A G protein-coupled receptor is required in cartilaginous and dense connective tissues to maintain spine alignment

SummaryAdolescent idiopathic scoliosis (AIS) is the most common spine disorder affecting children worldwide, yet little is known about the pathogenesis of this disorder. Here, we demonstrate that genetic regulation of structural components of the axial skeleton, the intervertebral discs and dense connective tissues (e.g., ligaments and tendons), are essential for maintenance of spinal alignment. We show that the G-coupled protein receptor Adgrg6, previously implicated in human AIS association studies, is required in these tissues to maintain typical spine morphology. We show that Adgrg6 regulates biomechanical properties of tendon and stimulates CREB signaling governing gene expression in cartilaginous tissues of the spine. Treatment with an cAMP agonist was able to mirror aspects of receptor function in culture defining core pathways for regulation of these axial connective tissues. As ADGRG6 is a key gene involved in human AIS, these findings open up novel therapeutic opportunities for human scoliosis.HighlightsKnockout mice lacking Adgrg6 function in the tendons and ligaments of the spine develop perinatal-onset thoracic scoliosis.Loss of Adgrg6 function in cartilaginous tissues of the discs contribute to the incidence and severity of scoliosis.The loss of Adgrg6 function in spine tissues provide a model of construct validity for human adolescent idiopathic scoliosisFine tuning of the biomechanical properties of dense connective tissues is essential for maintaining spine alignment.

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A G protein-coupled receptor is required in cartilaginous and dense connective tissues to maintain spine alignment

eLife ◽

10.7554/elife.67781 ◽

2021 ◽

Vol 10 ◽

Author(s):

Zhaoyang Liu ◽

Amro A Hussien ◽

Yunjia Wang ◽

Terry Heckmann ◽

Roberto Gonzalez ◽

...

Keyword(s):

G Protein ◽

Association Studies ◽

Genetic Regulation ◽

Biomechanical Properties ◽

Axial Skeleton ◽

Intervertebral Discs ◽

G Protein Coupled Receptor ◽

Connective Tissues ◽

Cartilaginous Tissues ◽

G Protein Coupled

Adolescent idiopathic scoliosis (AIS) is the most common spine disorder affecting children worldwide, yet little is known about the pathogenesis of this disorder. Here, we demonstrate that genetic regulation of structural components of the axial skeleton, the intervertebral discs, and dense connective tissues (i.e., ligaments and tendons) are essential for the maintenance of spinal alignment. We show that the adhesion G protein-coupled receptor ADGRG6, previously implicated in human AIS association studies, is required in these tissues to maintain typical spine alignment in mice. Furthermore, we show that ADGRG6 regulates biomechanical properties of tendon and stimulates CREB signaling governing gene expression in cartilaginous tissues of the spine. Treatment with a cAMP agonist could mirror aspects of receptor function in culture, thus defining core pathways for regulating these axial cartilaginous and connective tissues. As ADGRG6 is a key gene involved in human AIS, these findings open up novel therapeutic opportunities for human scoliosis.

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Genomic characterization of the adolescent idiopathic scoliosis associated transcriptome and regulome

10.1101/2020.03.02.973735 ◽

2020 ◽

Author(s):

Nadja Makki ◽

Jingjing Zhao ◽

Zhaoyang Liu ◽

Walter L. Eckalbar ◽

Aki Ushiki ◽

...

Keyword(s):

Adolescent Idiopathic Scoliosis ◽

Connective Tissue ◽

Idiopathic Scoliosis ◽

Association Studies ◽

Regulatory Elements ◽

Intervertebral Discs ◽

Genome Wide Association Studies ◽

Specific Expression ◽

Enhancer Activity ◽

Genome Wide

AbstractAdolescent idiopathic scoliosis (AIS), a sideways curvature of the spine, is the most common pediatric musculoskeletal disorder, affecting ∼3% of the population worldwide. However, its genetic bases and tissues of origin remain largely unknown. Several genome-wide association studies (GWAS) have implicated nucleotide variants in noncoding sequences that control genes with important roles in cartilage, muscle, bone, connective tissue and intervertebral discs (IVDs) as drivers of AIS susceptibility. Here, we set out to define the expression of AIS-associated genes and active regulatory elements by performing RNA-seq and ChIP-seq against H3K27ac in these tissues in mouse and human. Our study highlights genetic pathways involving AIS-associated loci that regulate chondrogenesis, IVD development and connective tissue maintenance and homeostasis. In addition, we identify thousands of putative AIS-associated regulatory elements which may orchestrate tissue-specific expression in musculoskeletal tissues of the spine. Quantification of enhancer activity of several candidate regulatory elements from our study identifies three functional enhancers carrying AIS-associated GWAS SNPs at the ADGRG6 and BNC2 loci. Our findings provide a novel genome-wide catalog of AIS-relevant genes and regulatory elements and aid in the identification of novel targets for AIS causality and treatment.

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Genomic characterization of the adolescent idiopathic scoliosis associated transcriptome and regulome

Human Molecular Genetics ◽

10.1093/hmg/ddaa242 ◽

2020 ◽

Author(s):

Nadja Makki ◽

Jingjing Zhao ◽

Zhaoyang Liu ◽

Walter L Eckalbar ◽

Aki Ushiki ◽

...

Keyword(s):

Adolescent Idiopathic Scoliosis ◽

Connective Tissue ◽

Idiopathic Scoliosis ◽

Association Studies ◽

Regulatory Elements ◽

Intervertebral Discs ◽

Genome Wide Association Studies ◽

Specific Expression ◽

Enhancer Activity ◽

Genome Wide

Abstract Adolescent idiopathic scoliosis (AIS), a sideways curvature of the spine, is the most common pediatric musculoskeletal disorder, affecting ~ 3% of the population worldwide. However, its genetic bases and tissues of origin remain largely unknown. Several genome-wide association studies (GWAS) have implicated nucleotide variants in noncoding sequences that control genes with important roles in cartilage, muscle, bone, connective tissue and intervertebral discs (IVDs) as drivers of AIS susceptibility. Here, we set out to define the expression of AIS-associated genes and active regulatory elements by performing RNA-seq and ChIP-seq against H3K27ac in these tissues in mouse and human. Our study highlights genetic pathways involving AIS-associated loci that regulate chondrogenesis, IVD development and connective tissue maintenance and homeostasis. In addition, we identify thousands of putative AIS-associated regulatory elements which may orchestrate tissue-specific expression in musculoskeletal tissues of the spine. Quantification of enhancer activity of several candidate regulatory elements from our study identifies three functional enhancers carrying AIS-associated GWAS SNPs at the ADGRG6 and BNC2 loci. Our findings provide a novel genome-wide catalog of AIS-relevant genes and regulatory elements and aid in the identification of novel targets for AIS causality and treatment.

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Adolescent Idiopathic Scoliosis – Future Molecular-Based Diagnostic and Prognostic Testing

Ortopedia Traumatologia Rehabilitacja ◽

10.5604/01.3001.0013.5070 ◽

2019 ◽

Vol 21 (4) ◽

pp. 253-260

Author(s):

Radoslav Zamborský ◽

Boris Liščák ◽

Martin Trepáč ◽

Andrey Švec ◽

Ľuboš Danisovič

Keyword(s):

Adolescent Idiopathic Scoliosis ◽

Idiopathic Scoliosis ◽

Association Studies ◽

Three Dimensional ◽

Reliability And Validity ◽

Genome Project ◽

Genome Wide Association Studies ◽

Appropriate Treatment ◽

Surgical Treatments ◽

The Human Genome Project

Adolescent idiopathic scoliosis (AIS) is a three-dimensional deformity of the spine mainly affecting the younger population. Earlier detection of the disorder leads to appropriate treatment and better outcomes, thus avoiding highly invasive surgical treatments. The currently available tests for the disease identification have lost their reliability and validity with time. In the past few decades, efforts have been directed towards developing a highly reliable prognostic test for AIS. Towards this end, several strategies have been employed including biochemical, biomechanical and gene-based tests. Among the three, the gene-based technology has received much attention in recent past. Notably, this is due to the fact that the human genome project, followed by genome-wide association studies (GWAS), facilitated the identification of candidate genes for disorders like AIS. Several promising biomarker genes have been identified. However, their global validations were disappointing as these genes were shown to be limited to a particular group of people/ethnicities. Such observations limit the development of a reliable global molecular/biochemical test for AIS. The currently used AIS ScoliScoreTM also has several limitations. With continued disappointments in the identification of biomarkers for AIS and lack of appropriate tests, researchers have diverted their efforts towards several alternative avenues. A ray of hope is emerging from recent observations on the association of non-coding microRNAs and epigenetic factors that might arise as future reliable markers for AIS, thus paving the way for appropriate clinical management of this disorder.

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Evaluation of the Degenerative Changes of the Distal Intervertebral Discs after Internal Fixation Surgery in Adolescent Idiopathic Scoliosis

Asian Spine Journal ◽

10.31616/asj.2018.12.6.1060 ◽

2018 ◽

Vol 12 (6) ◽

pp. 1060-1068 ◽

Cited By ~ 2

Author(s):

Morteza Dehnokhalaji ◽

Mohammad Reza Golbakhsh ◽

Babak Siavashi ◽

Parham Talebian ◽

Sina Javidmehr ◽

...

Keyword(s):

Adolescent Idiopathic Scoliosis ◽

Idiopathic Scoliosis ◽

Internal Fixation ◽

Intervertebral Discs ◽

Degenerative Changes

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Molecular Biological and Pathological Aspects of Intercostal Muscles and Intervertebral Discs in Adolescent Idiopathic Scoliosis in Korea

Journal of Korean Society of Spine Surgery ◽

10.4184/jkss.2003.10.3.209 ◽

2003 ◽

Vol 10 (3) ◽

pp. 209

Author(s):

Hak-Sun Kim ◽

Oh-Ryong Kwon ◽

Seong-Hwan Moon ◽

Kyung-Hee Kim ◽

Hyang Kim ◽

...

Keyword(s):

Adolescent Idiopathic Scoliosis ◽

Idiopathic Scoliosis ◽

Intervertebral Discs ◽

Intercostal Muscles

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Imaging study of wedge changes in the vertebral bodies and intervertebral discs in adolescent idiopathic scoliosis

Orthopaedic Surgery ◽

10.1111/j.1757-7861.2009.00044.x ◽

2009 ◽

Vol 1 (4) ◽

pp. 300-304 ◽

Cited By ~ 2

Author(s):

Hong-guang Xu ◽

Gui-xing Qiu ◽

Yi-peng Wang ◽

Jian-guo Zhang ◽

Yong Liu ◽

...

Keyword(s):

Adolescent Idiopathic Scoliosis ◽

Idiopathic Scoliosis ◽

Imaging Study ◽

Intervertebral Discs ◽

Vertebral Bodies

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Automatic Vertebrae Localization and Spine Centerline Extraction in Radiographs of Patients with Adolescent Idiopathic Scoliosis

Studies in Health Technology and Informatics - Public Health and Informatics ◽

10.3233/shti210166 ◽

2021 ◽

Author(s):

Gunarajulu Renganathan ◽

Navin Manaswi ◽

Ionuţ Ghionea ◽

Sasa Cukovic

Keyword(s):

Adolescent Idiopathic Scoliosis ◽

Idiopathic Scoliosis ◽

Frontal Plane ◽

Intervertebral Discs ◽

High Variability ◽

Spinal Curvature ◽

Anatomical Landmarks ◽

Spinal Alignment ◽

Centerline Extraction ◽

Correction Strategies

Adolescent Idiopathic Scoliosis (AIS) is lifetime disorder indicated by the abnormal spinal curvature, and it is usually detected in children and adolescents. Traditional radiographic assessment of scoliosis is time-consuming and unreliable due to high variability in images and manual interpretation. Vertebrae localization and centerline extraction from a biplanar X-ray is essential for pathological diagnosis, treatment planning, and decision making. The aim of this paper is to develop a fully automated framework to provide correct evaluation of anatomical landmarks and to extract vertebral and intervertebral discs’ centroids. By knowing coordinates of each centroid, developed framework will estimate 2D deformity curve (centerline) called Middle Spinal Alignment (MSA) in frontal plane. By analyzing the MSA lines and deformity segments, many deformity parameters can be calculated which include vertebral transpositions, Cobb angles, apex vertebra position, etc., for planning spinal correction strategies and monitoring.

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