Study Design. Experimental animal study. Objective. The aim of this study was to clarify chronological effects of mechanical stress on ligamentum flavum (LF) using a long-term fusion rabbit model. Summary of Background Data. LF hypertrophy is a major pathology of lumbar spinal stenosis (LSS), but its mechanism remains unclear. We previously demonstrated mechanical-stress-induced LF hypertrophy with a rabbit model. However, we only investigated LFs at a single time point in the short-term; the effects of long-term mechanical stress have not been elucidated. Methods. Eighteen-week-old male New Zealand White rabbits were randomly divided into two groups: the mechanical stress group underwent L2–3 and L4–5 posterolateral fusion and resection of the L3–4 supraspinal muscle, whereas the control group underwent only surgical exposure. Rabbits were sacrificed 16 and 52 weeks after the procedure. Axial specimens of LFs at L3–4 were evaluated histologically. Immunohistochemistry for alpha-smooth muscle actin (α-SMA) was performed to assess the numbers of vessels and myofibroblasts. Results. In the mechanical stress group, LFs at the L3–4 level exhibited hypertrophy with elastic fiber disruption and cartilage matrix production at 16 and 52 weeks. A trend test indicated that mechanical stress induced LF hypertrophy, elastic fiber disruption, and cartilage matrix production in a time-dependent manner, with the lowest levels before treatment and the highest at 52 weeks. Immunostaining for α-SMA showed similar numbers of vessels in both groups, whereas the percentage of myofibroblasts was significantly larger at 16 and 52 weeks in the mechanical stress group than in the control group. Conclusion. We demonstrated that long-term mechanical stress caused LF hypertrophy with progressive elastic fiber disruption and cartilage matrix production accompanied by enhanced myofibroblasts. In addition, the reported rabbit model could be extended to elucidate the mechanism of LF hypertrophy and to develop new therapeutic strategies for LSS by preventing LF hypertrophy. Level of Evidence: SSSSS
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