Induction of Interleukin-6 Release in Human Osteoblast-Like Cells Exposed to Titanium Particles In Vitro

Abstract

Orthopaedic wear debris induces release of bone-resorbing factors from macrophages and fibroblasts. However, the extent to which elemental metallic particles induce bone cells to express factors contributing to implant loosening remains unclear. This study showed that exposure of MG-63 osteoblast-like cells to titanium particles at a concentration of 0.30% v/v resulted in a 15-fold increase in IL-6 release into the culture medium after 24 hours, when compared with cells without particles. Northern blots revealed that exposure of MG-63 cells to titanium particles at a concentration of 0.30% v/v for 24 hours increased IL-6 mRNA signal levels by 9.6-fold, when compared with control cultures. Pretreatment of MG-63 cells with cytochalasin B prevented the particle-induced increase of IL-6 expression but did not alter the basal level of IL-6 release from cells cultured in the absence of particles. The protein kinase C inhibitor, H7, and the serine/threonine kinase inhibitor, genistein, abolished the particle-induced increase in IL-6 release at a concentration of 100 microM for each compound. In contrast, an inhibitor of protein kinase A, HA1004, had no effect on the particle-induced increase in IL-6 release. The transcription factors, nuclear factor IL-6 and nuclear factor kappa B, translocated into the nucleus within 1 hour of particle exposure. This study showed that osteoblast-like cells respond to titanium particles through increased expression of the proinflammatory cytokine, IL-6, in a process requiring phagocytosis and intracellular signaling pathways. These results suggest that osteoblasts play a direct role in implant loosening because of localized release of soluble mediators such as interleukin-6.

Inflammatory Microcrystals Alter the Functional Phenotype of Human Osteoblast-Like Cells In Vitro: Synergism with IL-1 to Overexpress Cyclooxygenase-2

“…Previous studies have shown that hOB are capable of IL-6 production in response to proinflammatory cytokines such as IL-1 and TNF and in response to solid particles such as wear debris of various types (18,20,21). Inflammatory microcrystals also stimulated the generation of IL-6 by hOB as reported here.…”

“…The present data indicate that the activation of hOB by MSUM and CPPD microcrystals did not require their internalization by the target cells. Moreover, the functional response of hOB to MSUM and CPPD microcrystals in term of stimulation of PGE 2 and IL-6 production or in term of inhibition of 1,25(OH) 2 D 3 -induced alkaline phosphatase and osteocalcin was of a similar magnitude to that previously reported with various prosthetic wear particles (17,18 (40), the most abundant eicosanoid in bone with anabolic or catabolic effects depending on its local concentration. The present study indicated that MSUM or CPPD microcrystals were capable of stimulating hOB to express a significant activity of COX-2 at concentrations lower than those previously reported for activation of neutrophils in vitro (28,(41)(42)(43)(44)(45).…”

Structural effects of titanium citrate on the human erythrocyte membrane

“…However, the exact effect of titanium on cells is still not well characterized [1]. One of the few studies showed that osteoblast-like cells respond to titanium particles through increased expression of the proinflammatory cytokine interleukin-6 in a process requiring phagocytosis and intracellular signalling pathways [3]. It has also been reported that approximately one third of patients with titanium alloy spinal implants exhibited abnormal 0162-0134/$ -see front matter Ó 2004 Elsevier Inc. All rights reserved.…”

Severe bone defects and reduced mineralization caused by massive metallosis after total knee arthroplasty: histopathologic and bone morphometric findings

“…4 Previous in vitro studies have reported that Ti particles can elicit bone resorption primarily by inducing osteoclast differentiation 5 and this process may be partly mediated by stimulated cytokine release and increased expression of receptor activator of nuclear factor κB ligand (RANKL) by osteoblastic cells. [6][7][8] Tissue responses to Ti particles in vivo have also been reported. Agins et al 9 and Witt and Swann 10 reported that metallosis due to Ti particles was associated with the invasion of numerous histiocytes containing metallic debris into the synovial membrane and periarticular soft tissues.…”