PGE2 and IL‐6 production by fibroblasts in response to titanium wear debris particles is mediated through a Cox‐2 dependent pathway

Abstract

Aseptic loosening of orthopaedic implants is precipitated by wear debris-induced osteolysis. Central to this process are the proinflammatory mediators that are produced in response to wear by the fibroblastic cells, which comprise the majority of periprosthetic membranes. Since this pro-inflammatory cascade is mediated by a plethora of factors with redundant functions, it is imperative to establish a hierarchy. Two well-known fibroblast derived pro-inflammatory factors that stimulate wear debris-induced osteoclastic resorption are prostaglandin E2 (PGE2) and IL-6. However, their relationship to each other in this process is poorly defined. Here we show immunohistochemistry of retrieval membranes indicating that COX-2 is the principal cyclooxygenase responsible for PGEZ production in fibroblasts around failed implants. We also performed in vitro experiments with fibroblasts derived from wild-type (WT), COX-I (-/-) and COX-2 (-/-) mice, which demonstrated that COX-2 is required for Ti wear debrisinduced PGEZ production. Interestingly, COX-2 was also required for IL-6 production in these assays, which could be rescued by the addition of exogenous PGE2 (lo-' M). Pharmacology studies that utilized the COX-1 selective inhibitor SC 560, the COX-2 selective inhibitor celecoxib, and the nonselective COX inhibitor indomethacin confirmed these results. Taken together, these results indicate that selective inhibition of prostaglandin signaling could favorably impact aseptic loosening beyond its direct effects on PGE2 synthesis, in that it inhibits downstream pro-inflammatory/pro-osteoclastic cytokine production.

Selective and non‐selective cyclooxygenase inhibitors delay stress fracture healing in the rat ulna

“…[40][41][42] Our data clearly indicate that COX-2 is also important in resorption associated with focal, directed remodeling in response to fatigue injury. Ibuprofen also inhibited lamellar bone formation within the resorption spaces along the fracture line.…”

Effects of bone cement particles on the function of pseudocapsule-derived fibroblasts

“…Previous studies have also reported that fibroblasts are capable of phagocytosing wear debris and secreting cytokines and RANKL to support osteoclast formation and bone resorption (Bukata et al 2004, Horiki et al 2004. Osteoclastogenesis supported by other sources of fibroblasts happened only in the presence of osteoclastogenic factors other than just M-CSF (such as dexamethasone), while pseudomembrane-derived fibroblasts were able to support osteoclastgenesis and bone resorption only in the presence of M-CSF.…”

“…Not only the fibroblasts from synovium and pseudocapsule (Sakai et al 2002, Mandelin et al 2005b), but also the fibroblasts from skin, spleen and respiratory diaphragm (Quinn et al 2000) have been reported to be able to secrete RANKL and support bone resorption. Using a mouse model, Bukata et al (2004) also proved that fibroblasts could phagocytose particles, which resulted in an increase in the secretion of proinflammatory cytokines. We therefore hypothesized that fibroblasts may play an important role in periprosthetic osteolysis, and that bone cement particles might stimulate secretion of sRANKL as well as other osteoclastogenic factors in fibroblasts, thus contributing to prosthetic osteolysis.…”

Impact of p38 mitogen-activated protein kinase inhibition on immunostimulatory properties of human 6-sulfo LacNAc dendritic cells

“…monocytes), DC remain viable when irradiated [37]. This is because DC (but not classical monocytes) have constitutively active DNArepair systems that repair double-strand DNA-breaks [38].…”