Abstract
IntroductionEarly degeneration of the intervertebral disc (IVD) involves a change in cellular differentiation from notochordal cells (NCs) in the nucleus pulposus (NP) to chondrocyte-like cells (CLCs). The purpose of this study was to investigate the gene expression profiles involved in this process using NP tissue from non-chondrodystrophic and chondrodystrophic dogs, a species with naturally occurring IVD degeneration.MethodsDual channel DNA microarrays were used to compare 1) healthy NP tissue containing only NCs (NC-rich), 2) NP tissue with a mixed population of NCs and CLCs (Mixed), and 3) NP tissue containing solely CLCs (CLC-rich) in both non-chondrodystrophic and chondrodystrophic dogs. Based on previous reports and the findings of the microarray analyses, canonical Wnt signaling was further evaluated using qPCR of relevant Wnt target genes. We hypothesized that caveolin-1, a regulator of Wnt signaling that showed significant changes in gene expression in the microarray analyses, played a significant role in early IVD degeneration. Caveolin-1 expression was investigated in IVD tissue sections and in cultured NCs. To investigate the significance of Caveolin-1 in IVD health and degeneration, the NP of 3-month-old Caveolin-1 knock-out mice was histopathologically evaluated and compared with the NP of wild-type mice of the same age.ResultsEarly IVD degeneration involved significant changes in numerous pathways, including Wnt/β-catenin signaling. With regard to Wnt/β-catenin signaling, axin2 gene expression was significantly higher in chondrodystrophic dogs compared with non-chondrodystrophic dogs. IVD degeneration involved significant down-regulation of axin2 gene expression. IVD degeneration involved significant down-regulation in Caveolin-1 gene and protein expression. NCs showed abundant caveolin-1 expression in vivo and in vitro, whereas CLCs did not. The NP of wild-type mice was rich in viable NCs, whereas the NP of Caveolin-1 knock-out mice contained chondroid-like matrix with mainly apoptotic, small, rounded cells.ConclusionsEarly IVD degeneration involves down-regulation of canonical Wnt signaling and Caveolin-1 expression, which appears to be essential to the physiology and preservation of NCs. Therefore, Caveolin-1 may be regarded an exciting target for developing strategies for IVD regeneration.
Highlights
Degeneration of the intervertebral disc (IVD) involves a change in cellular differentiation from notochordal cells (NCs) in the nucleus pulposus (NP) to chondrocyte-like cells (CLCs)
QPCR analysis revealed no significant differences in the expression of the notochordal markers Brachyury and Cytokeratin 8 in the different histopathological stages in non-chondrodystrophic dogs, indicating that the expression of NC marker genes was preserved in all histopathological stages despite significant changes in IVD morphology (Figure 2 and Additional file 3)
These results suggest that in chondrodystrophic dogs the transition from NC-rich to CLC-rich NP involves a significant downregulation in NC marker gene expression
Summary
Degeneration of the intervertebral disc (IVD) involves a change in cellular differentiation from notochordal cells (NCs) in the nucleus pulposus (NP) to chondrocyte-like cells (CLCs). Degeneration of the intervertebral disc (IVD) is a major cause of low back pain, a major health problem in the Western world [1]. Surgical therapies include decompression with partial discectomy (removal of the diseased IVD tissue), spinal fusion of the affected segment, or partial or total artificial IVD replacement [2,3] These surgical therapies are generally successful, they are suboptimal since they are not curative and are associated with various complications: decompression/partial discectomy results in spinal instability, spinal fusion can result in adjacent segment degeneration, and IVD replacements/prostheses are associated with failure of the surgical implants [4,5,6,7,8,9]. The biomolecular events involved in IVD degeneration remain largely unexplored [11,12,13]
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