mingyuan Yang
- Department of Orthopaedics, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai, 200438, People's Republic of China,
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Zhu Z, Xu L, Qiu Y. Current progress in genetic research of adolescent idiopathic scoliosis. ANNALS OF TRANSLATIONAL MEDICINE 2015; 3:S19. [PMID: 26046064 DOI: 10.3978/j.issn.2305-5839.2015.02.04] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Accepted: 02/02/2015] [Indexed: 11/14/2022]
Abstract
Previous genetic linkage analysis and candidate gene association analysis have unveiled dozens of variants associated with the development of adolescent idiopathic scoliosis (AIS), which however can seldom be replicated in different ethnics. Recently, two genome-wide association studies of AIS performed in Japan revealed that ladybird homeobox 1 (LBX1) gene and G protein-coupled receptor 126 (GPR126) gene could play a role in the etiopathogenesis of the disease. Since the association between these two genes and AIS were successfully validated in the Caucasian and the Chinese population, LBX1 gene and GPR126 gene were the most reliable genetic variants underling the development of AIS.
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Affiliation(s)
- Zezhang Zhu
- Spine Surgery, Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China
| | - Leilei Xu
- Spine Surgery, Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China
| | - Yong Qiu
- Spine Surgery, Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China
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Xu JF, Yang GH, Pan XH, Zhang SJ, Zhao C, Qiu BS, Gu HF, Hong JF, Cao L, Chen Y, Xia B, Bi Q, Wang YP. Association of GPR126 gene polymorphism with adolescent idiopathic scoliosis in Chinese populations. Genomics 2014; 105:101-7. [PMID: 25479386 DOI: 10.1016/j.ygeno.2014.11.009] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2014] [Revised: 10/19/2014] [Accepted: 11/16/2014] [Indexed: 11/27/2022]
Abstract
Idiopathic scoliosis is the most common pediatric spinal deformity affecting 1% to 3% of the population, and adolescent idiopathic scoliosis (AIS) accounts for approximately 80% of these cases; however, the etiology and pathogenesis of AIS are still uncertain. The current study aims to identify the relationship between G protein-coupled receptor 126 (GPR126) gene and AIS predisposition, to identify the relationship between the genotypes of the GPR126 SNPs and the clinical phenotypes of AIS. We conducted a case-control study and genotyped twenty SNPs of GPR126 gene including ten exonic SNPs and ten intronic polymorphisms in 352 Chinese sporadic AIS patients and 149 healthy controls. We provided evidence for strong association of three intronic SNPs of the GPR126 gene with AIS susceptibility: rs6570507 A > G (p =0 .0035, OR = 1.729), rs7774095 A > C (p = 0.0078, OR = 1.687), and rs7755109 A > G (p = 0.0078, OR = 1.687). However, we did not identify any significant association between ten exonic SNPs of GPR126 and AIS. Linkage disequilibrium analysis indicated that rs7774095 A > C and rs7755109 A > G could be parsed into one block. The association between the intronic haplotype and AIS was further confirmed in an independent population with 110 AIS individuals and 130 healthy controls (p = 0.046, OR = 1.680). Furthermore, molecular mechanisms underlying intronic SNP regulation of GPR126 gene were studied. Although intronic SNPs associated with AIS didn't influence GPR126 mRNA alternative splicing, there was a strong association of rs7755109 A > G with decreased GPR126 mRNA level and protein levels. Our findings indicate that genetic variants of GPR126 gene are associated with AIS susceptibility in Chinese populations. The genetic association of GPR126 gene and AIS might provide valuable insights into the pathogenesis of adolescent idiopathic scoliosis.
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Affiliation(s)
- Ji-Feng Xu
- Department of Orthopedics and Joint Surgery, Zhejiang Provincial People's Hospital, Hangzhou 310014, PR China.
| | - Guang-hai Yang
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PR China
| | - Xiao-Hong Pan
- Department of Cardiolopy, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, PR China
| | - Shui-Jun Zhang
- Department of Orthopedics and Joint Surgery, Zhejiang Provincial People's Hospital, Hangzhou 310014, PR China
| | - Chen Zhao
- Department of Orthopedics and Joint Surgery, Zhejiang Provincial People's Hospital, Hangzhou 310014, PR China
| | - Bin-Song Qiu
- Department of Orthopedics and Joint Surgery, Zhejiang Provincial People's Hospital, Hangzhou 310014, PR China
| | - Hai-Feng Gu
- Department of Orthopedics and Joint Surgery, Zhejiang Provincial People's Hospital, Hangzhou 310014, PR China
| | - Jian-Fei Hong
- Department of Orthopedics and Joint Surgery, Zhejiang Provincial People's Hospital, Hangzhou 310014, PR China
| | - Li Cao
- Department of Orthopedics and Joint Surgery, Zhejiang Provincial People's Hospital, Hangzhou 310014, PR China
| | - Yu Chen
- Department of Orthopedics and Joint Surgery, Zhejiang Provincial People's Hospital, Hangzhou 310014, PR China
| | - Bing Xia
- Department of Orthopedics and Joint Surgery, Zhejiang Provincial People's Hospital, Hangzhou 310014, PR China
| | - Qin Bi
- Department of Orthopedics and Joint Surgery, Zhejiang Provincial People's Hospital, Hangzhou 310014, PR China
| | - Ya-Ping Wang
- Department of Cardiolopy, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, PR China.
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Abstract
BACKGROUND The melatonin deficiency hypothesis as a central mechanism in the pathogenesis of adolescent idiopathic scoliosis (AIS) is certainly intriguing. However, the actual role of melatonin remains unclear. The aim of this study was to assess the potential clinical value of melatonin serum level in the pathogenesis and the prognosis of AIS progression in patients who were treated nonoperatively. METHODS Two groups of patients were enrolled. The study group consisted of patients with AIS aged below 14 years who were treated conservatively. In the second group, that is, the control group, age-matched, weight-matched, and height-matched healthy individuals were enrolled. Blood samples were collected from all patients on visit 1 and the serum levels of melatonin were evaluated with the enzyme-linked immunosorbent assay (ELISA) method. The blood sampling procedure was repeated exactly 1 year later (visit 2). RESULTS Forty-two patients formed the study group (with AIS) and 29 served as the control group. The mean serum value of melatonin on visit 1 was 19.32 pg/mL for the AIS group and 12.23 pg/mL for the control group. This difference was statistically significant (P = 0.014). One year later, 34 patients from the AIS group and 23 from the control group were reevaluated and the mean serum levels of melatonin were 52.43 and 68.44 pg/mL, respectively. No statistically significant difference was found between the 2 groups (P = 0.235). Statistical analysis of the serum melatonin levels of patients with progressing AIS (>5 degrees of the Cobb angle in 1 y) when compared with patients with stable AIS (P = 0.387) or the control group (P = 0.727) failed to show that the deficiency of melatonin may be associated with the progression of AIS. CONCLUSIONS Higher melatonin levels were observed in conservatively treated patients with AIS, whereas melatonin deficiency was not associated with AIS progression in this study. LEVEL OF EVIDENCE Level III-case-control study.
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Abnormal response of the proliferation and differentiation of growth plate chondrocytes to melatonin in adolescent idiopathic scoliosis. Int J Mol Sci 2014; 15:17100-14. [PMID: 25257530 PMCID: PMC4200781 DOI: 10.3390/ijms150917100] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2014] [Revised: 09/02/2014] [Accepted: 09/19/2014] [Indexed: 02/05/2023] Open
Abstract
Abnormalities in the melatonin signaling pathway and the involvement of melatonin receptor MT2 have been reported in patients with adolescent idiopathic scoliosis (AIS). Whether these abnormalities were involved in the systemic abnormal skeletal growth in AIS during the peripubertal period remain unknown. In this cross-sectional case-control study, growth plate chondrocytes (GPCs) were cultured from twenty AIS and ten normal control subjects. Although the MT2 receptor was identified in GPCs from both AIS and controls, its mRNA expression was significantly lower in AIS patients than the controls. GPCs were cultured in the presence of either the vehicle or various concentrations of melatonin, with or without the selective MT2 melatonin receptor antagonist 4-P-PDOT (10 µM). Then the cell viability and the mRNA expression of collagen type X (COLX) and alkaline phosphatase (ALP) were assessed by MTT and qPCR, respectively. In the control GPCs, melatonin at the concentrations of 1, 100 nM and 10 µM significantly reduced the population of viable cells, and the mRNA level of COLX and ALP compared to the vehicle. Similar changes were not observed in the presence of 4-P-PDOT. Further, neither proliferation nor differentiation of GPCs from AIS patients was affected by the melatonin treatment. These findings support the presence of a functional abnormality of the melatonin signaling pathway in AIS GPCs, which might be associated with the abnormal endochondral ossification in AIS patients.
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Yang M, Li C, Li M. The estrogen receptor α gene (XbaI, PvuII) polymorphisms and susceptibility to idiopathic scoliosis: a meta-analysis. J Orthop Sci 2014; 19:713-21. [PMID: 24961754 DOI: 10.1007/s00776-014-0597-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2014] [Accepted: 06/10/2014] [Indexed: 11/29/2022]
Abstract
STUDY DESIGN A genetic association meta-analysis of estrogen receptor α gene (ERα) polymorphisms with idiopathic scoliosis. OBJECTIVE To determine whether the ERα gene polymorphisms correlate with idiopathic scoliosis. Idiopathic scoliosis represents a complex genetic trait under the influence of multiple predisposition genes. Several studies showed that single nucleotide polymorphism (SNP) in ERα was associated with idiopathic scoliosis, but the results from some studies were conflicting. METHODS We searched PubMed, EMBASE, and Cochrane CENTRAL databases from January 1994 to January 2014. All the case-control studies included should mainly study the relationship between XbaI A/G, PvuII T/C polymorphisms and the susceptibility of idiopathic scoliosis. RESULTS A total of 299 articles were found, six of which fulfilled the inclusion criteria after being assessed by two reviewers. A pooled odds ratio (OR) with 95% confidence interval (95% CI) was calculated to assess the associations. Subgroup meta-analyses were performed according to ethnicity. Overall, ERα Xbal A/G polymorphism was not associated with risk of idiopathic scoliosis (G versus A, OR 1.07, 95% CI 0.88-1.30, P = 0.51; AG versus AA, OR 1.03, 95% CI 0.89-1.21, P = 0.67; GG versus AA, OR 1.12, 95% CI 0.72-1.73, P = 0.61; AG/GG versus AA, OR 1.05, 95% CI 0.91-1.22, P = 0.49; GG versus AG/AA, OR 1.10, 95% CI 0.75-1.63, P = 0.62). ERα PvuII T/C polymorphism was also not associated with risk of idiopathic scoliosis under five models (C versus T, OR 0.93, 95% CI 0.75-1.14, P = 0.48; TC versus TT, OR 0.99, 95% CI 0.80-1.23, P = 0.93; CC versus TT, OR 1.05, 95% CI 0.80-1.39, P = 0.72; TC/CC versus TT, OR 1.01, 95% CI 0.83-1.23, P = 0.93; CC versus TC/TT, OR 1.05, 95% CI 0.82-1.33, P = 0.72). CONCLUSION ERα Xbal and ERα PvuII polymorphisms are not obviously associated with risk of idiopathic scoliosis.
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Affiliation(s)
- Mingyuan Yang
- Department of Orthopaedics, Changhai Hospital, 168 Changhai Road, Shanghai, 200438, People's Republic of China,
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Association Between rs11190870 Polymorphism Near LBX1 and Susceptibility to Adolescent Idiopathic Scoliosis in East Asian Population: A Genetic Meta-Analysis. Spine (Phila Pa 1976) 2014; 39:862-869. [PMID: 24583738 DOI: 10.1097/brs.0000000000000303] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
STUDY DESIGN Meta-analysis to collect all the relevant studies to date to further investigate whether or not the rs11190870 polymorphism is associated with susceptibility to adolescent idiopathic scoliosis (AIS) in East Asian population. OBJECTIVE To investigate whether or not the rs11190870 polymorphism is associated with susceptibility to AIS in East Asian population. SUMMARY OF BACKGROUND DATA To date, the single nucleotide polymorphism rs11190870 was identified as the most significant common variant in Japanese females. Three association studies conducted in Chinese Han population from Hong Kong, Yangtze River region, and Southern region of mainland China replicated the association between AIS and rs1190870. However, there is limited published data about the association of rs11190870 with AIS in East Asian population. METHODS A systematic search of all relevant studies published through August 2013 was conducted using the MEDLINE, EMBASE, OVID, and ScienceDirect. Single nucleotide polymorphism of rs11190870 was evaluated. The included studies were assessed in the analysis of the following allele model: T allele versus C allele for the allele-level comparison; (b) TC + TT versus CC for dominant model of T allele; (c) TT versus TC + CC for recessive model of T allele, and (d) TT versus CC for extreme genotype. RESULTS Four studies with 8415 total participants (2889 patients with AIS and 5526 controls), who were all East Asian population, were eligible for inclusion. We searched for genotypes T allele versus C allele, TT versus TC + CC, TC + TT versus CC, and TT versus CC in a fixed/random-effects model. The effect summary odds ratios and 95 % confidence intervals were obtained, which shows significant association between rs11190870 and AIS in East Asian populations (all genetic models P < 0.001). Subgroup analyses were conducted according to sex. The results showed a significant association between rs11190870 and AIS in female (all genetic models, P < 0.001) but not in male (all genetic models, P > 0.05). CONCLUSION The present meta-analysis demonstrated that the T allele of single nucleotide polymorphism rs11190870 may be a major susceptibility locus in the East Asian population with AIS, especially in female. LEVEL OF EVIDENCE 1.
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Ultrastructure of Intervertebral Disc and Vertebra-Disc Junctions Zones as a Link in Etiopathogenesis of Idiopathic Scoliosis. ACTA ACUST UNITED AC 2014. [DOI: 10.1155/2014/850594] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Background Context. There is no general accepted theory on the etiology of idiopathic scoliosis (IS). An important role of the vertebrae endplate physes (VEPh) and intervertebral discs (IVD) in spinal curve progression is acknowledged, but ultrastructural mechanisms are not well understood. Purpose. To analyze the current literature on ultrastructural characteristics of VEPh and IVD in the context of IS etiology. Study Design/Setting. A literature review. Results. There is strong evidence for multifactorial etiology of IS. Early wedging of vertebra bodies is likely due to laterally directed appositional bone growth at the concave side, caused by a combination of increased cell proliferation at the vertebrae endplate and altered mechanical properties of the outer annulus fibrosus of the adjacent IVD. Genetic defects in bending proteins necessary for IVD lamellar organization underlie altered mechanical properties. Asymmetrical ligaments, muscular stretch, and spine instability may also play roles in curve formation. Conclusions. Development of a reliable, cost effective method for identifying patients at high risk for curve progression is needed and could lead to a paradigm shift in treatment options. Unnecessary anxiety, bracing, and radiation could potentially be minimized and high risk patient could receive surgery earlier, rendering better outcomes with fewer fused segments needed to mitigate curve progression.
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Qiu XS, Lv F, Zhu ZZ, Qian BP, Wang B, Yu Y, Qiu Y. Lack of association between the CHL1 gene and adolescent idiopathic scoliosis susceptibility in Han Chinese: a case-control study. BMC Musculoskelet Disord 2014; 15:38. [PMID: 24512353 PMCID: PMC3925962 DOI: 10.1186/1471-2474-15-38] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2013] [Accepted: 02/06/2014] [Indexed: 11/20/2022] Open
Abstract
Background A previous genome-wide association study (GWAS) suggested a strong association between the single nucleotide polymorphism (SNP) rs10510181 in the proximity of the gene encoding a cell adhesion molecule with homology to L1CAM (CHL1) and adolescent idiopathic scoliosis (AIS) in Caucasians. To clarify the role of CHL1 in the etiopathogenesis of AIS, we performed a case-control replication study in a Han Chinese population. Methods Five hundred female AIS patients between 10 and 18 years of age, as well as 500 age- and sex-matched controls were included. This study was conducted as a 2-stage case-control analysis: initial screening for the association between AIS and SNPs in and around the CHL1 gene (186 cases and 169 controls) followed by a confirmation test (314 cases and 331 controls). rs10510181 and 4 SNPs (rs2055314, rs331894, rs2272522, and rs2272524) in the CHL1 gene were selected for genotyping. Results Putative associations were shown between AIS and rs10510181, rs2055314, and rs2272522 in stage I. However, the associations were not confirmed in stage II. For rs10510181, the genotype frequencies were GG 28.8%, GA 46.2%, and AA 25.0% in AIS patients and GG 29.8%, GA 48.8%, and AA 21.4% in controls. No significant difference was found in genotype distribution between cases and controls (P = 0.39). Similarly, the genotype and allele distribution were comparable between case and control for rs2055314 and rs2272522. Conclusions There was no statistical association between polymorphisms of the CHL1 gene and idiopathic scoliosis in a Chinese population.
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Affiliation(s)
| | | | | | | | | | | | - Yong Qiu
- Spine Surgery, Drum Tower Hospital, Nanjing University Medical School, Nanjing, China.
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The association study of calmodulin 1 gene polymorphisms with susceptibility to adolescent idiopathic scoliosis. BIOMED RESEARCH INTERNATIONAL 2014; 2014:168106. [PMID: 24551838 PMCID: PMC3914287 DOI: 10.1155/2014/168106] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/20/2013] [Accepted: 11/27/2013] [Indexed: 12/19/2022]
Abstract
Objective. Idiopathic scoliosis is the most common pediatric spinal deformity affecting 1% to 3% of the population, and adolescent idiopathic scoliosis (AIS) accounts for approximately 80% of these cases; however, the etiology and pathogenesis of AIS are still uncertain. The current study aims to identify the relationship between calmodulin 1 (CALM1) gene and AIS predisposition, to identify the relationship between the genotypes of the SNPs and the clinical phenotypes of AIS. Methods. 146 AIS patients and 146 healthy controls were enrolled into this case-control study. 12 single nucleotide polymorphisms (SNPs) candidates in CALM1 gene were selected to determine the relationship between CALM1 gene and AIS predisposition. Case-only study was performed to determine the effects of these variants on the severity of the condition. Results. Three SNPs from 12 candidates were found to be associated with AIS predisposition. The ORs were observed as 0.549 (95% CI 0.3519–0.8579, P = 0.0079), 0.549 (95% CI 0.3519–0.8579, P = 0.0079), and 1.6139 (95% CI 1.0576–2.4634, P = 0.0257) for rs2300496, rs2300500, and rs3231718, respectively. There was no statistical difference between main curve, severity, and genotype distributions of all of 12 SNPs. Conclusion. Genetic variants of CALM1 gene are associated with AIS susceptibility.
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Comai S, Gobbi G. Unveiling the role of melatonin MT2 receptors in sleep, anxiety and other neuropsychiatric diseases: a novel target in psychopharmacology. J Psychiatry Neurosci 2014; 39:6-21. [PMID: 23971978 PMCID: PMC3868666 DOI: 10.1503/jpn.130009] [Citation(s) in RCA: 113] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Melatonin (MLT) is a pleiotropic neurohormone controlling many physiological processes and whose dysfunction may contribute to several different diseases, such as neurodegenerative diseases, circadian and mood disorders, insomnia, type 2 diabetes and pain. Melatonin is synthesized by the pineal gland during the night and acts through 2 G-protein coupled receptors (GPCRs), MT1 (MEL1a) and MT2 (MEL1b). Although a bulk of research has examined the physiopathological effects of MLT, few studies have investigated the selective role played by MT1 and MT2 receptors. Here we have reviewed current knowledge about the implications of MT2 receptors in brain functions. METHODS We searched PubMed, Web of Science, Scopus, Google Scholar and articles' reference lists for studies on MT2 receptor ligands in sleep, anxiety, neuropsychiatric diseases and psychopharmacology, including genetic studies on the MTNR1B gene, which encodes the melatonin MT2 receptor. RESULTS These studies demonstrate that MT2 receptors are involved in the pathophysiology and pharmacology of sleep disorders, anxiety, depression, Alzheimer disease and pain and that selective MT2 receptor agonists show hypnotic and anxiolytic properties. LIMITATIONS Studies examining the role of MT2 receptors in psychopharmacology are still limited. CONCLUSION The development of novel selective MT2 receptor ligands, together with further preclinical in vivo studies, may clarify the role of this receptor in brain function and psychopharmacology. The superfamily of GPCRs has proven to be among the most successful drug targets and, consequently, MT2 receptors have great potential for pioneer drug discovery in the treatment of mental diseases for which limited therapeutic targets are currently available.
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Affiliation(s)
| | - Gabriella Gobbi
- Correspondence to: G. Gobbi, Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University, 1033 Pine Ave. W, room 220, Montréal QC H3A 1A1;
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Yee A, Song YQ, Chan D, Cheung KMC. Understanding the Basis of Genetic Studies: Adolescent Idiopathic Scoliosis as an Example. Spine Deform 2014; 2:1-9. [PMID: 27927437 DOI: 10.1016/j.jspd.2013.09.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2013] [Revised: 08/24/2013] [Accepted: 09/01/2013] [Indexed: 12/31/2022]
Abstract
STUDY DESIGN A review of the general concepts of genetics studies with specific reference to adolescent idiopathic scoliosis (AIS). OBJECTIVES To equip the average spine surgeon with the vocabulary and understanding needed to understand the genetics of scoliosis and the approaches used to identify risk genes. SUMMARY OF BACKGROUND DATA Adolescent idiopathic scoliosis is a multifactorial disease. Increasing evidence from families and monozygotic twins suggests the involvement of genetic factors. An estimation of heritability also indicates a strong influence of genetics on the disease. Increasing focus has been placed on identifying genes and genetic variants associated with AIS. REVIEW This is a review of genes and genetic variations, the phenotype definition of AIS in genetics studies, concepts and approaches to identifying associated genes, and the evaluation of results. Different types of genetic variations are present in the genome. These variations may modulate the expression or function of protein products, which in turn alter individuals' susceptibility to disease. Identifying the variants related to AIS requires an objective and clearly defined phenotype, among which the Cobb angle is commonly used. The phenotype helps classify subjects into cases and controls. By selecting candidate genes of growth factors and hormonal receptors, which are speculated to be involved in the mechanism of disease, the variants within these genes were compared between cases and controls to identify any differences. Another approach was to use large families and inspect the co-segregation of variants and phenotypes. Recently, arrays covering the variants of the whole genome were developed and assist in high-throughput screening for associated genes. CONCLUSIONS Genetic factors have an important role in AIS. Deciphering the genes and genetic variants associated with AIS can improve our understanding of the mechanisms of the disease, as well as assist in designing treatment methods and preventive measures.
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Affiliation(s)
- Anita Yee
- Department of Biochemistry, University of Hong Kong, 3/F Laboratory Block, LKS Faculty of Medicine, 21 Sassoon Road, Pokfulam, Hong Kong, China
| | - You-Qiang Song
- Department of Biochemistry, University of Hong Kong, 3/F Laboratory Block, LKS Faculty of Medicine, 21 Sassoon Road, Pokfulam, Hong Kong, China
| | - Danny Chan
- Department of Biochemistry, University of Hong Kong, 3/F Laboratory Block, LKS Faculty of Medicine, 21 Sassoon Road, Pokfulam, Hong Kong, China
| | - Kenneth M C Cheung
- Department of Orthopaedics and Traumatology, 5/F Professorial Block, Queen Mary Hospital, University of Hong Kong, Pokfulam, Hong Kong, China.
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Aota Y, Terayama H, Saito T, Itoh M. Pinealectomy in a broiler chicken model impairs endochondral ossification and induces rapid cancellous bone loss. Spine J 2013; 13:1607-16. [PMID: 23791240 DOI: 10.1016/j.spinee.2013.05.017] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2012] [Revised: 09/30/2012] [Accepted: 05/04/2013] [Indexed: 02/03/2023]
Abstract
BACKGROUND CONTEXT Adolescent idiopathic scoliosis (AIS) in humans is a lateral curvature of the spine often associated with osteopenia. It has recently been accepted that the development of AIS is closely associated with spinal overgrowth. Pinealectomy (PNX) in a chicken model consistently induces scoliosis with anatomic features similar to human AIS; however, the mechanism of PNX inducing scoliosis is poorly understood. PURPOSE This experimental study attempts to improve the understanding of the mechanisms underlying the onset of scoliosis in a PNX broiler chicken model. METHODS A histomorphometric study was performed to analyze longitudinal bone growth and cancellous bone remodeling before the development of scoliosis. Static and dynamic parameters in cancellous bone and chondro-osseous junction of the 7th thoracic vertebral body at 9 days after hatching were compared between PNX chickens (n=9) and control chickens with no surgery (n=5). RESULTS PNX resulted in a rapid and marked loss of cancellous bone volume (7.9±0.9% vs. 14.2±1.8%, mean±SD, p<.0005) and profoundly disrupted trabecular structure with increases in dynamic formative parameters, such as mineralizing surface, mineralization apposition rate, and adjusted appositional rate. In the chondro-osseous junction, activated osteoclasts phagocytized degenerating chondrocytes, leaving a minimal amount of cartilage matrix and activated osteoblasts, losing their scaffolding for bone formation, and directly covering the hypertrophic zone cells. The osteoid surface and thickness in the chondro-osseous junction were significantly increased in PNX chickens (43.1±14.2% vs. 11.6±5.7% and 4.1±0.2 μm vs. 2.9±0.4 μm). In the subjacent cartilage regions being protected from further resorption, abundant labeled cartilage remained with higher cellularity. CONCLUSIONS It is known that fast-growing birds have a unique paradigm of rapid bone elongation with minimal metaphyseal bone production. A bone-forming surface exists at the front of cartilage ossification in the growth plate; therefore, papillae of hypertrophic chondrocytes become included between the trabeculae of metaphyseal bone and the overall thickness of the growth plate increases considerably in addition to distal expansion. Our results indicate that the unique mechanism for rapid bone elongation in chicken is more pronounced after PNX. PNX also induces high turnover osteoporosis, which may also contribute to the development of scoliosis in the chicken.
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Affiliation(s)
- Yoichi Aota
- Department of Orthopaedic Surgery, Yokohama City University Hospital, 3-9 Fukuura, Kanazawa-ku, Yokohama City, Kanagawa Prefecture, Yokohama 236-0004, Japan.
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Selective estrogen receptor modulation prevents scoliotic curve progression: radiologic and histomorphometric study on a bipedal C57Bl6 mice model. EUROPEAN SPINE JOURNAL : OFFICIAL PUBLICATION OF THE EUROPEAN SPINE SOCIETY, THE EUROPEAN SPINAL DEFORMITY SOCIETY, AND THE EUROPEAN SECTION OF THE CERVICAL SPINE RESEARCH SOCIETY 2013; 23:455-62. [PMID: 24136418 DOI: 10.1007/s00586-013-3072-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/01/2013] [Revised: 10/11/2013] [Accepted: 10/11/2013] [Indexed: 10/26/2022]
Abstract
PURPOSE Previous work has suggested that progression of experimental scoliotic curves in pinealectomized chicken and bipedal C57BL6 mice models may be prevented and reversed with Tamoxifen treatment. Raloxifene is another Selective Estrogen Receptor Modulator (SERM) with estrogen agonist effects on bone and increases bone density but with fewer side effects on humans. To investigate whether scoliosis progression in bipedal C57Bl6 mice model could be prevented with SERM treatment and the mechanisms associated with this effect. METHODS Eighty C57BL6 mice were rendered bipedal and divided into Tamoxifen (TMX), Raloxifene (RLX) and control groups. TMX and RLX groups received orally administered TMX and RLX for 40 weeks. Anteroposterior X-ray imaging and histomorphometric analysis (at 20th and 40th weeks) were performed. RESULTS At 20th week, TMX and RLX groups displayed higher rates (p = 0.033, p = 0.029) and larger curve magnitudes (p = 0.018). At 40th week, curve rates were similar between the groups but the curve magnitudes in TMX and RLX groups were smaller (p = 0.001). Histomorphometry revealed that treated animals had higher trabecular density (p = 0.04), lower total intervertebral disc (p = 0.038) and growth plate volumes (p = 0.005) and smaller vertebral bodies (p = 0.016). CONCLUSIONS Treatment with TMX or RLX did not reduce the incidence of scoliosis but decreased the curve magnitudes at 40 weeks. The underlying mechanism associated with the decrease in curve magnitudes may be the early maturation of growth plates, thereby possible deceleration of the growth rate of the vertebral column and increase in bone density. RLX is as effective as TMX in preventing the progression of scoliotic curves in melatonin deficient bipedal mice.
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Abstract
STUDY DESIGN Model-independent linkage analysis and tests of association were performed for 22 single nucleotide polymorphisms in the CHD7 gene in 244 families of European descent with familial idiopathic scoliosis (FIS). OBJECTIVE To replicate an association between FIS and the CHD7 gene on 8q12.2 in an independent sample of families of European descent. SUMMARY OF BACKGROUND DATA The CHD7 gene on chromosome 8, responsible for the CHARGE syndrome, was previously associated with FIS in an independent study that included 52 families of European descent. METHODS Model-independent linkage analysis and intrafamilial tests of association were performed on the degree of lateral curvature considered as a qualitative trait (with thresholds of ≥10°, ≥15°, ≥20°, and ≥30°) and as a quantitative trait (degree of lateral curvature). Results from the tests of associations from this study and the previous study were combined in a weighted meta-analysis. RESULTS No significant results (P < 0.01) were found for linkage analysis or tests of association between genetic variants of the CHD7 and FIS in this study, failing to replicate the findings from the previous study. Furthermore, no significant results (P < 0.01) were found from meta-analysis of the results from the tests of association from this sample and from the previous sample. CONCLUSION No association between the 22 genotyped single nucleotide polymorphisms in the CHD7 gene and FIS within this study sample was found, failing to replicate the earlier findings. Further investigation of the CHD7 gene and its potential association to FIS may be required. LEVEL OF EVIDENCE N/A.
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Miyake A, Kou I, Takahashi Y, Johnson TA, Ogura Y, Dai J, Qiu X, Takahashi A, Jiang H, Yan H, Kono K, Kawakami N, Uno K, Ito M, Minami S, Yanagida H, Taneichi H, Hosono N, Tsuji T, Suzuki T, Sudo H, Kotani T, Yonezawa I, Kubo M, Tsunoda T, Watanabe K, Chiba K, Toyama Y, Qiu Y, Matsumoto M, Ikegawa S. Identification of a susceptibility locus for severe adolescent idiopathic scoliosis on chromosome 17q24.3. PLoS One 2013; 8:e72802. [PMID: 24023777 PMCID: PMC3762929 DOI: 10.1371/journal.pone.0072802] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2013] [Accepted: 07/12/2013] [Indexed: 12/22/2022] Open
Abstract
Adolescent idiopathic scoliosis (AIS) is the most common spinal deformity, affecting around 2% of adolescents worldwide. Genetic factors play an important role in its etiology. Using a genome-wide association study (GWAS), we recently identified novel AIS susceptibility loci on chromosomes 10q24.31 and 6q24.1. To identify more AIS susceptibility loci relating to its severity and progression, we performed GWAS by limiting the case subjects to those with severe AIS. Through a two-stage association study using a total of ∼12,000 Japanese subjects, we identified a common variant, rs12946942 that showed a significant association with severe AIS in the recessive model (P = 4.00×10−8, odds ratio [OR] = 2.05). Its association was replicated in a Chinese population (combined P = 6.43×10−12, OR = 2.21). rs12946942 is on chromosome 17q24.3 near the genes SOX9 and KCNJ2, which when mutated cause scoliosis phenotypes. Our findings will offer new insight into the etiology and progression of AIS.
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Affiliation(s)
- Atsushi Miyake
- Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Science, Tokyo, Japan
- Department of Orthopaedic Surgery, School of Medicine, Keio University, Tokyo, Japan
| | - Ikuyo Kou
- Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Science, Tokyo, Japan
| | - Yohei Takahashi
- Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Science, Tokyo, Japan
- Department of Orthopaedic Surgery, School of Medicine, Keio University, Tokyo, Japan
| | - Todd A. Johnson
- Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Science, Yokohama, Japan
| | - Yoji Ogura
- Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Science, Tokyo, Japan
- Department of Orthopaedic Surgery, School of Medicine, Keio University, Tokyo, Japan
| | - Jin Dai
- Department of Orthopaedics, The Center of Diagnosis and Treatment for Joint Disease, Drum Tower Hospital Affiliated to Medical School of Nanjing University, Nanjing, China
| | - Xusheng Qiu
- Department of Spine Surgery, Drum Tower Hospital Affiliated to Medical School of Nanjing University, Nanjing, China
| | - Atsushi Takahashi
- Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Science, Tokyo, Japan
| | - Hua Jiang
- Department of Spine Surgery, Drum Tower Hospital Affiliated to Medical School of Nanjing University, Nanjing, China
| | - Huang Yan
- Department of Spine Surgery, Drum Tower Hospital Affiliated to Medical School of Nanjing University, Nanjing, China
| | - Katsuki Kono
- Scoliosis Center, Saiseikai Central Hospital, Tokyo, Japan
| | - Noriaki Kawakami
- Department of Orthopaedic Surgery, Meijo Hospital, Nagoya, Japan
| | - Koki Uno
- Department of Orthopaedic Surgery, National Hospital Organization, Kobe Medical Center, Kobe, Japan
| | - Manabu Ito
- Department of Advanced Medicine for Spine and Spinal Cord Disorders, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Shohei Minami
- Department of Orthopaedic Surgery, Seirei Sakura Citizen Hospital, Sakura, Japan
| | - Haruhisa Yanagida
- Department of Orthopaedic Surgery, Fukuoka Children's Hospital, Fukuoka, Japan
| | - Hiroshi Taneichi
- Department of Orthopaedic Surgery, Dokkyo Medical University School of Medicine, Mibu, Japan
| | - Naoya Hosono
- Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Science, Yokohama, Japan
| | - Taichi Tsuji
- Department of Orthopaedic Surgery, Meijo Hospital, Nagoya, Japan
| | - Teppei Suzuki
- Department of Orthopaedic Surgery, National Hospital Organization, Kobe Medical Center, Kobe, Japan
| | - Hideki Sudo
- Department of Advanced Medicine for Spine and Spinal Cord Disorders, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Toshiaki Kotani
- Department of Orthopaedic Surgery, Seirei Sakura Citizen Hospital, Sakura, Japan
| | - Ikuho Yonezawa
- Department of Orthopaedic Surgery, Juntendo University School of Medicine, Tokyo, Japan
| | - Michiaki Kubo
- Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Science, Yokohama, Japan
| | - Tatsuhiko Tsunoda
- Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Science, Yokohama, Japan
| | - Kota Watanabe
- Department of Orthopaedic Surgery, School of Medicine, Keio University, Tokyo, Japan
| | - Kazuhiro Chiba
- Department of Orthopaedic Surgery, Kitasato University Kitasato Institute Hospital, Tokyo, Japan
| | - Yoshiaki Toyama
- Department of Orthopaedic Surgery, School of Medicine, Keio University, Tokyo, Japan
| | - Yong Qiu
- Department of Spine Surgery, Drum Tower Hospital Affiliated to Medical School of Nanjing University, Nanjing, China
| | - Morio Matsumoto
- Department of Orthopaedic Surgery, School of Medicine, Keio University, Tokyo, Japan
- * E-mail: (SI); (MM)
| | - Shiro Ikegawa
- Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Science, Tokyo, Japan
- * E-mail: (SI); (MM)
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A replication study for association of 53 single nucleotide polymorphisms in a scoliosis prognostic test with progression of adolescent idiopathic scoliosis in Japanese. Spine (Phila Pa 1976) 2013; 38:1375-9. [PMID: 23591653 DOI: 10.1097/brs.0b013e3182947d21] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
STUDY DESIGN A genetic association study of single nucleotide polymorphisms (SNPs) previously reported to be associated with curve progression of adolescent idiopathic scoliosis (AIS). OBJECTIVE To determine whether the association of 53 SNPs with curve progression reported in white patients with AIS are replicated in Japanese patients with AIS. SUMMARY OF BACKGROUND DATA Predicting curve progression is important in clinical practice of AIS. The progression of AIS is reported to be associated with a number of genes. Associations with 53 SNPs have been reported, and the SNPs are used for a progression test in white patients with AIS; however, there has been no replication study for their association. METHODS We recruited 2117 patients with AIS with 10° or more (Cobb angle) of scoliosis curves. They were divided into progression and nonprogression groups according to their Cobb angle. We defined the progression of the curve as Cobb angle more than 50° for skeletally mature subjects and more than 40° for immature patients, subjects. We defined the nonprogression of the curve as Cobb angle 50° or less only for skeletally mature subjects. Of the 2117 patients, 1714 patients with AIS were allocated to either the progression or nonprogression group. We evaluated the association of 53 SNPs with curve progression by comparing risk allele frequencies between the 2 groups. RESULTS We evaluated the progression (N = 600) and nonprogression (N = 1114) subjects. Their risk allele frequencies were not different significantly. We found no replication of the association on AIS curve progression in any of the SNPs. CONCLUSION The associations of the 53 SNPs with progression of AIS curve are not definite. Large-scale association studies based on appropriate criteria for progression would be necessary to identify SNPs associated with the curve progression. LEVEL OF EVIDENCE N/A.
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