Abstract
Herniation of the intervertebral disc (IVDH) is the most common cause of neurological and intervertebral disc degeneration-related diseases. Since the disc starts to degenerate before it can be observed by currently available diagnostic methods, there is an urgent need for novel diagnostic approaches. To identify molecular networks and pathways which may play important roles in intervertebral disc herniation, as well as to reveal the potential features which could be useful for monitoring disease progression and prognosis, multi-omics profiling, including high-resolution liquid chromatography-mass spectrometry (LC-MS)-based metabolomics and tandem mass tag (TMT)-based proteomics was performed. Cerebrospinal fluid of nine dogs with IVDH and six healthy controls were used for the analyses, and an additional five IVDH samples were used for proteomic data validation. Furthermore, multi-omics data were integrated to decipher a complex interaction between individual omics layers, leading to an improved prediction model. Together with metabolic pathways related to amino acids and lipid metabolism and coagulation cascades, our integromics prediction model identified the key features in IVDH, namely the proteins follistatin Like 1 (FSTL1), secretogranin V (SCG5), nucleobindin 1 (NUCB1), calcitonin re-ceptor-stimulating peptide 2 precursor (CRSP2) and the metabolites N-acetyl-D-glucosamine and adenine, involved in neuropathic pain, myelination, and neurotransmission and inflammatory response, respectively. Their clinical application is to be further investigated. The utilization of a novel integrative interdisciplinary approach may provide new opportunities to apply innovative diagnostic and monitoring methods as well as improve treatment strategies and personalized care for patients with degenerative spinal disorders.
Highlights
Lower back pain (LBP) is a common disorder with a lifetime prevalence over 70% in the global human population, causing major human health problems and extensive health care utilization [1]
The principal component analysis (PCA) score plot revealed two clear clusters of samples, with the intervertebral disc herniation (IVDH) group being more heterogeneous based on tandem mass tag (TMT)-based proteomic results (Supplementary Figure S1)
The lists of significantly changed genes and metabolites were imported into the Metscape, and human was set as a model organism, to obtain pathway-based CompoundReaction-Enzyme-Gene (C-R-E-G) network using standard workflow. Complex conditions, such as IVDH, require a systems biology-based approach that can reveal progressive structural and functional changes of patients and various pathophysiological processes that could be linked to the disease severity and patient’s outcome
Summary
Lower back pain (LBP) is a common disorder with a lifetime prevalence over 70% in the global human population, causing major human health problems and extensive health care utilization [1]. LBP may be caused by degenerative spinal disorders (intervertebral disc damage—herniation or fractures), vertebral infections, or even cancer [2]. Experimental animals have been used to study degenerative spinal disorders, according to 3R (reduction, refinement and replacement) principles, dogs are reported as the most suitable translational model for biomechanical studies and surgical procedures of the spine and related pathophysiological processes [1,3,4]. Intervertebral disc herniation (IVDH)-related diseases are the most common cause of spinal cord injury and sensory deficiency [1]. The canine intervertebral disc (IVD) is an elastic structure located between the bony vertebrae and is responsible for the stability and flexibility of the vertebral column [5]. The healthy intervertebral disc consists of the inner nucleus pulposus (NP) encompassing the annulus fibrosus (AF) which, together with the cartilaginous endplates, abut the vertebrae [6].
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