User Tools

Site Tools


intervertebral_disc_degeneration

Intervertebral disc degeneration

Degeneration of one or more intervertebral disc(s), often called “degenerative disc disease” (DDD) or “degenerative disc disorder, is a disease of aging, and though for most people is not a problem, in certain individuals a degenerated disc can cause severe chronic pain if left untreated.

Its one of the most common causes of low back pain and neck pain, and also one of the most misunderstood.

Degradation of the nucleus pulposus (NP) is an early hallmark of intervertebral disc degeneration.

Intervertebral disc degeneration is associated with back pain and disc herniation.

see Cervical disc disease

see Lumbar intervertebral disc degeneration.

Etiology

The potential relationship between disc infection and disc degeneration-related symptoms remain controversial, with contradictory evidence available in the literature. Several studies have demonstrated the presence of infected extruded nucleus tissue from first-time disc herniation, implicating the role of disc microbial infection in disc degeneration. The current study is a pilot study evaluating if high infection rates are prevalent in Australian degenerate disc cohort.

Institutional ethics approval was obtained (HREC 13/218). The pilot project was a single spine centre prospective cohort of patients undergoing spine surgery for degenerate disc disease. In each case, disc material was obtained and prolonged aerobic and anaerobic cultures performed as per methods used by Stirling et al.

To date, a total of 168 patients have been enrolled, with male: female = 1:1. Surgical caseload includes: 17.9% anterior cervical fusion, 35.0% anterior lumbar fusion, 40.7% lumbar discectomy and 5.7% posterior lumbar fusions. 34.1% patients presented with neck pain, 31.6% with arm pain, 59.3% with leg pain and 64.2% with back pain. 20.2% of the patients received transforaminal or epidural or facet joint injections prior to surgery. In this pilot study, 19.6% were culture positive, with P. acnes predominant in 50%. Disc only cultures were positive in 27.8% of lumbar cases and 18.5% of cervical cases, with predominant organisms being P. acnes.

Similar to the infection rates from previous studies, this Australian cohort had 19.6% infection rates when disc only cultures are performed. P. acnes is the predominant organism followed by streptococcus sp. It is imperative to perform contaminant controls as such high infection with skin bugs is a significant finding 1).

Pathophysiology

Degeneration of intervertebral disc (IVD) tissue is characterized by several structural changes that result in variations in disc physiology and loss of biomechanical function. The complex process of degeneration exhibits highly intercorrelated biomechanical, biochemical, and cellular interactions. There is currently some understanding of the cellular changes in degenerated intervertebral disc tissue, but microstructural changes and deterioration of the tissue matrix has previously been rarely explored.

In a work, sequestered IVD tissue was successfully characterized using histology, light microscopy, and scanning electron microscopy (SEM) to quantitatively evaluate parameters of interest for intervertebral disc degeneration (IDD) such as delamination of the collagenous matrix, cell density, cell size, and extra cellular matrix (ECM) thickness. Additional qualitative parameters investigated included matrix fibration and irregularity, neovascularization of the IVD, granular inclusions in the matrix, and cell cluster formation. The results of this study corroborated several previously published findings, including those positively correlating female gender and IVD cell density, age and cell size, and female gender and ECM thickness. Additionally, an array of quantitative and qualitative investigations of IVD degeneration could be successfully evaluated using the given methodology, resin-embedded SEM in particular. SEM is especially practical for studying micromorphological changes in tissue, as other microscopy methods can cause artificial tissue damage due to the preparation method. Investigation of the microstructural changes occurring in degenerated tissue provides a greater understanding of the complex process of disc degeneration as a whole. Developing a more complete picture of the degenerative changes taking place in the intervertebral disc is crucial for the advancement and application of regenerative therapies based on the pathology of intervertebral disc degeneration 2).

Bioinformatic analysis of the gene expression profiles

Herniation of nuclear or disc material along with inflammatory chemokines such as prostaglandin E2, interleukin-6, matrix metalloproteinase and nitric oxide has definite correlations, possibly they are over produced 3).

The gene expression profiles data were obtained using the same microarray platform for two groups of patients suffering from degenerative disc diseases: GSE41883 (Human annulus disc cells exposed to TNF-a; 4 samples) and GSE27494 (Human annulus disc cells exposed to IL-1β;; 4 samples). The genes that were differentially expressed in these two datasets compared to control disc cells (without cytokine exposure; 4 samples each) were identified using the R language, and were pooled using the Excel software program to select the common differentially expressed genes in the two datasets. The initial functional clustering, signaling pathways and protein-protein interaction relationship analyses were conducted using the DAVID and STRING software programs.

Of the 255 concomitantly and differentially expressed genes identified after respective treatment with TNF-α and IL-1β, 141 were up-regulated and 114 were down-regulated. The gene ontology annotation analysis showed that these differentially expressed genes were primarily associated with cytokine activity, growth factor activity, the inflammatory reaction and the response to injury. The signaling pathway analysis showed that these differentially expressed genes were mainly related to the interactions of cytokines, apoptosis and NOD-like receptor signaling pathways. The interaction network analysis indicated that PTGS2, ICAM1, NOV and other genes may play a role in disc degeneration.

ICAM1 and other genes may play a role in the development of disc degeneration induced by inflammatory reactions using a bioinformatics analysis of the gene expression profiles of degenerative intervertebral disc cells stimulated with inflammatory factors, suggesting that bioinformatics methods can be used to identify potential target for intervertebral disc degeneration 4).

Symptoms

Disc degeneration and associated low back pain are major causes of suffering and disability.

Pain of discogenic origin with degeneration of the disc confirmed by patient history and radiographic studies.

Diagnosis

Imaging, primarily with MRI and CT, is used to evaluate the source of both low back pain (LBP) and neck pain. These imaging modalities commonly identify disc degeneration, disc herniations, and posterior element arthopathy; however, the imaging findings of spine degeneration are present in a high proportion of asymptomatic individuals and increase with age 5) 6).

Although many imaged-based degenerative changes are due to the normal aging process, such imaging findings are often interpreted as the cause of the patient's back pain and initiate a cascade of medical and surgical interventions, which may not be helpful in relieving the symptoms 7).

With disk degeneration, the adjacent vertebral endplates and subchondral bone will commonly show signal intensity changes on MRI (ie, Modic changes).

Treatment

Current surgical treatment provides relief to the accompanying pain and disability but does not restore the biological function of the intervertebral disc. NOVOCART™ Disc plus, an autologous cell compound for autologous disc chondrocyte transplantation, was developed to reduce the degenerative sequelae after lumbar disc surgery or to prophylactically avoid degeneration in adjacent discs.

Cell therapy for the degenerating intervertebral disc

Spinal conditions related to intervertebral disc degeneration cost billions of dollars in the US annually. Despite the prevalence and soaring cost, there is no specific treatment that restores the physiological function of the diseased IVD. Thus, it is vital to develop new treatment strategies to repair the degenerating IVD. Persons with IVD degeneration without back pain or radicular leg pain often do not require any intervention. Only patients with severe back pain related to the IVD degeneration or biomechanical instability are likely candidates for cell therapy. The IVD progressively degenerates with age in humans, and strategies to repair the IVD depend on the stage of degeneration. Cell therapy and cell-based gene therapy aim to address moderate disc degeneration; advanced stage disease may require surgery. Studies involving autologous, allogeneic, and xenogeneic cells have all shown good survival of these cells in the IVD, confirming that the disc niche is an immunologically privileged site, permitting long-term survival of transplanted cells. All of the animal studies reviewed here reported some improvement in disc structure, and 2 studies showed attenuation of local inflammation. Among the 50 studies reviewed, 25 used some type of scaffold, and cell leakage is a consistently noted problem, though some studies showed reduced cell leakage. Hydrogel scaffolds may prevent cell leakage and provide biomechanical support until cells can become established matrix producers. However, these gels need to be optimized to prevent this leakage. Many animal models have been leveraged in this research space. Rabbit is the most frequently used model (28 of 50), followed by rat, pig, and dog. Sheep and goat IVDs resemble those of humans in size and in the absence of notochordal cells. Despite this advantage, there were only 2 sheep and 1 goat studies of 50 studies in this cohort. It is also unclear if a study in large animals is needed before clinical trials since some of the clinical trials proceeded without a study in large animals. No animal studies or clinical trials completely restored IVD structure. However, results suggest cause for optimism. In light of the fact that patients primarily seek medical care for back pain, attenuating local inflammation should be a priority in benchmarks for success. Clinicians generally agree that short-term back pain should be treated conservatively. When interventions are considered, the ideal therapy should also be minimally invasive and concurrent with other procedures such as discography or discectomy. Restoration of tissue structure and preservation of spinal motion are desirable 8).


Self complementary adeno associated virus (scAAV) vectors, which do not express any viral gene and are not linked with any known disease in humans, are attractive therapeutic gene delivery vectors in intervertebral disc degeneration (IVD). However, scAAV-based silencing of catabolic or inflammatory factor has not yet been investigated in human IVD cells. Therefore, Shenegelegn Mern et al., used scAAV6, the most suitable serotype for transduction of human nucleus pulposus (NP) cells, to knockdown the major catabolic gene (ADAMTS4) of IVD degeneration. IVD degeneration grades were determined by preoperative magnetic resonance imaging. Lumbar NP tissues of degeneration grade III were removed from 12 patients by nucleotomy. NP cells were isolated and cultured with low-glucose. Titre of recombinant scAAV6 vectors targeting ADAMTS4, transduction efficiencies, transduction units, cell viabilities and expression levels of target genes were analysed using quantitative PCR, fluorescence microscopy, fluorescence-activated cell sorting, 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide assays, quantitative reverse transcription PCR, western blot and enzyme-linked immunosorbent assays during 48 days of post-transduction. Transduction efficiencies between 98.2% and 37.4% and transduction units between 611 and 245 TU/cell were verified during 48 days of post-transduction (p<0.001). scAAV6-mediated knockdown of ADAMTS4 with maximum 87.7% and minimum 40.1% was confirmed on day 8 and 48 with enhanced the level of aggrecan 48.5% and 30.2% respectively (p<0.001). scAAV6-mediated knockdown of ADAMTS4 showed no impact on cell viability and expression levels of other inflammatory catabolic proteins.

Thus, the results are promising and may help to design long-term and less immunogenic gene therapeutic approaches in IVD disorders, which usually need prolonged therapeutic period between weeks and months 9).

1)
Rao PJ, Phan K, Reddy R, Scherman DB, Taylor P, Mobbs RJ. DISC (Degenerate- disc Infection Study with Contaminant control): Pilaot Study of Australian Cohort of Patients Without the Contaminant Control. Spine (Phila Pa 1976). 2015 Dec 14. [Epub ahead of print] PubMed PMID: 26679882.
2)
Friedmann A, Goehre F, Ludtka C, Mendel T, Meisel HJ, Heilmann A, Schwan S. Microstructure analysis method for evaluating degenerated intervertebral disc tissue. Micron. 2016 Oct 21;92:51-62. doi: 10.1016/j.micron.2016.10.002. [Epub ahead of print] PubMed PMID: 27871028.
3)
Kalichman L, Hunter DJ. The genetics of intervertebral disc degeneration. Associated genes. Joint Bone Spine. 2008;75:388–96.
4)
Liu C, Zhang JF, Sun ZY, Tian JW. Bioinformatic analysis of the gene expression profiles in human intervertebral disc degeneration associated with inflammatory cytokines. J Neurosurg Sci. 2015 Jul 22. [Epub ahead of print] PubMed PMID: 26200140.
5)
Brinjikji W, Luetmer PH, Comstock B, et al. Systematic literature review of imaging features of spinal degeneration in asymptomatic populations. AJNR Am J Neuroradiol. 2015;36(4):811–816.
6)
Boden SD, Davis DO, Dina TS, Patronas NJ, Wiesel SW. Abnormal magnetic-resonance scans of the lumbar spine in asymptomatic subjects: a prospective investigation. J Bone Joint Surg Am. 1990;72(3):403–408.
7)
Carragee E, Alamin T, Cheng I, Franklin T, van den Haak E, Hurwitz E. Are first-time episodes of serious LBP associated with new MRI findings? Spine J. 2006;6(6):624–635.
8)
Tong W, Lu Z, Qin L, Mauck RL, Smith HE, Smith LJ, Malhotra NR, Heyworth MF, Caldera F, Enomoto-Iwamoto M, Zhang Y. Cell therapy for the degenerating intervertebral disc. Transl Res. 2016 Nov 28. pii: S1931-5244(16)30403-0. doi: 10.1016/j.trsl.2016.11.008. [Epub ahead of print] Review. PubMed PMID: 27986604.
9)
Shenegelegn Mern D, Tschugg A, Hartmann S, Thomé C. Self-complementary adeno-associated virus serotype 6 mediated knockdown of ADAMTS4 induces long-term and effective enhancement of aggrecan in degenerative human nucleus pulposus cells: A new therapeutic approach for intervertebral disc disorders. PLoS One. 2017 Feb 16;12(2):e0172181. doi: 10.1371/journal.pone.0172181. PubMed PMID: 28207788.
intervertebral_disc_degeneration.txt · Last modified: 2017/02/17 14:07 (external edit)