Differential MMP 1 and MMP 13 expression in proliferation and ligamentization phases of graft remodeling in anterior cruciate ligament reconstruction

Purpose: Graft remodeling in anterior cruciate ligament reconstruction (ACLR) demonstrates three distinct phases: necrosis, proliferation and ligamentization. Biological enhancement involves modulating these processes, but the cellular activities related to extracellular matrix remodeling have not been investigated. We hypothesized that changes in matrix metalloproteinases (MMPs) 1 and 13 expression are involved in the transition of proliferation phase to ligamentization phase of graft remodeling. Materials and methods: Thirty-three rats underwent ACLR. Tendon grafts were harvested at week 1 (necrosis), 2 (proliferation), or 12 (ligamentization) post-operation for histological examination (n = 3), or for isolation of graft-derived cells (n = 8) for flow cytometry, proliferation assay, cell invasion assay, measurement of gene expression related to matrix remodeling (Col1A1, Col3A1, MMP1, tissue inhibitor of marix metalloproteinase 1 (TIMP1), and MMP13) and total MMP activities. Results: Increased cellularity in tendon graft was contributed by active cell proliferation and migration at week 2 post-operation, while decreased cellularity were paralleled by increased apoptosis at week 12. All genes measured (Col1A1, Col3A1, MMP1, TIMP1, and MMP13) increased significantly in week 2 cells compared to week 1 cells. MMP1 expression subsided at week 12, while MMP13 expression kept increasing till 12 weeks post-operation. Total MMP activities was 3-fold higher in cultured graft-derived cells from week 2 as compared to cells from week 12. Two distinct processes of graft remodeling were identified, characterized by increased MMP1 expression with cell proliferation and increased MMP13 expression with cell apoptosis. Conclusions: Unfavorable matrix remodeling during the proliferation phase is found with increased MMP1, while remodeling leading to ligamentization is associated with increased MMP13 expression.