In vivo experimental intervertebral disc degeneration induced by bleomycin in the rhesus monkey

Abstract

BackgroundRecently, biological therapies for early intervention of degenerative disc disease have been introduced and developed; however, a functional animal model that mimics slowly progressive disc degeneration of humans does not exist. The objective of this study was to establish a slowly progressive and reproducible intervertebral disc (IVD) degeneration model.MethodsThe subchondral bone adjacent to the lumbar IVDs (L3/4 and L5/6) of ten rhesus monkeys was randomly injected with 4 ml bleomycin solution (1.5 mg/ml), or 4 ml phosphate buffer saline (PBS) per segment as control, respectively. The degenerative process was investigated by using radiography and T1ρ MR imaging at 1, 3, 6, 9, 12 and 15 months postoperatively. Histological scoring, Sulfated Glycosaminoglycans (GAGs) analysis and real-time PCR were performed at 15 months. The correlation between histological score, GAGs and T1ρ values were also analyzed.ResultsThe results showed that the mean T1ρ values of nucleus pulposus (NP) and annulus fibrosus (AF) in the bleomycin group significantly decreased after 3 and 6 months respectively, followed by slowly decrease until at 15 months. At 15 months, the histological scores was significantly higher, and the GAGs of NP was significantly lower in the bleomycin group, compared with the control group (P < 0.05). The results of real-time PCR revealed a significant increase in matrix metalloprotease (MMP)-3, A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-5, tumor necrosis factor α, interleukin-1β, interleukin-6 expressions, transforming growth factor (TGF-β1) and marked reduction in aggrecan, type II collagen, von willebrand factor (vWF) expressions at the mRNA levels in the bleomycin group. Spearman correlation analysis showed a strong positive correlation between GAGs and T1ρ values of NP (r =0.740, P < 0.01), and a significant inverse correlation between histological score and T1ρ values of NP and AF (r = -0.761, r = -0.729, respectively, P < 0.01).ConclusionsInjection of bleomycin into the subchondral bone adjacent to the lumbar IVDs of rhesus monkeys can results in mild, slowly progressive disc degeneration, which mimics the onset of human disc degeneration. T1ρ MR imaging is an effective and noninvasive technique for assessment of early stage disc degeneration.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2474-15-340) contains supplementary material, which is available to authorized users.

MicroRNA-494 inhibition protects nucleus pulposus cells from TNF-α-induced apoptosis by targeting JunD

“…Therefore, we believe that miR-494 plays a critical role in TNF-a-induced HNPC apoptosis. Recently, biological therapies for early interventions for degenerative disc disease have been introduced and developed [34]. The protection of NP cells from apoptosis is essential for the prevention of intervertebral disc degeneration.…”

MMPs and ADAMTSs in intervertebral disc degeneration

“…In a rabbit IDD model that was established by an annular stab with a 16-gauge needle to the L2-L3, L3-L4, and L4-L5 discs, MMP-3 gene expression in NP tissue markedly increases at 3 weeks, decreases to a low level from 6 to 12 weeks, and then has a second, late peak at 24 weeks, revealing a double peak characteristic [41]. Wei et al also reported that the levels of MMP-3 mRNA are significantly increased at 15 months in degenerative IVD tissue induced by bleomycin in the rhesus monkey [42]. Interleukin 1 (IL-1) is potentially important in the pathogenesis of IDD, because it can promote production of matrix degradation enzymes and inhibit matrix synthesis.…”

A Momentary Impact Injury of Vertebral Endplates, even without Structural Disruption, Initiates Disc Degeneration In Vitro.

“…Intervertebral disc degeneration (IDD) is strongly associated with low back pain (LBP) [1,2], which accounts for about $100 billion in annual medical expenditure lost wages, and decreased productivity in the of the United States [3]. Degeneration of the disc is usually attributed to aging ageing, genetic, mechanical, and nutritional factors, the environment and individual which is characterized by a decrease in proteoglycans, cell population, water content, and loss of disc height [4]. The environment and behavioral factors et al [4,5].are also believed to in uence this degenerative process [5].…”

“…Degeneration of the disc is usually attributed to aging ageing, genetic, mechanical, and nutritional factors, the environment and individual which is characterized by a decrease in proteoglycans, cell population, water content, and loss of disc height [4]. The environment and behavioral factors et al [4,5].are also believed to in uence this degenerative process [5].…”