Chronic inflammation in biomaterial-induced periprosthetic osteolysis: NF-κB as a therapeutic target

Abstract

Biomaterial-induced tissue responses in patients with total joint replacement are associated with the generation of wear particles, which may lead to chronic inflammation and local bone destruction (periprosthetic osteolysis). Inflammatory reactions associated with wear particles are mediated by several important signaling pathways, the most important of which involves the transcription factor NF-κB. NF-κB activation is essential for macrophage recruitment and maturation, as well as the production of pro-inflammatory cytokines and chemokines such as TNF-α, IL-1β, IL-6 and MCP1. In addition, NF-κB activation contributes to osteoclast differentiation and maturation via RANK/RANKL signaling, which increases bone destruction and reduces bone formation. Targeting individual downstream cytokines directly (such as TNF-α or IL-1β) may not effectively prevent wear particle induced osteolysis. A more logical upstream therapeutic approach may be provided by direct modulation of the core IκB/IKKα/β/NF-κB signaling pathway in the local environment. However, the timing, dose and strategy for administration should be considered. Suppression of chronic inflammation via inhibition of NF-κB activity in patients with malfunctioning joint replacements may be an effective strategy to mitigate wear particle induced periprosthetic osteolysis.

Keywords: Biomaterials; Chronic inflammation; NF-κB; Periprosthetic osteolysis.

Fig 1. Tissue response and generation of wear particles to implanted biomaterials

A) Tissue damage caused by the initial surgery activate the complement system and release DAMP, forming a protein layer (pink) coated on the implanted device immediately. B) Acute phase inflammation involves the efflux of neutrophils (N) and macrophages (Mϕ), which produce reactive oxygen species (ROS), proteinase, cytokines, and chemokines. C) Macrophage infiltration are dominant in the chronic inflammation stage. PAMP can be recognized by PRR that results in macrophage activation and generation of excess wear particles. D) Macrophages may undergo cell fusion to form FBGC, resulting in ongoing inflammation and tissue damage.

Fig 2. The central role of NF-κB signaling in wear-particle induced periprosthetic osteolysis

Wear particles directly or indirectly activate NF-κB upstream including the TNF-α receptor (TNFR), IL-1 receptor (IL1R), and toll-like receptor (TLR) in macrophages. The activation of NF-κB enhances the expression of chemokines, RANKL, and proteinases that lead to osteolysis via different mechanisms (green boxes). Chemokines recruit macrophages, osteoprogenitor cells, and mesenchymal stem cells (MSC), whereas RANKL induces the maturation of osteoclasts. Suppression of NF-κB activation can be achieved by targeting 1) upstream activators; 2) IκB; 3) IKK kinase; 4) the core component of NF-κB (RelA/p50); or 5) nuclear translocation and DNA binding ability of NF-κB. Notably, the NF-κB downstream target genes may also affect osteoblasts and MSCs (pink box).