Novel biological strategies for treatment of wear particle-induced periprosthetic osteolysis of orthopaedic implants for joint replacement

Abstract

Wear particles and by-products from joint replacements and other orthopaedic implants may result in a local chronic inflammatory and foreign body reaction. This may lead to persistent synovitis resulting in joint pain and swelling, periprosthetic osteolysis, implant loosening and pathologic fracture. Strategies to modulate the adverse effects of wear debris may improve the function and longevity of joint replacements and other orthopaedic implants, potentially delaying or avoiding complex revision surgical procedures. Three novel biological strategies to mitigate the chronic inflammatory reaction to orthopaedic wear particles are reported. These include (i) interference with systemic macrophage trafficking to the local implant site, (ii) modulation of macrophages from an M1 (pro-inflammatory) to an M2 (anti-inflammatory, pro-tissue healing) phenotype in the periprosthetic tissues, and (iii) local inhibition of the transcription factor nuclear factor kappa B (NF-κB) by delivery of an NF-κB decoy oligodeoxynucleotide, thereby interfering with the production of pro-inflammatory mediators. These three approaches have been shown to be viable strategies for mitigating the undesirable effects of wear particles in preclinical studies. Targeted local delivery of specific biologics may potentially extend the lifetime of orthopaedic implants.

Keywords: NF-κB; cell trafficking; inflammation; macrophage polarization; orthopaedic implants; wear particles.

Figure 1.

Biological strategies for treatment of wear particle-induced periprosthetic osteolysis. This figure outlines some potential biological approaches to preventing and treating periprosthetic osteolysis owing to wear particles from orthopaedic implants.

Figure 2.

Wear particle-induced macrophage activation in macrophage subsets. (a) DAMP-coated wear particles are recognized by TLRs and possibly by other PRRs. Signalling via these receptors leads to NF-κB activation and production of TNF-α and other pro-inflammatory cytokines from M0 macrophages. Activation of TLR4 (for example by LPS or cobalt ions) leads to the production of type 1 interferon via the activation of transcription factor IRF3. (b) Type 1 interferon and TNF-α lead to activation of transcription factors STAT1 and AP-1, which are directly responsible for the transcription of M1-related genes. This auto- and paracrine signalling might offer one mechanistic explanation as to why wear particles induce the M1 macrophage phenotype. IFN-γ produced by NK cells or by Th1 cells leads to STAT1 activation which enhances macrophage inflammatory responses by upregulating TLR expression and synergizing with NF-κB; this may explain the exacerbation of wear particle-induced inflammatory response in IFN-γ primed M1 macrophages. (c) IL-4 signalling leads to the activation of transcription factor STAT6, which is directly responsible for the transcription of M2 phenotype-related genes. Furthermore, IL-4 signalling leads to activation of PPAR-γ which has direct suppressive effect on NF-κB, AP-1 and STAT1, thus offering a possible explanation as to why the inflammatory wear particle responses in the M2 macrophages are effectively suppressed. M2-polarization is further characterized by production of IL-10, which acting in auto- and paracrine manner, exerts additional suppression of inflammatory transcription factors via activation of STAT3. The mode in which M2 macrophages react to particle stimulus is not yet fully determined.

Figure 3.

The role of NF-κB in wear particle-induced periprosthetic osteolysis. Inhibition of NF-κB decreases the production and release of pro-inflammatory substances from macrophages, and the differentiation and function of osteoclasts.