The Role of JAK-STAT Signaling Activation in Hypertrophied Ligamentum Flavum

Delen, Emre; Doğanlar, Oğuzhan; Delen, Özlem; Doğanlar, Zeynep Banu; Kılınçer, Cumhur

doi:10.1016/j.wneu.2020.02.024

Cited by 5 publications

(4 citation statements)

References 28 publications

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“…The lysate was centrifuged at 14,000 g for 20 minutes and in the range of 2.13–3.17 mg/mL of total protein was detected by the protein A280 method with a micro-volume spectrophotometer (Optizen Nano Q; Mecasys). The protein level was measured using a Western blot assay and SDS-PAGE (sodium dodecyl sulfate–polyacrylamide gel electrophoresis) electrophoresis, as described by Delen et al [ 15 ] with two primary antibodies (DDR1 [NBP1-33134; Novus Biologicals, Littleton, CO, USA] and DDR2 [NBP2-14927; Novus Biologicals]) and normalized with a beta-actin antibody (NB600-503; Novus Biologicals). Protein quantities were determined with the ProteinQuant software and given as relative density.…”

Section: Methodsmentioning

confidence: 99%

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Effects of Expression of Matrix Metalloproteinases and Discoidin Domain Receptors in Ligamentum Flavum Fibrosis in Patients with Degenerative Lumbar Canal Stenosis

Torun

Doğanlar

et al. 2023

Asian Spine J

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This study aimed to clarify the role of crosstalk between discoidin domain receptors (DDRs) and matrix metalloproteinases (MMPs) in the ligamentum flavum (LF) fibrosis obtained from patients with degenerative lumbar canal stenosis (DLCS). Overview of Literature: The DDRs, DDR1 and DDR2, are cell surface receptors and have an essential role in collagen fiber accumulation in several fibrotic diseases. MMPs are one of the critical factors in extracellular matrix remodeling and elastic fiber degradation in LF tissues. However, the crosstalk between DDRs and MMPs and the role of this molecular signal in LF fibrosis remain unclear. Methods: A total of 35 patients were divided into two groups in this study. Spinal surgery was performed in 23 of these patients with the diagnosis of DLCS. Twelve patients with lumbar disk herniation (LDH) were included in the control group. On axial T2-weighted magnetic resonance imaging, LF thickness was measured bilaterally at the level of the facet joint. Histology, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blot analyses were performed on LF tissue samples. LF tissues were stained with hematoxylin and eosin. In addition, the grade of fibrosis was histologically assessed using Masson trichrome triple staining. DDR1 and DDR2 Western blot analyses were performed. DDR1, DDR2, MMP2, MMP3, MMP9, and MMP13 expression levels were measured using qRT-PCR analysis. Results: The grade of fibrosis and LF thickness were significantly higher in the DLCS patients than in the LDH patients. DDR1 and DDR2 gene expression and protein levels in LF tissues are significantly greater in DLCS samples than in control samples, according to both qRT-PCR and Western blot analyses. In addition, we detected a significant expression of the MMP3, MMP9, and MMP13, which are known to have important roles in extracellular matrix remodeling in DLCS. Furthermore, we discovered a link between DDR protein levels and LF thickness, fibrosis, and MMP3/MMP9. Conclusions: Our results indicate that DDR1, DDR2, and MMP3 and MMP9 signals can be correlated with each other in LF tissues and be promoted LF fibrosis leading to spinal canal narrowing in patients with DLCS.

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Section: Methodsmentioning

confidence: 99%

“…The protein level was measured using a Western blot assay and SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis) electrophoresis, as described by Delen et al[15] with two primary antibodies (DDR1 [NBP1-33134; Novus Biologicals, Littleton, CO, USA] and DDR2 [NBP2-14927; Novus Biologicals]) and normalized with a…”

mentioning

confidence: 99%

Effects of Expression of Matrix Metalloproteinases and Discoidin Domain Receptors in Ligamentum Flavum Fibrosis in Patients with Degenerative Lumbar Canal Stenosis

Torun

Doğanlar

et al. 2023

Asian Spine J

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“…IL-6 is an important modulator of the inflammatory process involved in fibroblast differentiation, activation, and proliferation, and it affects ECM remodeling in several diseases (200). The JAK1/ STAT3 pathway plays an essential role in the inflammatory response to thickening in the dorsal LF of LSS (201). Particularly, IL-6 activates JAK and STAT proteins (202, 203) and regulates MMP expression and activity.…”

Section: Postn-mediated Effected Of Low-level Inflammation On the Yel...mentioning

confidence: 99%

Mechanisms of tissue degeneration mediated by periostin in spinal degenerative diseases and their implications for pathology and diagnosis: a review

Yoshihara,

Morimoto,

Hirata

et al. 2023

Front. Med.

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Periostin (POSTN) serves a dual role as both a matricellular protein and an extracellular matrix (ECM) protein and is widely expressed in various tissues and cells. As an ECM protein, POSTN binds to integrin receptors, transduces signals to cells, enabling cell activation. POSTN has been linked with various diseases, including atopic dermatitis, asthma, and the progression of multiple cancers. Recently, its association with orthopedic diseases, such as osteoporosis, osteoarthritis resulting from cartilage destruction, degenerative diseases of the intervertebral disks, and ligament degenerative diseases, has also become apparent. Furthermore, POSTN has been shown to be a valuable biomarker for understanding the pathophysiology of orthopedic diseases. In addition to serum POSTN, synovial fluid POSTN in joints has been reported to be useful as a biomarker. Risk factors for spinal degenerative diseases include aging, mechanical stress, trauma, genetic predisposition, obesity, and metabolic syndrome, but the cause of spinal degenerative diseases (SDDs) remains unclear. Studies on the pathophysiological effects of POSTN may significantly contribute toward the diagnosis and treatment of spinal degenerative diseases. Therefore, in this review, we aim to examine the mechanisms of tissue degeneration caused by mechanical and inflammatory stresses in the bones, cartilage, intervertebral disks, and ligaments, which are crucial components of the spine, with a focus on POSTN.

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“…Ligamentum flavum (LF) hypertrophy (LFH) is an important cause of spinal canal stenosis and posterior longitudinal ligament ossification, which are diseases that lead to sensory and motor impairments in the upper and lower limbs due to the compression of the spinal cord and spinal nerve root or cauda equina nerve (1,2). Spinal stenosis and posterior longitudinal ligament ossification are common spinal diseases affecting the elderly, and Ciol et al estimated that by the year 2025, the number of such cases will reach 64 million (3).…”

Section: Introductionmentioning

confidence: 99%

ADAM10 promotes the proliferation of ligamentum flavum cells by activating the PI3K/AKT pathway

et al. 2020

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Ligamentum flavum hypertrophy (LFH) is an important cause of spinal canal stenosis and posterior longitudinal ligament ossification. Although a number of studies have focused on the mechanisms responsible for LFH, the cellular mechanisms remain poorly understood. The aim of the present study was to investigate the roles of differentially expressed genes (DEGs) in LFH, elucidate the mechanisms responsible for LFH and provide a potential therapeutic target for further studies. The GSE113212 dataset was downloaded from the Gene Expression Omnibus (GEO) database. The microarray data were analyzed and DEGs were obtained. Bioinformatics methods, such as Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment and protein-protein interaction (PPI) network analyses were used to obtain the key genes and signaling pathways. In addition, cells derived from hypertrophied ligamentum flavum were cultured, and the key genes and signaling pathways in ligamentum cells were identified through in vitro cell biology and molecular biology experiments. A total of 2,123 genes were screened as DEGs. Among these DEGs, 1,384 genes were upregulated and 739 genes were downregulated. The KEGG pathway analysis revealed that the dEGs were mainly enriched in the PI3K/AKT signaling pathway, and the PPI network analysis screened A disintegrin and metalloproteinase 10 (ADAM10) as a key gene. In vitro experimental verification revealed that ADAM10 promoted the proliferation of ligamentum flavum cells and led to the hypertrophy of the ligamentum by activating the PI3K/AKT pathway. On the whole, the in vitro experimental results suggested that ADAM10 promoted the proliferation of ligamentum flavum cells by activating the PI3K/AKT pathway, which may represent a pathogenic mechanism of LFH. The findings of the present study may provide a basis and direction for further studies on the cellular mechanisms of LFH and present a potential novel therapeutic target and clinical approach.

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The Role of JAK-STAT Signaling Activation in Hypertrophied Ligamentum Flavum

Cited by 5 publications

References 28 publications

Effects of Expression of Matrix Metalloproteinases and Discoidin Domain Receptors in Ligamentum Flavum Fibrosis in Patients with Degenerative Lumbar Canal Stenosis

Effects of Expression of Matrix Metalloproteinases and Discoidin Domain Receptors in Ligamentum Flavum Fibrosis in Patients with Degenerative Lumbar Canal Stenosis

Mechanisms of tissue degeneration mediated by periostin in spinal degenerative diseases and their implications for pathology and diagnosis: a review

ADAM10 promotes the proliferation of ligamentum flavum cells by activating the PI3K/AKT pathway

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