Abstract
Purpose
Aseptic loosening is the most common complication of total joint replacement, which most likely results from an inflammatory response to wear debris shed from the implant. In this study we aimed to investigate whether the lentivirus-mediated microRNA (miRNA) targeting vascular endothelial growth factor (VEGF) could inhibit wear debris-induced inflammation in a murine model.
Methods
Titanium alloy particles were introduced into established air pouches on BALB/c mice, followed by implantation of calvarial bone from a syngeneic mouse. After treatment by locally delivered lentivirus-mediated VEGF miRNA, inflammatory tissues were collected for histology and molecular analysis.
Results
We found that (1) locally delivered miRNA inhibited titanium alloy particle-induced tissue inflammation, including the diminished pouch membrane thickness and reduced inflammatory cellular infiltration and that (2) locally delivered miRNA inhibited expressions of the inflammatory cytokines VEGF, tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and receptor activator of nuclear factor kappa B ligand (RANKL).
Conclusions
These findings suggest that local VEGF inhibition might be a promising therapeutic candidate to alleviate particle-induced inflammation.
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References
Holt G, Murnaghan C, Reilly J et al (2007) The biology of aseptic osteolysis. Clin Orthop Relat Res 460:240–252
Quanli Y, Kevin P, Somying P (2008) VEGF enhancement of osteoclast survival and bone resorption involves VEGF receptor-2 signaling and β3-integrin. Matrix Biol 27:589–599
Chamekh M, Phalipon A, Quertainmont R et al (2008) Delivery of biologically active anti-inflammatory cytokines IL-10 and IL-1ra in vivo by the Shigella type III secretion apparatus. J Immunol 180:4292–4298
Fire A, Xu S, Montgomery MK (1998) Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391:806–811
Meister G, Tuschl T (2004) Mechanisms of gene silencing by double-stranded RNA. Nature 431:343–349
Depeyre C, Chen-Kuo-Chang M, Payet O et al (2006) A murine model of transitory optic neuropathy based on small interference RNA-induced OPA1 silencing in vivo (gene mutation associated with Kjer’s disease). J Fr Ophtalmol 29:875–880
Peng X, Tao K, Cheng T et al (2008) Efficient inhibition of wear debris-induced inflammation by locally delivered siRNA. Biochem Biophys Res Commun 377:532–537
Sun T, Sun BC, Ni CS et al (2008) Pilot study on the interaction between B16 melanoma cell-line and bone-marrow derived mesenchymal stem cells. Cancer Lett 263:35–43
Clohisy JC, Calvert G, Tull F et al (2004) Reasons for revision hip surgery: a retrospective review. Clin Orthop Relat Res 429:188–192
Epstein NJ, Warme BA, Spanogle J et al (2005) Interleukin-1 modulates periprosthetic tissue formation in an intramedullary model of particle-induced inflammation. J Orthop Res 23:501–510
Waddell J, Pritzker KP, Boynton EL (2005) Increased cytokine secretion in patients with failed implants compared with patients with primary implants. Clin Orthop Relat Res 434:170–176
Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9:669–676
Ren WP, Li XY, Chen BD et al (2004) Erythromycin inhibits wear debris-induced osteoclastogenesis by modulation of murine macrophage NF-kB activity. J Orthop Res 22:21–29
Wooley PH, Schwarz EM (2004) Aseptic loosening. Gene Ther 11:402–407
Ren WP, Markel DC, Zhang RW et al (2006) Association between UHMWPE particle-induced inflammatory osteoclastogenesis and expression of RANKL, VEGF, and Flt-1 in vivo. Biomaterials 27:5161–5169
McCoy MK, Ruhn KA, Martinez TN et al (2008) Intranigral lentiviral delivery of dominant-negative TNF attenuates neurodegeneration and behavioral deficits in hemiparkinsonian rats. Mol Ther 16:1572–1579
Brummelkamp TR, Bernards R, Agami R (2002) A system for stable expression of short interfering RNAs in mammalian cells. Science 296:550–553
Schwarz EM, Lu AP, Goater JJ, Benz EB et al (2000) Tumor necrosis factor-alpha/nuclear transcription factor-kappaB signaling in periprosthetic osteolysis. J Orthop Res 18:472–480
Acknowledgements
This study was supported by grants from Shanghai basic research key project (No. 08JC1412500).
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The authors declare that they have no conflict of interest.
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Zhang, W., Peng, X., Cheng, T. et al. Vascular endothelial growth factor gene silencing suppresses wear debris-induced inflammation. International Orthopaedics (SICOT) 35, 1883–1888 (2011). https://doi.org/10.1007/s00264-011-1252-4
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DOI: https://doi.org/10.1007/s00264-011-1252-4