Mechanical instability and titanium particles induce similar transcriptomic changes in a rat model for periprosthetic osteolysis and aseptic loosening

Abstract

Wear debris particles released from prosthetic bearing surfaces and mechanical instability of implants are two main causes of periprosthetic osteolysis. While particle-induced loosening has been studied extensively, mechanisms through which mechanical factors lead to implant loosening have been less investigated. This study compares the transcriptional profiles associated with osteolysis in a rat model for aseptic loosening, induced by either mechanical instability or titanium particles. Rats were exposed to mechanical instability or titanium particles. After 15 min, 3, 48 or 120 h from start of the stimulation, gene expression changes in periprosthetic bone tissue was determined by microarray analysis. Microarray data were analyzed by PANTHER Gene List Analysis tool and Ingenuity Pathway Analysis (IPA). Both types of osteolytic stimulation led to gene regulation in comparison to unstimulated controls after 3, 48 or 120 h. However, when mechanical instability was compared to titanium particles, no gene showed a statistically significant difference (fold change ≥ ± 1.5 and adjusted p-value ≤ 0.05) at any time point. There was a remarkable similarity in numbers and functional classification of regulated genes. Pathway analysis showed several inflammatory pathways activated by both stimuli, including Acute Phase Response signaling, IL-6 signaling and Oncostatin M signaling. Quantitative PCR confirmed the changes in expression of key genes involved in osteolysis observed by global transcriptomics. Inflammatory mediators including interleukin (IL)-6, IL-1β, chemokine (C-C motif) ligand (CCL)2, prostaglandin-endoperoxide synthase (Ptgs)2 and leukemia inhibitory factor (LIF) showed strong upregulation, as assessed by both microarray and qPCR. By investigating genome-wide expression changes we show that, despite the different nature of mechanical implant instability and titanium particles, osteolysis seems to be induced through similar biological and signaling pathways in this rat model for aseptic loosening. Pathways associated to the innate inflammatory response appear to be a major driver for osteolysis. Our findings implicate early restriction of inflammation to be critical to prevent or mitigate osteolysis and aseptic loosening of orthopedic implants.

Periprosthetic Osteolysis: Mechanisms, Prevention and Treatment

“…Based on the above, one may conclude that there is relatively strong evidence for the role of mechanical forces and pressures in PPOL. In addition, these mechanical pressures and forces can interact with biological processes of PPOL [133]. Finally, some believe that mechanical forces are the primary causative mechanism while the inflammatory pathways are secondary to mechanical loosening [134].…”

Total hip arthroplasty following failure of tantalum rod implantation for osteonecrosis of the femoral head with 5- to 10-year follow-up

“…Tantalum particles at high concentrations may cause an inflammatory reaction and disrupt the balance between bone tissue formation and break down [30, 31]. Furthermore, the retained debris at the interface of the cementless prosthesis and femur can cause mechanical instability, which is a risk factor of periprosthetic osteolysis and aseptic loosening [32]. …”

Label-Free Monitoring of Uptake and Toxicity of Endoprosthetic Wear Particles in Human Cell Cultures

“…Aseptic implant loosening is the main reason for revision [ 1 ], and is associated with the generation of wear particles and ions. Nowadays, manufacturing processes of endoprosthetic materials are refined to decrease the volumetric wear of the bearing surfaces [ 2 ], but the occurrence of wear debris caused by articulation or mechanical instability is still an issue [ 3 ]. In periprosthetic tissue, the interaction of different cell types with generated particles as well as ions triggers different cellular reactions [ 4 , 5 ].…”