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A significant obstacle to the study of degenerative disc disease and therapeutic strategies to treat DDD has been the lack of a suitable animal model. Here, we detail a mechanistic investigation of the changes in the molecular phenotype of the cells within the intervertebral disc in a preclinical rodent model of IVD degeneration following needle puncture.Material and Methods   Using a stereotactic device and fluoroscopic imaging control, we injured four IVDs/tail using 12-week-old female wistar rats and a 26-gauge needle. The needle was directed completely through the IVD annulus fibrosus (AD) to emerge through the contralateral annulus. The needle was then retracted back into the NP and after 1 minute, the needle was slowly removed over a further minute. The animals were allowed to recover for 10 weeks following which they were humanely euthanized and the discs recovered for biochemical, immunohistochemical, and protein analysis (Western blots).Results   The healthy rat NP changes drastically 10-weeks following needle puncture injury such that the former notochordal cell-rich NP assumes a fibrocartilaginous phenotype by 10 weeks. Initially, there is an increase in the expression of the notochordal cell markers galectin-3 and brachyury beginning at 72 hours; however, these are undetectable by 10 weeks with only scant appearance of immunopositive cells. Before injury, there are barely detectable chondrocyte-like cell (CLC) markers such as carbonic anhydrase-12 and Sox9, however, following injury there is a steady increase in their expression maximizing by 4 to 8 weeks. The strong expression of the stemness marker Oct3/4 steadily increases its expression post injury that reaches a peak at 6 weeks; however, this stemness marker is undetectable at 10 weeks. A similar trend is seen with the cell signaling protein β-catenin that is barely detectable at baseline but is strongly expressed at 72 hours postinjury and steadily increases until 4 weeks and then decreases to lower level expression at 10 weeks. There is an increase in the expression of collagen types 1 and 2 beginning 72 hours postinjury with a continued increase through 10 weeks. Interestingly, there is a reciprocal relationship between the matrix metalloproteinases (MMPs) and the tissue inhibitors of MMPs (TIMPS). MMP-3 and MMP-13 become detectable at 8 to 10 weeks precisely following the steady increase in expression of the natural inhibitor TIMP-1 which is completely undetectable when MMP-3 and MMP-13 increase their expression. ADAMTS-4 gradually increases its expression beginning at 72 hours through 8 weeks but is undetectable at 10 weeks.Conclusion   Here, for the first time, we present a novel method of inducing degeneration in the rat tail IVD disc and have quantified the changes in the molecular phenotype of the IVD over 10 weeks. The injured rat tail IVD goes through a significant alteration in cellular and extracellular configuration that suggests a failed attempt on the part of notochordal and stem cells to induce repair resulting in the development of a fibrocartilaginous NP. This animal model and our characterization in the changes that causes postinjury can be used to quantify the effects of potential biological therapies in the treatment of DDD.

global spine journal

A Quantitative Assessment of the Changes in the Molecular Phenotype of the Rat Tail Intervertebral Disc Induced by Stereotactic, Image-Guided Needle Puncture