gms | German Medical Science

Objectives: Degenerative Disc Disease (DDD) is a major cause for low back pain, accounting for significant global socioeconomic burden. DDD is associated with extracellular matrix degradation, release of proinflammatory cytokines, altered spinal biomechanics, and neovascularization. Recent research identified the expression of the tissue-Renin-Angiotensin-System (tRAS) in the rat and bovine intervertebral disc (IVD). The major effector of tRAS is Angiotensin II, which participates in proinflammatory pathways. As inflammation contributes to DDD, the present study sought to investigate whether tRAS is expressed in the human IVD in order to assess whether tRAS factors might function as potential target for novel anti-inflammatory treatment approaches.

Methods: IVD tissue was collected during spine surgery of patients undergoing spinal fusion. Tissue samples were distributed into 4 groups according to principal diagnosis: trauma (n=9, 62±19 years (y)), degeneration (n=47, 62±17y), scoliosis (n=6, 48±24y) and infection (n=2, 69±7y). Gene expression levels of tRAS components, proinflammatory, and catabolic markers in the IVD tissue were assessed by real-time PCR. IVD tissue was analyzed for determination of hydroxyproline (OHP) and glycosaminoglycan (GAG) content. Immunohistochemistry was performed to identify tRAS components within IVD tissue. Radiographic and clinical outcome measures of patients donating IVD tissue were extracted. Statistical analyses were performed using Mann-Whitney and Kruskal-Wallis test and Graphpad Prism v6.0. P-values <0.05 were considered statistically significant.

Results and conclusion: Gene expression of tRAS components such as angiotensin-converting-enzyme (ACE), ang-II-receptor-Type-2, angiotensinogen (AGT), and cathepsin D (CTSD) in human IVDs was confirmed. IVD samples were classified into 2 groups: one group expressing tRAS (n=21) and the other group which did not express tRAS (n=37). tRAS positive samples revealed significantly higher molecular signaling of interleukin 6 (IL6), tumor necrosis factor-α, disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) 4 and 5 compared to tRAS-negative samples.

Furthermore, within tRAS-positive samples, AGT, MMP13, MMP3, IL1, IL6 and IL8 were significantly higher expressed in trauma compared to degenerated IVDs. Immunohistochemistry confirmed the presence of Angiotensin 2 in the human IVD.

The present study confirmed the existence of tRAS in the human IVD on gene and protein level. Increased expression levels of proinflammatory and catabolic markers in the tRAS-positive group compared to the tRAS-negative group suggest a correlation between tRAS expression, inflammation, and ultimately DDD. The absence of Renin strengthened the hypothesis of CTSD being a renin-like-enzyme. Future studies will investigate whether a local inhibition of tRAS components might slow down the progression of DDD and relieve pain.