Abstract
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.
Highlights
Thoracic ossification of the ligamentum flavum (TOLF) is a pathological heterotopic ossification that occupies the thoracic canal, which can cause severe thoracic myelopathy in East Asian population
According to the results of RNA-sequencing and Gene Ontology (GO) analysis, we investigated the effect of angiopoietin-2 (ANGPT2) on Notch signaling pathway and osteogenic differentiation in primary thoracic ligamentum flavum cells via ANGPT2 stimulation and knockdown
Investigating angiogenesis and osteogensis of thoracic ligamentum flavum cells would likely lead to better understanding of the pathogenesis of TOLF
Summary
Thoracic ossification of the ligamentum flavum (TOLF) is a pathological heterotopic ossification that occupies the thoracic canal, which can cause severe thoracic myelopathy in East Asian population. Several investigations suggested that potential contributing factors associated with TOLF, such as mechanical effects[5,6,7], inflammatory factors [8, 9]and genetic factors[10, 11], but the underlying mechanism of TOLF has not yet been clarified.
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