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Inhibitory effects of erythromycin on wear debris-induced VEGF/Flt-1 gene production and osteolysis

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Abstract

Objectives

A highly vascularized and inflammatory periprosthetic tissue augments the progress of aseptic loosening, a major clinical problem after total joint replacement. The purpose of this study is to investigate the effect of erythromycin (EM) on ultra high molecular weight polyethylene (UHMWPE) particle-induced VEGF/VEGF receptor 1 (Flt-1) gene production and inflammatory osteolysis in a mouse model.

Methods

UHMWPE particles were introduced into established air pouches on BALB/c mice, followed by implantation of calvaria bone from syngeneic littermates. EM treatment started 2 weeks after bone implantation (5 mg/kg day, i.p. injection). Mice without drug treatment as well as mice injected with saline alone were included. Pouch tissues were harvested 2 weeks after bone implantation. Expression of VEGF, Flt-1, RANKL, IL-1, TNF and CD68 was measured by immunostain and RT-PCR, and implanted bone resorption was analyzed by micro-CT (μCT).

Results

Exposure to UHMWPE induced pouch tissue inflammation, increase of VEGF/Flt-1 proteins, and increased bone resorption. EM treatment significantly improved UHMWPE particle-induced tissue inflammation, reduced VEGF/Flt-1 protein expression, and diminished the number of TRAP+ cells, as well as the implanted bone resorption.

Conclusion

This study demonstrated that EM inhibited VEGF and Flt-1 gene expression. The molecular mechanism of EM action on VEGF/Flt-1 signaling-mediated osteoclastogenesis warrants further investigation.

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Abbreviations

VEGF:

Vascular endothelial growth factor

EM:

Erythromycin

Flt-1:

VEGF receptor I

FLK:

VEGF receptor II

RANK:

Receptor activator of NF-κB

RANKL:

RANK ligand

TNF:

Tumor necrosis factor

IL-1:

Interleukin-1

TRAP:

Tartrate-resistant acid phosphatase

AL:

Aseptic loosening

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Acknowledgment

This study was supported by a grant from Stryker Orthopedics.

Author information

Authors and Affiliations

  1. Department of Orthopaedic Surgery, Wayne State University, Detroit, MI, 48201, USA

    David C. Markel

  2. Department of Biomedical Engineering, Wayne State University, 818 W. Hancock, Detroit, MI, 48201, USA

    Tong Shi & Weiping Ren

  3. Stryker Company, Rutherford, NJ, 07070, USA

    Renwen Zhang & Monica Hawkins

Authors
  1. David C. Markel
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  2. Renwen Zhang
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  3. Tong Shi
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  4. Monica Hawkins
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  5. Weiping Ren
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Corresponding author

Correspondence to Weiping Ren.

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Responsible Editor: M. Parnham.

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Markel, D.C., Zhang, R., Shi, T. et al. Inhibitory effects of erythromycin on wear debris-induced VEGF/Flt-1 gene production and osteolysis. Inflamm. Res. 58, 413–421 (2009). https://doi.org/10.1007/s00011-009-0007-9

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  • DOI: https://doi.org/10.1007/s00011-009-0007-9

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