New treatment strategies for canine intervertebral disc degeneration

Abstract

Degeneration of the intervertebral disc (IVD) is a common problem in dogs and humans. IVD degeneration can lead to herniation of the IVD with subsequent compression of neural structures and various clinical signs, including back pain. Current treatment of IVD disease is conservative or surgical. However, these therapies do not restore health or functionality to the IVD and may lead to spinal instability and recurrence of clinical signs. Therefore, the aim of this thesis was to investigate the process of IVD degeneration and develop new treatment strategies for dogs with IVD degenerative disease, as well as for humans with IVD degenerative disease using the dog as a research model for translational research purposes. The key findings of the thesis were: Surgical treatments for canine IVD disease that involve partial removal of the IVD result in a significant loss of disc height and spinal stability. Additional stabilization and restoration of IVD functionality are required for optimal treatment of dogs with IVD degenerative diseases. Pedicle screw-rod fixation of the lumbosacral junction can successfully stabilize spinal segments affected by IVD degeneration in middle-sized and large-breed dogs. Although this procedure does not result in interbody fusion of the spinal segment, the surgical outcome is successful and appears to restore the propulsive function of the hind limbs in patients affected by degenerative lumbosacral stenosis. Ways to improve the surgical technique to achieve spinal fusion have been identified. Functional repair of the nuclectomized IVD can be achieved by inserting a nucleus pulposus prosthesis into the nuclear cavity created after nuclectomy. The success of prosthesis insertion can be evaluated by radiography, computed tomography, and magnetic resonance imaging. When intact, in situ, and with adequate closure of the annulus fibrosus, the prosthesis significantly restores disc height and spinal stiffness to the nuclectomized spinal segment, and therefore may serve as a valuable future treatment for dogs with IVD disease. IVD degeneration alters the biomechanics of the spine. The spinal biomechanics of chondrodystrophic dogs (with nucleus pulposus rich in chondrocyte-like cells) and non-chondrodystrophic dogs (with nucleus pulposus rich in notochordal cells) are markedly different, probably as a result of differences in the cell population and the extracellular matrix of the nucleus pulposus, and other biomechanical factors. The notochordal cell, the main cell type of the healthy canine nucleus pulposus, exhibits basal canonical Wnt signaling. Early IVD degeneration, which involves the replacement/differentiation of notochordal cells by/into chondrocyte-like cells, is associated with down-regulation of canonical Wnt signaling and with a decreased expression of caveolin-1, a protein that appears to be fundamental to the preservation of notochordal cells. Early IVD degeneration is accompanied by significant changes in the expression of genes involved in numerous biomolecular signaling pathways, including extracellular matrix remodeling and bone morphogenetic protein signaling. These findings might facilitate the design of strategies for IVD regeneration and help clarify several points debated in the current scientific literature.