Wnt signaling pathway correlates with ossification of the spinal ligament: A microRNA array and immunohistochemical study

Yayama, Takafumi; Mori, Kanji; Okumura, Noriaki; Nishizawa, Kazuya; Kumagai, Kosuke; Nakamura, Akira; Imai, Shunsuke

doi:10.1016/j.jos.2017.09.024

Cited by 18 publications

(53 citation statements)

References 26 publications

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“…Various signaling pathways have been associated with TOLF pathogenesis[25–27]. Among them, Notch signaling regulates angiogenic and osteogenic differentiation, and is increasingly recognized as a vital participant in skeletal development [28].…”

Section: Introductionmentioning

confidence: 99%

Angiopoietin-2 promotes osteogenic differentiation of thoracic ligamentum flavum cells via modulating the Notch signaling pathway

et al. 2018

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Thoracic ossification of the ligamentum flavum (TOLF) is heterotopic ossification of spinal ligaments, which may cause serious thoracic spinal canal stenosis and myelopathy. However, the underlying etiology remains inadequately understood. In this study, the ossification patterns of TOLF were analyzed by micro-computer tomography (micro-CT). The expression profile of genes associated with angiogenesis was analyzed in thoracic ligamentum flavum cells at sites of different patterns of ossification using RNA sequencing. Significant differences in the expression profile of several genes were identified from Gene Ontology (GO) analysis. Angiopoietin-2 (ANGPT2) was significantly up-regulated in primary thoracic ligamentum flavum cells during osteogenic differentiation. To address the effect of ANGPT2 on Notch signaling and osteogenesis, ANGPT2 stimulation increased the expression of Notch2 and osteogenic markers of primary thoracic ligamentum flavum cells of immature ossification, while inhibition of ANGPT2 exhibited opposite effect on Notch pathway and osteogenesis of cells of mature ossification. These findings provide the first evidence for positive regulation of ANGPT2 on osteogenic differentiation in human thoracic ligamentum flavum cells via modulating the Notch signaling pathway.

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Section: Introductionmentioning

confidence: 99%

Angiopoietin-2 promotes osteogenic differentiation of thoracic ligamentum flavum cells via modulating the Notch signaling pathway

et al. 2018

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“…Although there have been previous studies that examined the roles of miRNAs in OLF, all of these studies focused on miRNAs that regulate osteogenic differentiation related genes (17–20,39). miRNAs related with inflammation and cell proliferation in OLF have rarely been reported.…”

Section: Discussionmentioning

confidence: 99%

“…Overexpression of miR-615-3p by its mimics suppressed the osteogenic differentiation of LF cells by reducing the expression of GDF5 (17). miR-199b-5p and miR-487b-3p were reported to inhibit osteogenic differentiation in LF cells by downregulating Notch and Wnt signaling pathway genes, respectively (19,20). However, the OLF-related miRNAs have rarely been reported and the inflammation-associated miRNAs in OLF have not been identified.…”

Section: Introductionmentioning

confidence: 99%

Identification of crucial miRNAs and lncRNAs for ossification of ligamentum flavum

et al. 2019

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The present study aimed to screen crucial micro (mi)RNAs and long non-coding (lnc)RNAs involved in the development of ossification of ligamentum flavum (OLF) based on the miRNA-mRNA and lncRNA-miRNA-mRNA competing endogenous (ce)RNA regulatory network analyses, which are rarely reported. The differentially expressed genes (DEGs), differentially expressed lncRNAs (DELs) and differentially expressed miRNAs (DEMs) between 4 OLF and 4 healthy controls were identified using two microarray datasets GSE106253 and GSE106256 collected from the Gene Expression Omnibus database. A protein-protein interaction (PPI) network was constructed, followed by calculation of topological characteristics and sub-module analysis in order to obtain hub DEGs. The miRNA-mRNA and lncRNA-miRNA networks that were established based on their interaction pairs, obtained from miRwalk and starBase databases, respectively, were integrated to form the ceRNA network. The underlying functions of mRNAs were predicted using the Database for Annotation, Visualization and Integrated Discovery (DAVID). The present study screened 828 DEGs, 119 DELs and 81 DEMs between OLF and controls. PPI network and module analyses identified interleukin (IL)10, adenylate cyclase (ADCY)5, suppressor of cytokine signaling (SOCS)3, G protein subunit gamma (GNG) 4, collagen type II α 1 chain (COL2A1) and collagen type XIII α 1 chain (COL13A1) as hub genes. The miRNA-mRNA network analysis demonstrated IL10 could be regulated by miR-210-3p, while COL13A1 and COL2A1 could be modulated by miR-329-3p and miR-222-5p, respectively. lncRNA-miRNA-mRNA ceRNA network analysis identified that small nucleolar RNA host gene 16-hsa-miR-196a-5p-SOCS3, ankyrin repeat and SOCS box containing 16-AS1-hsa-miR-379-5p-GNG4, nuclear enriched abundant transcript 1-has-miR-181b-5p-ADCY5, rhophilin 1-AS1-hsa-miR-299-3p-WNT7B interaction axes may be crucial. DAVID analysis predicted IL10, ADCY5, GNG4 and SOCS3 were involved in ‘adaptive immune response’, ‘Chemokine signaling pathway’ and ‘regulation of apoptosis’ processes, while COL2A1, COL13A1 and WNT7B may be ossification related. In conclusion, the identification of these crucial miRNAs and lncRNAs may be conducive for explaining the pathogenesis of OLF and provide certain natural, endogenous and nontoxic drug targets for the treatment of OLF.

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“…In a study of 1736 southern Chinese volunteers (1068 women and 668 men with mean 38 years of age) showed that the overall incidence of OLF is 8.3% in population, and 68.2% cases OLF was present at a single-level, whereas in 31.8% cases OLF was present at multiple levels 2 . Recently, several studies have reported that chronic pressure and genetic factors are the common cause for the development of OLF [4][5][6] . Since OLF only occured in limited areas of the world, genetic factors were considered as being more important in pathogenetic process.…”

Section: Introductionmentioning

confidence: 99%

“…Application of gene analysis and molecular biology approaches were used to clarify etiolo gy and pathology of OLF. Genes, for example, bone morphogenetic protein-2 (BMP2), transforming growth factorbeta 1(TGF-β1), and osteocalcin (OCN) related to osteogenic differentiation are believed to be associated with OLF 6,8 . Recently there have been intensively studies of epigenetic control of OPLL, and most studies focused on genetic polymorphisms and noncoding RNAs 9,10 .…”

Section: Introductionmentioning

confidence: 99%

IGF-2 Modified by the m6A Demethylation Enzyme ALKBH5 in the Ossification of the Ligamentum Flavum

Kuang

Wang

Qiu

et al. 2020

Preprint

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Background: Ossification of the ligamentum flavum (OLF) is a pathological heterotopic ossification of the paravertebral ligament. However, the specific pathophysiology mechanism of this disease is still unknown. The m6A methylation and its potential functions in OLF remain to be unexplored. Method: In this study, we performed a transcriptome-wide methylation analysis using the OLF and normal ligaments to explore the mechanism of OLF. Common and region-specific methylation have different preferences for methylation site selection and thereby different impacts on their biological functions. We screened out the methylase-ALKBH5, and by promoting or inhibiting its expression, observing the content of m6A, and measuring the ossification of ligaments, and then measuring IGF expression situation by alizarin red staining, alkaline phosphatase, immunofluorescence, immunohistochemistry, etc. Result: MeRIP-seq and qPCR showed that the m6A methylation level of OLF group was usually higher than that of control group. In addition, we found that ALKBH5 is an important demethyltransferase in OLF, which promotes the expression of m6A. ALKBH5 promotes the expression of IGF-2, which in turn promotes osteogenesis in OLF.Conclusion: Overall, we provided a region-specific map of m6A methylation and characterized the distinct features of specific and common methylation in OLF, and we proved that IGF-2 can be regulated by ALKBH5 to promote the process of OLF.

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Wnt signaling pathway correlates with ossification of the spinal ligament: A microRNA array and immunohistochemical study

Cited by 18 publications

References 26 publications

Angiopoietin-2 promotes osteogenic differentiation of thoracic ligamentum flavum cells via modulating the Notch signaling pathway

Angiopoietin-2 promotes osteogenic differentiation of thoracic ligamentum flavum cells via modulating the Notch signaling pathway

Identification of crucial miRNAs and lncRNAs for ossification of ligamentum flavum

IGF-2 Modified by the m6A Demethylation Enzyme ALKBH5 in the Ossification of the Ligamentum Flavum

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Wnt signaling pathway correlates with ossification of the spinal ligament: A microRNA array and immunohistochemical study

Cited by 18 publications

References 26 publications

Angiopoietin-2 promotes osteogenic differentiation of thoracic ligamentum flavum cells via modulating the Notch signaling pathway

Angiopoietin-2 promotes osteogenic differentiation of thoracic ligamentum flavum cells via modulating the Notch signaling pathway

Identification of crucial miRNAs and lncRNAs for ossification of ligamentum flavum

IGF-2 Modified by the m6A&nbsp;Demethylation Enzyme ALKBH5&nbsp;in the Ossification of the Ligamentum Flavum

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IGF-2 Modified by the m6A Demethylation Enzyme ALKBH5 in the Ossification of the Ligamentum Flavum