Wear particle-induced periprosthetic osteolysis remains the principal cause of aseptic loosening of orthopaedic implants. Monocytes/macrophages phagocytose wear particles and release cytokines that induce inflammatory response. This response promotes osteoclast differentiation and osteolysis. The precise mechanisms by which wear particles are recognized and induce the accumulation of inflammatory cells in the periprosthetic tissue have not been fully elucidated. Recent studies have shown that toll-like receptors (TLRs) contribute to the cellular interaction with wear particles. Wear particles are recognized by monocytes/macrophages through TLRs coupled with the adaptor protein MyD88. After the initial interaction, wear particles induce both local and systemic migration of monocytes/macrophages to the periprosthetic region. The cellular migration is mediated through chemokines including interleukin-8, macrophage chemotactic protein-1, and macrophage inhibitory protein-1 in the periprosthetic tissues. Interfering with chemokine-receptor axis can inhibit cellular migration and inflammatory response. This paper highlights recent advances in TLR, and chemokine participated in the pathogenesis of aseptic loosening. A comprehensive understanding of the recognition and migration mechanism is critical to the development of measures that prevent wear particle-induced aseptic loosening of orthopaedic implants.
Total joint replacement (TJR) by the implantation of indwelling prostheses is an effective operation in terms of relieving pain and restoring function. The common long-term complication of TJR is loosening of an artificial joint that requires revision surgery [
The dominant theory about the causes of aseptic loosening is the particle disease theory [
Although numerous studies have demonstrated the events underlying periprosthetic inflammation and osteolysis, there are still more questions. First, the mechanisms of the initial cellular interaction with wear particles and the subsequent inflammatory mediator production remain unknown. Second, wear particles induce not only a local response but also a systemic reaction. The mechanism of cellular migration induced by wear particles needs further clarification. In 2007, Takagi et al. first reported that toll-like receptors (TLRs) were detected in the tissues around aseptically loosened implants [
TLRs belong to a class of pattern recognition receptors that enable the innate immune system to distinguish self- from nonself-structure. Thirteen TLRs have been identified in mammals since 1997. TLR1, TLR2, TLR4, TLR5, TLR6, TLR10, and TLR11 are expressed on the cell surface, whereas TLR3, TLR7, TLR8, and TLR9 are expressed intracellularly on endosomal membranes [
Toll-like receptors and their corresponding ligands.
TLR | Exogenous ligands (PAMPs) | Endogenous ligands (DAMPs) |
---|---|---|
TLR1 | Triacyl lipopeptide |
|
TLR2 |
Lipoglycans (mycobacterium) |
HSP 60, HSP70, gp96, |
TLR3 | dsRNA | mRNA |
TLR4 | LPS (gram-negative bacteria) |
HMGB1, surfactant proteins, |
TLR5 | Flagellin (gram-negative bacteria) | Undetermined |
TLR6 | Diacylpolypeptide |
Undetermined |
TLR7/8 | ss RNA (virus) | Antiphospholipid antibodies, cardiac myosin, ss RNA, |
TLR9 | CpG motif (bacteria, virus) | IgG-chromatin complexes, mitochondrial DNA |
TLR10 | Diacylated peptide? | Immunostimulatory CpG motifs |
TLR11 | Profilin-like molecule | Undetermined |
Ligand-TLR interactions trigger the recruitment of adaptor proteins through the cytoplasmic TIR domain. So far, five TIR-containing adaptors have been identified: myeloid differentiation primary response gene 88 (MyD88), TIR domain-containing adaptor protein (TIRAP)/Mal, TIR domain-containing adaptor protein-inducing IFN-
TLR signaling mediatesinflammatoryresponses which are important for host defense. However, inappropriate TLR signaling may be responsible for the pathogenesis of autoimmune diseases, chronic inflammatory diseases, and aseptic inflammatory diseases [
TLRs have been observed on variety of cells including monocytes/macrophages, lymphocytes, fibroblasts, osteoblasts, and osteoclasts. It hasrecently been reported that TLRs were found in periprosthetictissues of patients with aseptic loosening. The TLR-positive cells are dominantly monocyte/macrophages [
TLR1 and TLR2 are expressed on the cell surface and canform heterodimer [
TLR4 is the membrane receptor that can recognize LPS, mannan, glycoinositolphospholipids, envelope proteins, or some self-proteins including HSP60 and HSP70 [
Ligand-TLR binding induces rearrangements of TIR domains and recruitment of adaptors (MyD88, TRIF, and TIRAP), triggering the activation of NF-
Wear particles induced TLR signal pathway. TLRs recognize wear particles with adherent PAMPs or DAMPs via MyD88. The binding of TLR and MyD88 phosphorylates IRAK4 which in turn phosphorylates IRAK1. The activation of AP-1 and NF-
Chemokines are a group of small proteins with a crucial role in leukocyte migration and activation. These molecules can also affect cytokine secretion, apoptosis, phagocytosis, angiogenesis, and collagen production [
The effects of chemokines are mediated by a family of G protein-coupled receptor on the target cell surface [
In the early time, it was assumed that wear particles induced a localized response. In brief, wear particles stimulated resident cells (including macrophages, osteoblast) to produce cytokines such as TNF-
Wear particles induced chemokine expression and cellular migration.
IL-8, also known as CXCL8, is a member of the CXC chemokine family [
MCP-1, also known as CCL2, was identified based on its ability to chemoattract monocytes
MIP-1 includes MIP-1
CCL17 and CCL22 are the two recognized ligands for the chemokine receptor CCR4. They are known to be mainly produced by cell lineages closely related to osteoclasts such as dendritic cells. CCL22 has been shown to be expressed by activated macrophages and mature dendritic cells, whereas CCL17 has been shown to be secreted by keratinocytes and endothelial cells. Titanium particles increased the expressions of CCL17 and CCL22 in osteoclasts and hFOB cells. Moreover, the expression of CCR4 was upregulated when osteoclast precursors were stimulated with titanium particles. These results implied a role for CCL17 and CCL22 in the chemotaxis of CCR4 expressing osteoclast progenitors to the site around implants [
Aseptic loosening is the common cause of the failure of TJR, and the mechanisms underlying it appear complex and multifaceted. A large number of scholars have focused on the biological activity of wear particles. Macrophages recognize wear particles and release proinflammatory mediators, leading to osteoclast activation and osteolysis. Although it has been accepted that the interaction between wear particles and macrophages is critical, little is known about how wear particles are recognized and activate macrophages in the early inflammatory response.
Given the fact that wear particles are recognized via TLRs, effective strategies can be designed to block the event. For example, MyD88 interfering may block TLR downstream signaling pathway and then prevent wear particle-induced periprosthetic osteolysis. Another promising approach involves inhibiting recruitment of macrophages and other cells to the inflammatory site. Pharmacologic intervention targeted at chemokine-receptor axis may provide the means to mitigate the response to wear particles. Indeed,