Systemic trafficking of macrophages induced by bone cement particles in nude mice
Introduction
Excessive production of wear particles from joint replacements is associated with periprosthetic osteolysis, which can lead to implant loosening [1], [2], [3], [4], [5], [6], [7]. Phagocytic cells engulf particulate debris and become activated; releasing proinflammatory cytokines, chemokines, degradative enzymes, reactive oxygen radicals and other substances which stimulate osteoclasts to undermine the prosthetic bed [8], [9], [10], [11], [12], [13], [14]. The key cell in the foreign body and chronic inflammatory response to wear particles is the macrophage [15], [16], [17]. Cells of the monocyte/macrophage lineage differentiate and maturate into phagocytic macrophages, foreign body giant cells and osteoclast precursors. These cells (in communication with stromal cells and other cell types) are primarily responsible for the cascade of events culminating in periprosthetic osteolysis. Despite ongoing research into the cellular and molecular processes associated with periprosthetic osteolysis, no in vivo studies have elucidated whether remote macrophages are stimulated to migrate to wear particles, or whether these events are a local phenomenon only. If macrophage recruitment to particles is a systemic phenomenon then novel strategies to mitigate these events may be potential targets for treatment.
We hypothesized that exogenous reporter macrophages introduced from a distant site would migrate and concentrate to an area in which phagocytosable polymer particles have been implanted. To examine this hypothesis, we use a model of femoral intramedullary polymer particle placement [18] in nude mice, a murine macrophage cell line transfected with a bioluminescent reporter gene, and sequential non-invasive imaging in vivo using bioluminescence.
Section snippets
Animals and cells
8 to 11-week-old adult male nude mice (Charles River Laboratories, Inc., MA) were housed and fed in our Institution's Animal Facility. The murine macrophage cell line RAW264.7 was transfected with the lentiviral vector to express the bioluminescent optical reporter gene, firefly luciferase (fluc), and a fluorescence reporter gene, green fluorescent protein (gfp) [19].
Bone cement particles
Simplex® P bone cement (BC) powder (Howmedica Osteonics, Allendale, NJ) was used in the study. The BC powder is composed of 15%
Polarized light microscopy of frozen section of femora
To demonstrate the presence of the BC particles in the femoral medullary canal of experimental animals, femora of selected mice were harvested immediately after injection. Frozen sections were stained with hematoxylin and eosin (H&E). The adopted histological protocol utilized reagents that precluded particle disruption and dissolution during preparation of the slides. Polarized light microscopy was used to observe the birefringence of the BC particles. As shown in Fig. 1, bright white spots
Discussion
Wear particles, periprosthetic osteolysis and implant loosening jeopardize the longevity of joint replacements. Macrophages play an important role in these biological processes [8], [15], [17], [21], [22], [23], [24], [25]. Macrophages release proinflammatory cytokines, chemokines and other factors, and can differentiate into osteoclasts that resorb bone [8], [15], [17], [21], [22], [23], [24], [25], [26], [27]. The precursor cells for activated macrophages, foreign body giant cells and
Conclusion
This study employing the techniques of sequential in vivo imaging using bioluminescence and immunohistochemistry clearly demonstrates that exogenous reporter macrophages injected into the tail vein of nude mice are systemically recruited to a distant site, the femur that contains bone cement particles. Modulation of the signaling mechanisms that regulate systemic macrophage recruitment and homing may provide a new strategy for mitigating the chronic inflammatory response associated with wear
Acknowledgements
We gratefully acknowledge Dr. Gobalakrishnan Sundaresan who supplied the fluc and gfp expressing RAW264.7 macrophage cell line. This study was supported in part by Grants R21 AR053189 and R01 AR055650-01 from the National Institute of Health, the Ellenburg Chair in Surgery.
References (39)
- et al.
Particle bioreactivity and wear-mediated osteolysis
J Arthroplasty
(2004) - et al.
Tumor necrosis factor-α mediates orthopedic implant osteolysis
Am J Pathol
(1999) - et al.
Interleukin-1 modulates periprosthetic tissue formation in an intramedullary model of particle-induced inflammation
J Orthop Res.
(2005) - et al.
Noninvasive imaging of lentiviral-mediated reporter gene expression in living mice
Mol Ther
(2003) - et al.
A discrete adjuvant-induced monoarthritis in the rat: effects of adjuvant dose
J Neurosci Meth
(1993) - et al.
Cement disease
Clin Orthop Relat Res
(1987) - et al.
Periprosthetic bone loss in total hip arthroplasty
J Bone Joint Surg Am
(1992) - et al.
Periprosthetic osteolysis in total hip arthroplasty: the role of particulate wear debris
J Bone Joint Surg Am
(1995) - et al.
The effect of particle wear debris on NFkappaB activation and pro-inflammatory cytokine release in differentiated THP-1 cells
J Biomed Mater Res
(2002) - et al.
Pharmacologic modulation of periprosthetic osteolysis
Clin Orthop Relat Res
(2005)
The cellular and molecular biology of periprosthetic osteolysis
Clin Orthop Relat Res
Bone resorption activity of particulate-stimulated macrophages
J Bone Miner Res
Induction of matrix metalloproteinase expression in human macrophages by orthopaedic particulate debris in vitro
J Bone Joint Surg Br
Signaling pathways for tumor necrosis factor-alpha and interleukin-6 expression in human macrophages exposed to titanium-alloy particulate debris in vitro
J Bone Joint Surg Am
Role of free radicals in aseptic loosening of hip arthroplasty
J Orthop Res
Nonsurgical management of osteolysis: challenges and opportunities
Clin Orthop Relat Res
Mechanisms of disease: molecular insights into aseptic loosening of orthopedic implants
Nat Clin Pract Rheumatol
Resorption of bone by inflammatory cells derived from the joint capsule of hip arthroplasties
J Bone Joint Surg Br
Mediator interactions in macrophage/particulate bone resorption
J Biomed Mater Res
Cited by (41)
Antifibrotic strategies for medical devices
2020, Advanced Drug Delivery ReviewsDynamic imaging of the effect of mesenchymal stem cells on osteoclast precursor cell chemotaxis for bone defects in the mouse skull
2018, Journal of Dental SciencesCitation Excerpt :The fluorescence intensity of the MSCs transplant group at the bone defect part was significantly higher on days 3, 5, and 7 (p < 0.01) and on days 1 and 9 (p < 0.05) compared with the control group (Fig. 2B), and significantly higher on days 3, 5, and 7 compared with the MSCs non-transplant group (p < 0.05). The dynamics of immune cells such as macrophages and neutrophils have been extensively studied using molecular imaging technique,7,11,12 of which cell tracking using in vivo imaging is particularly useful. In this study, transplanted MSCs were shown to remain around the transplant region for more than 19 days.
Orthopaedic implant materials drive M1 macrophage polarization in a spleen tyrosine kinase- and mitogen-activated protein kinase-dependent manner
2018, Acta BiomaterialiaCitation Excerpt :In fact, periprosthetic osteolysis accounts for 75% of implant failures, and as a result, individuals must undergo revision surgery which, in itself, is associated with shorter duration of implant survival and higher patient risk [2]. A number of studies have reported that macrophages play an integral role in the initiation of periprosthetic osteolysis [3–5]. These cells can undergo phenotypic polarization to form pro-inflammatory M1 macrophages, which promote pathogen killing and are associated with chronic inflammation, or anti-inflammatory M2 macrophages which are associated with immunoregulation, tissue repair and remodelling.
7.6 Biological effects of wear debris from joint arthroplasties
2017, Comprehensive Biomaterials IIHost Response to Orthopedic Implants (Metals and Plastics)
2015, Host Response to Biomaterials: The Impact of Host Response on Biomaterial SelectionOsteoclasts in the interface with electrospun hydroxyapatite
2015, Colloids and Surfaces B: Biointerfaces