Protection against titanium particle‐induced osteoclastogenesis by cyclooxygenase‐2 selective inhibitor

Abstract

Wear particle-induced osteoclastogenesis is the most common cause of aseptic loosening in total joint arthroplasty. Although cyclooxygenase (COX)-2, an inducible regulator of prostaglandin E2 (PGE2) synthesis, is known to be involved in osteoclast differentiation, its effect on osteoclastogenesis in response to wear particles remains unclear. In this study, we investigated the role of COX-2 in the regulation of osteoclast differentiation in the osteoclast precursor cell line RAW264.7 stimulated with titanium (Ti) particles. The results showed COX-2 expression in the early stages of RAW264.7 differentiation when stimulated with receptor activator of nuclear factor kappa B ligand (RANKL) and Ti particles. Blockade of COX-2 by celecoxib, a COX-2 selective inhibitor, effectively reduced the expression of PGE2 and inhibited differentiation of RAW264.7 cells into tartrate-resistant acid phosphatase-positive (TRAP+) osteoclastic cells. Quantitative real-time polymerase chain reaction revealed that celecoxib inhibited mRNA expression of RANK, cathepsin K (CPK), TRAP, and the nuclear factor of activated T cells c1 (NFATc1) in RAW264.7 cells stimulated by Ti particles and RANKL. Moreover, exogenous PGE2 reversed the inhibitory effects of celecoxib. These results provide direct evidence that COX-2 dependent PGE2 induced by RANKL and Ti particles is required for osteoclastogenesis and suggests that reduced production of PGE2 by inactivation of COX-2 would provide a promising therapeutic target for the treatment of osteoclastogenesis induced by wear particles.

Strontium inhibits titanium particle-induced osteoclast activation and chronic inflammation via suppression of NF-κB pathway

“…Infiltration of multinucleated osteoclast in model and peri-prosthesis tissue has been well defined, and our previous work confirmed that Ti particles significantly increased osteoclastogenesis in vivo and in vitro 891213. Therapeutic strategy targeting osteoclast formation significant inhibits particle-associated bone resorption1013.…”

“…Briefly, there are three important events in wear particle-induced-osteolysis, including chronic inflammation, osteoclast formation, and osteoclastic bone resorption5678910111213. Particles worn from prosthesis are easily phagocytized by the peri-prosthetic phagocytes in the tissue4.…”

“…Particles worn from prosthesis are easily phagocytized by the peri-prosthetic phagocytes in the tissue4. Engulfing these wear particles, phagocytes can be activated and secrete amount of pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and IL-65791112. These factors mediate fibroblasts and osteoblasts secreting high levels of receptor activator of nuclear factor-κB (RANK) ligand (RANKL)1415.…”

Titanium particle-induced osteogenic inhibition and bone destruction are mediated by the GSK-3β/β-catenin signal pathway

“…To understand the biology between wear debris and aseptic loosening, we and others previously investigated how wear debris affects osteoclast stimulation. 17, 18 However, particle exposure not only has a direct effect on bone homeostasis by stimulating osteoclastogenesis, but also has adverse effects on osteoblastogenesis. 19 Recent studies demonstrated that marked impairment of bone formation from reduced osteoblast activity was a common feature of peri-prosthesis in wear particle-induced osteolytic bone disease.…”

Inhibiting wear particles-induced osteolysis with naringin

“…Therefore, wear particles may cause adverse biological reactions in the following order: inflammation, increased osteoclastogenesis, and subsequent osteoclastic bone resorption [11]. Since osteoclastogenesis and osteoclast activation play essential roles in wear particles-induced osteolysis, inhibiting osteoclastogenesis and osteoclast function should be an important therapeutic strategy for the treatment of aseptic loosening after total joint replacement [12,13].…”