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

Abstract

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.

XCR1 promotes cell growth and migration and is correlated with bone metastasis in non-small cell lung cancer

“…MMP2 and MMP9 were reported as the activators of osteoclast differentiation and tumor cell invasion [28,29]. Meanwhile, the overexpression of MMP2 and MMP9 in lung cancer has been confirmed previously [30].…”

Gene Expression in Osteolysis: Review on the Identification of Altered Molecular Pathways in Preclinical and Clinical Studies

“…Three different models of osteolysis were adopted: air-pouch [16,29,33,56,57,58,59,60], calvarial [18,53,61,62,63,64] and pin-implantation [65] models. One study compared two methods to induce osteolysis in vivo: fluid pressure and particle injection [55].…”

“…Opposite to what was observed in vitro, these in vivo studies used only two types of wear particles: Ti [16,29,33,53,55,56,57,58,59,60,64,65], the most employed ones, and PE [18,61,62,63]. The size of Ti particles ranged between 0.1 and 20 µm while PE particles were 7 [61,62,63] or 5.1 [18] µm.…”

“…The size of Ti particles ranged between 0.1 and 20 µm while PE particles were 7 [61,62,63] or 5.1 [18] µm. The amount of Ti particles varied from 10 to 150 mg/mL in the murine air-pouch model [16,29,33,53,56,57,58,59,60,65] to 300 mg/mL in the murine calvarial model [64]. The amount of PE was between 0.5 and 20 mg/mL [18,61,62,63] (Table 2).…”

Are Biologic Treatments a Potential Approach to Wear- and Corrosion-related Problems?

“…These agents include estrogen receptor antagonist to block TNF production and luteolin to inhibit TNF, both agents reducing osteolysis [29,42]. Intraperitoneal application of the antibiotic tetracycline as an inhibitor of matrix metalloproteinase-9 decreased RANKL production [10]. Application of the p38 mitogen-activated protein (MAP) kinase inhibitor SB203580 decreased osteolysis [9].…”