Abstract
Total hip arthroplasty (THA) wear debris induced macrophage expression of pro-inflammatory cytokines has been associated with osteolysis both in vitro and in animal and human subjects. Interleukin-1 receptor antagonist (IL-1RA) is an anti-inflammatory cytokine which may limit bone destruction. Polymorphisms (SNPs) within the IL-1RN gene are associated with differences in susceptibility to infectious and inflammatory conditions and disorders of bone remodelling. This study investigated the association between the IL-1RA+2018T/C SNP (rs419598) and osteolysis after THA, and with mRNA and protein expression in an in-vitro wear debris-macrophage stimulation assay.
611 North European Caucasians who had received a cemented THA for primary osteoarthritis were genotyped for the IL-1RN+2018 SNP using Taqman methods. 62 subjects with a Charnley THA were selected from the genotyping population. Control subjects had no radiographic osteolysis and the osteolysis group had previously undergone revision surgery for aseptic loosening. Peripheral blood mononuclear cells were extracted and stimulated with endotoxin-stripped titanium particles (TiCL, endotoxin level 0 Eu/ml) and endotoxin-stripped particles with adherent LPS added back (TiAB, endotoxin level 140 Eu/ml); non-stimulated and LPS-stimulated cells were used as negative and positive controls. Cell lysate IL-1RA mRNA levels were assessed by rqRT-PCT following a 3-hour stimulation. Cell supernatant IL-1RA protein levels were assayed after 24 hours stimulation using a multiplex method.
The IL-1RN+2018C allele was underrepresented in patients with osteolysis after THA versus control THA subjects (chi-squared test 5.96, P=0.015). After correction for other risk factors for osteolysis, the adjusted odds ratio for osteolysis associated with carriage of the IL-1RN+2018C SNP was 0.69 (0.48 to 0.99, p=0.048). IL-1RA mRNA expression increased linearly with IL-1RN+2018C allele copy number in gene-dose dependent manner (ANOVA p=0.013). The IL-1RA+2018C allele did not significantly affect IL-1RA protein expression (ANOVA p> 0.05), however a similar trend towards increased levels with increased C allele copy number was observed.
Carriage of the IL-1RA+2018C allele is associated with both a decreased risk of osteolysis after THA and increased IL-1RA mRNA expression in-vitro. The mechanism for this functional effect remains unclear, however these findings support the importance of the IL-1RA in osteolysis and aseptic loosening.
Correspondence should be addressed to Dr Roger Bayston, Division of Orthopaedic and Accident Surgery, Queen’s Medical Centre, Nottingham, NG7 2UH, England.
