Can simvastatin reduce the inflammatory response to orthopaedic biomaterials?

ABSTRACT NUMBER: NESS PRIZE FOR JUNIOR TRAINEES (BELOW ST3)_1

MAIN ABSTRACT TEXT

Introduction
The most common indication for revision surgery following total hip arthroplasty is aseptic loosening of implants secondary to osteolysis, caused by immune-mediated reactions to implant debris. These debris can cause pseudotumour formation. Toll-like receptor 4 (TLR4) has been shown to mediate immune responses to cobalt ions. Statin use has been associated with reduced risk of revision surgery and there is evidence that statins can modulate TLR4 activity. This study investigates simvastatin’s effect on orthopaedic biomaterial-mediated changes in protein expression of key inflammatory markers and soluble-ICAM-1 (sICAM-1), an angiogenic factor implicated in pseudotumour formation.

Methods
Human macrophage THP-1 cells were pre-incubated with 50µM simvastatin for 2-hours or a vehicle control (VC), before being exposed to 0.75mM cobalt chloride, 50μm3 per cell zirconium oxide or LPS as a positive control, in addition to a further 24-hour co-incubation with 50µM simvastatin or VC. Interleukin -8 (IL-8), sICAM-1, chemokine ligand 2 (CCL2), CCL3 and CCL4 protein secretion was measured by enzyme-linked immunosorbent assay (ELISA). Statistical analysis included a one-way ANOVA.

Results
Pre-treatment with simvastatin significantly reduced LPS and cobalt-mediated IL-8 secretion (n=3) and sICAM-1 protein secretion (n=2) in THP-1 cells. Pre-treatment with simvastatin significantly reduced LPS-mediated but not cobalt ion-mediated CCL2 (n=3) and CCL3 protein (n=3) secretion in THP-1 cells. Simvastatin significantly reduced zirconium oxide-mediated CCL4 secretion (n=3).

Conclusion
Simvastatin significantly reduced cobalt-ion mediated IL-8 and sICAM-1 protein secretion in THP-1 cells. This in-vitro finding demonstrates the potential for simvastatin to reduce leukocyte recruitment which mediate the deleterious inflammatory processes driving implant failure.