MMP-9 inhibition suppresses wear debris-induced inflammatory osteolysis through downregulation of RANK/RANKL in a murine osteolysis model.

Wear debris-induced osteolysis in periprosthetic tissue with aseptic loosening is a serious problem after total joint arthroplasty. Matrix metalloproteinase-9 (MMP-9) is expressed in osteoclast cells that surround loosening peri-implant tissue, but the molecular mechanism of MMP-9 action in wear debris-induced osteolysis remains ambiguous. We used a murine osteolysis model to examine the hypothesis that administration of an MMP-9 inhibitor reduces the expression of receptor activator of nuclear factor-κB (RANK) and nuclear factor-κB ligand (RANKL) and, thereby, suppressesdebris-induced inflammatory osteolysis. Experiments were performed in 3 groups of 15 mice: a control, a titanium (Ti) and a Ti plus tetracycline group. To provoke inflammatory osteolysis, calvarial bone was implanted from syngeneic littermates, followed by injection of Ti particles into established air pouches for all groups except the control. Tetracycline was administered daily by intraperitoneal (i.p.) injection, and PBS was administered by i.p. injection to the control and Ti groups. Mice were sacrificed 14 days after bone-Ti implantation. Pouch membranes with the intact bone implants were collected for histological and molecular analysis. Tetracycline had minimum effect on the expression of MMP-9 and tumor necrosis factor-α (TNF-α) but it decreased gene activation and inhibited the expression of RANK and RANKL, thereby inhibiting Ti-particle-induced inflammatory osteolysis. Tetracycline decreased the number of tartrate-resistant acid phosphatase (TRAP)-positive cells in the pouch tissues. Our results in the murine osteolysis model suggest that through the downregulation of RANK/RANKL, tetracycline significantly inhibits debris-induced inflammatory osteolysis. Its use in clinical practice may help prevent complications experienced by patients who have undergone total joint arthroplasty.