Protective effect of p38 MAPK inhibitor on wear debris-induced inflammatory osteolysis through downregulating RANK/RANKL in a mouse model

Abstract

ABSTRACT. Aseptic loosening associated with wear particle-induced inflammation is a major cause of joint implant failure. Recent studies have demonstrated the therapeutic effects of p38 mitogen-activated protein kinase (MAPK)-based therapies on chronic inflammatory diseases. The purpose of this study was to investigate whether SB203580, a p38 MAPK inhibitor, inhibits wear debris-induced inflammatory osteolysis in mice through downregulation of receptor activator of nuclear factor kβ (RANK)/RANK ligand (RANKL). We used a murine osteolysis model to study the effect of SB203580 on RANKL/RANK signaling and titanium particle-induced osteolysis in vivo. Pouch membranes p38 inhibitor on wear debris-induced inflammatory osteolysis with intact bone implants were analyzed using histological analysis and transmission electron microscopy, and the levels of RANK and RANKL protein and mRNA were evaluated by immunohistological staining and real-time reverse transcriptase-polymerase chain reaction. SB203580 had less of an effect on RANK and RANKL expression under wear debris-induced conditions. The number of TRAP-positive cells was remarkably reduced in Ti-particle-induced pouch tissues. These effects were confirmed through the transmission electron microscopy results. These results suggest that p38 MAPK-based therapies are beneficial in preventing aseptic loosening associated with total joint replacement by modulating RANK-RANKL signaling.

Blockade of NF-κB and MAPK pathways by ulinastatin attenuates wear particle-stimulated osteoclast differentiation in vitro and in vivo

“…These results indicate that UTI inhibited the secretion of proinflammatory mediators in LPS/PMMA-activated cells. In addition, the murine osteolysis model of distal femur is believed to mimic the pathological processes of wear particle-induced osteolysis in humans [34,35]. The high dose of UTI (5000 units/kg per day) was chosen to be used in animal models as physiologically relevant.…”

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).…”

“…In the most numerous group of in vivo studies, which employed the murine air-pouch model, the authors agreed that Ti particles increased the expression of genes encoding for inflammatory and catabolic proteins (such as MMP9, TNFα, COX 2 , IL1β and TNF receptor associated factor 6 (TRAF6)), for proteins related to osteoclastogenesis (such as RANK, RANKL and NFATC1), for growth factors (such as VEGFA) and CB2 [16,29,33,58,59,60]. These results were also confirmed in the study employing metallic wear particles obtained from the stem of hip prosthesis containing not only Ti, but also Co and Cr [56].…”