Alendronate retards the progression of lumbar intervertebral disc degeneration in ovariectomized rats

摘要

Objective: Increasing evidence has revealed a positive correlation between postmenopausal osteoporosis and intervertebral disc degeneration, the underlying mechanism of which might be associated with changes in the vertebral bone and endplate. Alendronate (ALN) can increase bone mass and improve the microstructure of osteoporotic vertebrae, which might be helpful in preserving disc morphology and mechanical properties. This study aims to investigate the effects of ALN on lumbar intervertebral disc degeneration related to osteoporosis using an ovariectomized (OVX) rat model. Methods: Thirty female Sprague-Dawley rats aged 3. months were randomly divided into three groups (with 10 rats each) as follows: the Sham group underwent sham surgery; the OVXALN group had twice-a-week subcutaneous injections of ALN (15. μg/kg) for 6. months. The OVXV group received an equivalent volume of saline solution as placebo post-OVX. After animals were sacrificed at 6. months post-OVX, the L3-6 spinal segments were harvested. Bone mineral density (BMD), micro-CT analysis and biomechanical testing were performed to evaluate the bone quality and microstructural changes in the lumbar vertebral bodies. Histological analysis with van Gieson stain and the histological score were used to identify the characteristics of the degenerative discs. The disc height and the thickness of the cartilage endplate were measured and compared. Immunohistochemistry and real-time PCR measurements for aggrecan, type I collagen, type II collagen, and matrix metalloprotease (MMP)-1, MMP-3 and MMP-13 expressions on the disc were performed to assess the underlying molecular signaling changes in matrix metabolism during intervertebral disc degeneration. Results: The OVXALN group significantly maintained vertebrae BMD, percent bone volume and biomechanical strength, when compared with the OVXV group. Histological evaluation suggests that there was no significant difference in disc height between the OVXALN and Sham groups, and ALN significantly prevented cartilage endplate thickening and the development of abnormal bony tissues within the cartilage endplate. The histological score in the OVXALN group was significantly lower than the OVXV group, suggesting that ALN treatment was effective in delaying the process of the disc degeneration. The results of molecular analysis revealed a significant increase in aggrecan and type II collagen expressions, but marked reductions in MMP-1, MMP-3 and MMP-13 expressions at both the protein and mRNA levels in the OVXALN group. Conclusions: ALN can retard the progression of lumbar intervertebral disc degeneration in OVX rats. The underlying mechanisms might be related to preservation of the structural integrity and function of the adjacent structures, including the vertebrae and endplates, which further links with modulations in extracellular matrix metabolism to protect the disc from degeneration. These results suggest that ALN might be a promising drug agent for preventing lumbar intervertebral disc degeneration related to osteoporosis.