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RNA sequencing identifies gene regulatory networks controlling extracellular matrix synthesis in intervertebral disk tissues.

ABSTRACT: Degenerative disk disease of the spine is a major cause of back pain and disability. Optimization of regenerative medical therapies for degenerative disk disease requires a deep mechanistic understanding of the factors controlling the structural integrity of spinal tissues. In this investigation, we sought to identify candidate regulatory genes controlling extracellular matrix synthesis in spinal tissues. To achieve this goal we performed high throughput next generation RNA sequencing on 39 annulus fibrosus and 21 nucleus pulposus human tissue samples. Specimens were collected from patients undergoing surgical discectomy for the treatment of degenerative disk disease. Our studies identified associations between extracellular matrix genes, growth factors, and other important regulatory molecules. The fibrous matrix characteristic of annulus fibrosus was associated with expression of the growth factors platelet derived growth factor beta (PDGFB), vascular endothelial growth factor C (VEGFC), and fibroblast growth factor 9 (FGF9). Additionally we observed high expression of multiple signaling proteins involved in the NOTCH and WNT signaling cascades. Nucleus pulposus extracellular matrix related genes were associated with the expression of numerous diffusible growth factors largely associated with the transforming growth signaling cascade, including transforming factor alpha (TGFA), inhibin alpha (INHA), inhibin beta A (INHBA), bone morphogenetic proteins (BMP2, BMP6), and others. CLINICAL SIGNIFICANCE:this investigation provides important data on extracellular matrix gene regulatory networks in disk tissues. This information can be used to optimize pharmacologic, stem cell, and tissue engineering strategies for regeneration of the intervertebral disk and the treatment of back pain. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1356-1369, 2018.

SUBMITTER: Riester SM

PROVIDER: S-EPMC5990467 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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RNA sequencing identifies gene regulatory networks controlling extracellular matrix synthesis in intervertebral disk tissues.

Riester Scott M SM Lin Yang Y Wang Wei W Cong Lin L Mohamed Ali Abdel-Moneim AM Peck Sun H SH Smith Lachlan J LJ Currier Bradford L BL Clark Michelle M Huddleston Paul P Krauss William W Yaszemski Michael J MJ Morrey Mark E ME Abdel Matthew P MP Bydon Mohamad M Qu Wenchun W Larson Annalise N AN van Wijnen Andre J AJ Nassr Ahmad A

Journal of orthopaedic research : official publication of the Orthopaedic Research Society 20180110 5

Degenerative disk disease of the spine is a major cause of back pain and disability. Optimization of regenerative medical therapies for degenerative disk disease requires a deep mechanistic understanding of the factors controlling the structural integrity of spinal tissues. In this investigation, we sought to identify candidate regulatory genes controlling extracellular matrix synthesis in spinal tissues. To achieve this goal we performed high throughput next generation RNA sequencing on 39 annu ...[more]

PMID: 29227558

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Project description:PurposeTo investigate the association of polymorphism of IL-1β rs16944(T/C) with intervertebral disk degeneration (IDD), explore the possible mechanism and evaluate the predictive value of IL-1β for IDD.Patients and methodsA total of 196 consecutive patients with IDD were recruited, and 196 healthy controls were matched to these patients based on sex and age (±3 years). The polymorphisms of IL-1β rs16944(T/C), rs1143623(G/C), rs10490571(T/C) and rs2853550(A/G) were determined, and serum IL-1β, MMP-1, MMP-3, MMP-9 and a disintegrin-like and metalloproteinase with thrombospondin motif-4 (ADAMTS-4) levels were measured. Univariate analysis was performed with Student t-test or one-way ANOVA followed by post hoc and Chi-square test. Variables with two-sided P<0.10 were included in multivariate analysis, which employed a backward stepwise logistic regression model. Receiver operating characteristic (ROC) curve was used to evaluate the predictive value.ResultsMultivariate analysis showed that the polymorphism of IL-1β rs16944(T/C) was independently associated with IDD. The risk for IDD was significantly increased in TT and TC genotype compared with CC genotype, and the OR of TT genotype was higher than that of TC genotype. ANOVA analysis showed that serum concentration of IL-1β was highest in IL-1β rs16944 TT genotype, intermediate in TC genotype, and lowest in CC genotype. Similarly, serum concentrations of MMP-3 and ADAMTS-4 demonstrated the same tendency of TT > TC > CC genotype. Serum concentrations of MMP-1 and MMP-9 were higher in TT genotype than in TC and CC genotype. The area under curve (AUC) of IL-1β levels in predicting IDD was 0.788 (SE: 0.023, P=0.001, 95% CI: 0.742-0.834), and the predictive value was modest with a sensitivity of 77.0% and a specificity of 75%.ConclusionPolymorphism of IL-1β rs16944(T/C) affected IDD susceptibility through upregulation of serum levels of IL-1β and subsequent stimulation of ECM degradation. IL-1β levels could be applied in predicting IDD.

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RNA sequencing identifies gene regulatory networks controlling extracellular matrix synthesis in intervertebral disk tissues.

Publications

RNA sequencing identifies gene regulatory networks controlling extracellular matrix synthesis in intervertebral disk tissues.

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