Mutant MAPK7-Induced Idiopathic Scoliosis is Linked to Impaired Osteogenesis

Zhou, Taifeng; Chen, Chong; Xu, Caixia; Zhou, Hang; Gao, Bo; Su, Deying; Liao, Zhiheng; Li, Yongyong; Yang, Shulan; Su, Peiqiang

doi:10.1159/000491956

Cited by 21 publications

(15 citation statements)

References 42 publications

(52 reference statements)

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“…88 More recently, MapK7 was shown to be associated with severe spinal deformity and a defective osteogenesis phenotype in idiopathic scoliosis. 162 Understanding the molecular underpinnings that generate spinal deformities may allow for early targeted therapy based on a child's underlying genetic profile. The development and refinement of new fusionless surgical techniques may allow for early treatment of pediatric patients with high risk of deformity progression without the long-term consequences of current fusion constructs.…”

Section: Fusionless Spine Surgerymentioning

confidence: 99%

Spinal instrumentation in infants, children, and adolescents: a review

Mendenhall

Mobasser

Relyea

et al. 2019

Journal of Neurosurgery: Pediatrics

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OBJECTIVEThe evolution of pediatric spinal instrumentation has progressed in the last 70 years since the popularization of the Harrington rod showing the feasibility of placing spinal instrumentation into the pediatric spine. Although lacking in pediatric-specific spinal instrumentation, when possible, adult instrumentation techniques and tools have been adapted for the pediatric spine. A new generation of pediatric neurosurgeons with interest in complex spine disorder has pushed the field forward, while keeping the special nuances of the growing immature spine in mind. The authors sought to review their own experience with various types of spinal instrumentation in the pediatric spine and document the state of the art for pediatric spine surgery.METHODSThe authors retrospectively reviewed patients in their practice who underwent complex spine surgery. Patient demographics, operative data, and perioperative complications were recorded. At the same time, the authors surveyed the literature for spinal instrumentation techniques that have been utilized in the pediatric spine. The authors chronicle the past and present of pediatric spinal instrumentation, and speculate about its future.RESULTSThe medical records of the first 361 patients who underwent 384 procedures involving spinal instrumentation from July 1, 2007, to May 31, 2018, were analyzed. The mean age at surgery was 12 years and 6 months (range 3 months to 21 years and 4 months). The types of spinal instrumentation utilized included occipital screws (94 cases); C1 lateral mass screws (115 cases); C2 pars/translaminar screws (143 cases); subaxial cervical lateral mass screws (95 cases); thoracic and lumbar spine traditional-trajectory and cortical-trajectory pedicle screws (234 cases); thoracic and lumbar sublaminar, subtransverse, and subcostal polyester bands (65 cases); S1 pedicle screws (103 cases); and S2 alar-iliac/iliac screws (56 cases). Complications related to spinal instrumentation included hardware-related skin breakdown (1.8%), infection (1.8%), proximal junctional kyphosis (1.0%), pseudarthroses (1.0%), screw malpositioning (0.5%), CSF leak (0.5%), hardware failure (0.5%), graft migration (0.3%), nerve root injury (0.3%), and vertebral artery injury (0.3%).CONCLUSIONSPediatric neurosurgeons with an interest in complex spine disorders in children should develop a comprehensive armamentarium of safe techniques for placing rigid and nonrigid spinal instrumentation even in the smallest of children, with low complication rates. The authors’ review provides some benchmarks and outcomes for comparison, and furnishes a historical perspective of the past and future of pediatric spine surgery.

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Section: Fusionless Spine Surgerymentioning

confidence: 99%

Spinal instrumentation in infants, children, and adolescents: a review

Mendenhall

Mobasser

Relyea

et al. 2019

Journal of Neurosurgery: Pediatrics

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“…In future perspective, it would be highly interesting to investigate how common risk factors affect the disbalance between MAPK7 activity and EZH2 expression in larger cohort studies. In addition, and since polymorphisms in MAPK7 48 – 50 and EZH2 51 – 54 are identified, it would be highly interesting to investigate whether these polymorphisms associate to a higher cardiovascular risk.…”

Section: Discussionmentioning

confidence: 99%

Reciprocal regulation of endothelial–mesenchymal transition by MAPK7 and EZH2 in intimal hyperplasia and coronary artery disease

Vanchin

Sol

Gjaltema

et al. 2021

Sci Rep

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Endothelial–mesenchymal transition (EndMT) is a form of endothelial dysfunction wherein endothelial cells acquire a mesenchymal phenotype and lose endothelial functions, which contributes to the pathogenesis of intimal hyperplasia and atherosclerosis. The mitogen activated protein kinase 7 (MAPK7) inhibits EndMT and decreases the expression of the histone methyltransferase Enhancer-of-Zeste homologue 2 (EZH2), thereby maintaining endothelial quiescence. EZH2 is the catalytic subunit of the Polycomb Repressive Complex 2 that methylates lysine 27 on histone 3 (H3K27me3). It is elusive how the crosstalk between MAPK7 and EZH2 is regulated in the endothelium and if the balance between MAPK7 and EZH2 is disturbed in vascular disease. In human coronary artery disease, we assessed the expression levels of MAPK7 and EZH2 and found that with increasing intima/media thickness ratio, MAPK7 expression decreased, whereas EZH2 expression increased. In vitro, MAPK7 activation decreased EZH2 expression, whereas endothelial cells deficient of EZH2 had increased MAPK7 activity. MAPK7 activation results in increased expression of microRNA (miR)-101, a repressor of EZH2. This loss of EZH2 in turn results in the increased expression of the miR-200 family, culminating in decreased expression of the dual-specificity phosphatases 1 and 6 who may repress MAPK7 activity. Transfection of endothelial cells with miR-200 family members decreased the endothelial sensitivity to TGFβ1-induced EndMT. In endothelial cells there is reciprocity between MAPK7 signaling and EZH2 expression and disturbances in this reciprocal signaling associate with the induction of EndMT and severity of human coronary artery disease.

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“…In addition, MAP2K1, which was shown to be down regulated in the expression study, interacts directly with PRKG1, and is involved in cGMP-PKG signaling, as well as MAPK and PI3K-Akt signaling. Mutant MAPK7-induced AIS has been linked to impaired osteogenesis 28 . Previous study has indicated that p38 and MAPK play important roles in the production of collagen in fibroblasts 29 .…”

Section: Discussionmentioning

confidence: 99%

Upregulation of cGMP‐dependent Protein Kinase (PRKG1) in the Development of Adolescent Idiopathic Scoliosis

Hou

Cheng

et al. 2020

Orthopaedic Surgery

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Objective To explore the molecular regulatory mechanisms underlying fibroblast differentiation and dysfunction in the development of adolescent idiopathic scoliosis (AIS) in an effort to identify candidate therapeutic targets for AIS. Methods The GSE110359 dataset, obtained from the bone marrow stromal cells of 12 AIS patients and five healthy controls, was retrieved from the GEO database. The data were preprocessed and differentially expressed genes (DEGs) were identified. KEGG pathway and Gene Ontology (GO)‐Biological Process (BP) enrichment analyses were performed to identify the function of the DEGs. A protein–protein interaction (PPI) and a microRNA‐transcription factor (TF)‐target co‐regulatory network were constructed to identify hub genes in the development of AIS. In addition, hub DEGs were evaluated by quantitative PCR (qPCR) and immunohistochemical staining. Results A total of 188 DEGs including 100 up‐regulated and 88 down‐regulated genes were obtained. The up‐regulated DEGs were related to “p53 signaling pathway”, “FoxO signaling pathway”, and “cGMP‐PKG signaling pathway” terms, while the down‐regulated DEGs were significantly enriched in seven terms including “protein processing in endoplasmic reticulum”. The key up‐regulated genes, PRKG1, CCNG2, and KAT2B, and the key down‐regulated genes, MAP2K1 and DUSP6, were identified by the PPI and miRNA‐TF‐Target regulatory network analyses. mRNA expression patterns for PRKG1, DUSP6, and KAT2B were successfully verified by qPCR. In addition, PRKG1 protein levels were found to be elevated during the immunohistochemical analysis. Conclusion Increased expression of PRKG1 in AIS patients might be an attractive therapeutic target for AIS. However, further gain or loss‐of‐function studies should be conducted.

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Mutant MAPK7-Induced Idiopathic Scoliosis is Linked to Impaired Osteogenesis

Cited by 21 publications

References 42 publications

Spinal instrumentation in infants, children, and adolescents: a review

Spinal instrumentation in infants, children, and adolescents: a review

Reciprocal regulation of endothelial–mesenchymal transition by MAPK7 and EZH2 in intimal hyperplasia and coronary artery disease

Upregulation of cGMP‐dependent Protein Kinase (PRKG1) in the Development of Adolescent Idiopathic Scoliosis

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