Increased matrix metalloproteinase‐2 in ligamentum flavum hypertrophy and the regulation of MMP‐2/TIMPs by elastin‐derived peptides

Abstract

The study aimed to examine matrix metalloproteinase‐2 (MMP‐2) expression in a rat ligamentum flavum (LF) hypertrophy model in vivo, and the effect of elastin‐derived peptides (EDPs) on MMP‐2 and tissue inhibitors of metalloproteinases (TIMPs) in rat LF cells in vitro. Surgical destabilization was performed at the rat spinal L3/4 level to induce increased mechanical stress. Rats were killed at 6‐ and 12‐weeks postsurgery for histological staining, immunohistochemical staining, RT‐qPCR and western blot. 100 µg/mL EDPs were applied to isolated normal rat LF cells, with or without pretreatment of elastin receptor complex (ERC) inhibitors, to assess the expression of MMP‐2, TIMP‐1, and TIMP‐2. Spinal destabilization led to LF hypertrophy, observed through increased LF thickness and area, along with histological changes of chondrometaplasia and elastic fiber degradation. LF was also stained positively for Col I and Col II, where elastic fiber has broken down. MMP‐2 expression was notably elevated in the hypertrophied LF, accompanied by increased TIMP‐2 and TIMP‐3 levels. EDPs were found to suppress MMP‐2 expression and reduce TIMP‐1 and TIMP‐2 levels in rat LF cells. Interestingly, exposure to EDPs led to a significant rise in MMP‐2/TIMP‐1 and MMP‐2/TIMP‐2 ratios, dependent on the ERC. Collectively, the study suggests that increased MMP‐2 activity contributes to elastic fiber degradation in hypertrophied LF, generating EDPs that further enhance the MMP‐2/TIMPs ratio in LF cells in an ERC‐dependent manner. Further research is essential to delve into the mechanisms of EDPs in LF hypertrophy.