Abstract
Progressive generation of total joint implant‐derived wear particles is one of the major risk factors in development of peri‐prosthetic osteolysis especially in the aging society. It is commonly accepted that macrophages predominantly drive the inflammatory response to wear debris particles. Among various surface receptors that activate the macrophages to phagocytize particles, it is believed that the Toll‐like receptor 4 (TLR4) and the scavenger macrophage receptor with collagenous structure (MARCO) play key roles in recognition of wear debris particles. However, a strong body of evidence indicates an age‐dependent diminished function of human TLRs. Thus, we hypothesized that the MARCO receptor may be more engaged than TLRs in the phagocytosis of wear debris particles which in turn up‐regulate production of pro‐inflammatory cytokines from aged macrophages. We demonstrated that peritoneal macrophages isolated from aged mice show elevated expression of MARCO receptor compared to that from young mice. In contrast the expression of TLR4 was significantly decreased on the surface of aged macrophages. Furthermore, using anti‐MARCO and anti‐TLR4 neutralizing mAbs, we demonstrated the age‐dependent pathogenic role of MARCO, but not TLR4, receptor in promoting poly‐methyl methacrylate (PMMA) bone cement particles phagocytosis by macrophages leading to the release of pro‐inflammatory cytokines migration inhibitory factor and tumour necrosis factor in vitro. These data also suggest that the approach to neutralize MARCO may lead to the development of therapeutic regimen for the prevention of particle‐induced osteolysis in aged patients.
Highlights
One million arthroplasty surgeries are performed annually, whereas about 20% of patients need implant replace‐ ment within a decade from initial surgery as a result of developing particle‐induced osteolysis.[1]
Because it is reported that Toll‐like re‐ ceptor 4 (TLR4) and macrophage receptor with collagenous structure (MARCO) contribute to the cellular interaction with particles produced from the implant device,[4] we evaluated the expression of TLR4 and MARCO receptors on the surface of mouse F4/80 + peritoneal Mф (pMф)
Because we reported earlier that pro‐inflammatory cytokines migration inhibitory factor (MIF) and tumour necrosis factor (TNF)‐α are engaged in the particle‐induced bone osteolysis,[3] we compared the effects of anti‐MARCO and anti‐TLR4 mAbs on the production of these cytokines by aged and young pMф in response to poly‐methyl meth‐ acrylate (PMMA) particles
Summary
One million arthroplasty surgeries are performed annually, whereas about 20% of patients need implant replace‐ ment within a decade from initial surgery as a result of developing particle‐induced osteolysis.[1] It has been observed that particles generated from the prosthetic joint articular surface as well as from the artificial bone cements are the major factors determining the survival of joint implants leading to the development of bone osteol‐ ysis.[1] Multiple lines of evidence indicate that patients aged 65+ are more susceptible to bone peripheral lesions compared to younger individuals, indicating a critical need for the development of new. We report that MARCO receptor appears to play a critical role in the in vitro phagocytosis of bone cement poly‐methyl methacrylate (PMMA) particles by peritoneal Mф (pMф) isolated from aged mice, causing excess productions of various pro‐ inflammatory cytokines (MIF and TNF‐α)
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