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Noninvasive cumulative axial load may induce intervertebral disc degeneration-A potential rabbit model.

ABSTRACT: Intervertebral disc degeneration (IDD) is considered to be the main cause of many spinal disorders; however, its underlying pathophysiology is not clearly understood. Recent studies indicate that excessive mechanical loading may serve a major role in the initiation of IDD. The aim of the present study was to explore the effect of noninvasive cumulative axial loading on the intervertebral discs of the lumbar spine using a novel rabbit model. Rabbits in the experimental group were placed into individual tubes specifically designed to force maintenance of an upright posture and were loaded with a heavy collar to increase the intradiscal pressure of their lumbar spine. Radiograph imaging and magnetic resonance imaging (MRI) was performed every 4 weeks to provide evidence of disc degeneration. At the end of the experiment, the animals were sacrificed and disc specimens were harvested for quantitative polymerase chain reaction and histological analysis. MRI results revealed significant and progressive reductions in the signal intensities of lumbar discs in the experimental group compared with the control group throughout the 14-week study period. The expression level of type I collagen was significantly increased and the expression levels of type II collagen and aggrecan were significantly decreased in the experimental group compared with the control group (P<0.05). Histological examination revealed marked structural changes in the experimental group, including fibrocartilage-like tissue ingrowth and accelerated fibrotic changes of the nucleus pulposus. The results of the present study indicate that noninvasive cumulative axial load is able to induce accelerated degenerative changes in rabbit lumbar discs, which may provide useful information for the establishment of a novel animal model of IDD for the research of IDD in humans.

SUBMITTER: Bai X

PROVIDER: S-EPMC5377280 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Noninvasive cumulative axial load may induce intervertebral disc degeneration-A potential rabbit model.

Bai Xuedong X Wang Deli D Zhou Mingyue M Xu Cheng C Li Wei W Tao Hui H He Qing Q Ruan Dike D

Experimental and therapeutic medicine 20170221 4

Intervertebral disc degeneration (IDD) is considered to be the main cause of many spinal disorders; however, its underlying pathophysiology is not clearly understood. Recent studies indicate that excessive mechanical loading may serve a major role in the initiation of IDD. The aim of the present study was to explore the effect of noninvasive cumulative axial loading on the intervertebral discs of the lumbar spine using a novel rabbit model. Rabbits in the experimental group were placed into indi ...[more]

PMID: 28413490

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Project description:BackgroundIntervertebral disc degeneration (IVDD) is the major cause of low-back pain. Histone deacetylase 9 (HDAC9) was dramatically decreased in the degenerative nucleus pulposus (NP) samples of patients with intervertebral disc degeneration (IVDD) according to bioinformatics analysis of Gene Expression Omnibus (GEO) GSE56081 dataset. This study aims to investigate the role of HDAC9 in IVDD progression.MethodsThe contribution of HDAC9 to the progression of IVDD was assessed using HDAC9 knockout (HDAC9KO) mice and NP-targeted HDAC9-overexpressing mice by IVD injection of adenovirus-mediated HDAC9 under a Col2a1 promoter. Magnetic resonance imaging (MRI) and histological analysis were used to examine the degeneration of IVD. NP cells were isolated from mice to investigate the effects of HDAC9 on apoptosis and viability. mRNA-seq and coimmunoprecipitation/mass spectrometry (co-IP/MS) analysis were used to analyze the HDAC9-regulated factors in the primary cultured NP cells.ResultsHDAC9 was statistically decreased in the NP tissues in aged mice. HDAC9KO mice spontaneously developed age-related IVDD compared with wild-type (HDAC9WT) mice. In addition, overexpression of HDAC9 in NP cells alleviated IVDD symptoms in a surgically-induced IVDD mouse model. In an in vitro assay, knockdown of HDAC9 inhibited cell viability and promoted cell apoptosis of NP cells, and HDAC9 overexpression had the opposite effects in NP cells isolated from HDAC9KO mice. Results of mRNA-seq and co-IP/MS analysis revealed the possible proteins and signaling pathways regulated by HDAC9 in NP cells. RUNX family transcription factor 3 (RUNX3) was screened out for further study, and RUNX3 was found to be deacetylated and stabilized by HDAC9. Knockdown of RUNX3 restored the effects of HDAC9 silencing on NP cells by inhibiting apoptosis and increasing viability.ConclusionOur results suggest that HDAC9 plays an important role in the development and progression of IVDD. It might be required to protect NP cells against the loss of cell viability and apoptosis by inhibiting RUNX3 acetylation and expression during IVDD. Together, our findings suggest that HDAC9 may be a potential therapeutic target in IVDD.

Project description:Introduction:Estimation of intervertebral disc degeneration on magnetic resonance imaging (MRI) is challenging. Qualitative schemes used in clinical practice correlate poorly with pain and quantitative techniques have not entered widespread clinical use. Methods:As part of a prior study, 25 New Zealand white rabbits underwent annular puncture to induce disc degeneration in 50 noncontiguous lumbar discs. At 16?weeks, the animals underwent multi-echo T2 MRI scanning and were euthanized. The discs were stained and examined histologically. Quantitative T2 relaxation maps were prepared using the nonlinear least squares method. Decay Variance maps were created using a novel technique of aggregating the deviation in the intensity of each echo signal from the expected intensity based on the previous rate of decay. Results:Decay Variance maps showed a clear and well demarcated nucleus pulposus with a consistent rate of decay (low Decay Variance) in healthy discs that showed progressively more variable decay (higher Decay Variance) with increasing degeneration. Decay Variance maps required significantly less time to generate (1.0?±?0.0 second) compared with traditional T2 relaxometry maps (5 (±0.9) to 1788.9 (±116) seconds). Histology scores correlated strongly with Decay Variance scores (r = 0.82, P?<?.01) and weakly with T2 signal intensity (r = 0.32, P?<?.01) and quantitative T2 relaxometry (r = 0.39, P?<?.01). Decay Variance had superior sensitivity and specificity for the detection of degenerate discs when compared to T2 signal intensity or Quantitative T2 mapping. Conclusion:Our results show that using a multi-echo T2 MRI sequence, Decay Variance can quantitatively assess disc degeneration more accurately and with less image-processing time than quantitative T2 relaxometry in a rabbit disc puncture model. The technique is a viable candidate for quantitative assessment of disc degeneration on MRI scans. Further validation on human subjects is needed.

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Noninvasive cumulative axial load may induce intervertebral disc degeneration-A potential rabbit model.

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Noninvasive cumulative axial load may induce intervertebral disc degeneration-A potential rabbit model.

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