title: Inhibition of osteolysis and increase of bone formation after local administration of siRNA-targeting RANK in a polyethylene particle-induced osteolysis model.
abstract: Receptor activator of nuclear factor kappa-B (RANK) and RANK-ligand are relevant targets for the treatment of polyethylene particle-induced osteolysis. This study assessed the local administration of siRNA, targeting both human RANK and mouse Rank transcripts in a mouse model. Four groups of mice were implanted with polyethylene (PE) particles in the calvaria and treated locally with 2.5, 5 and 10 μg of RANK siRNA or a control siRNA delivered by the cationic liposome DMAPAP/DOPE. The tissues were harvested at day 9 after surgery and evaluated by micro-computed tomography, tartrate-resistant acid phosphatase (TRAP) immunohistochemistry for macrophages and osteoblasts, and gene relative expression of inflammatory and osteolytic markers. 10 μg of RANK siRNA exerted a protective effect against PE particle-induced osteolysis, decreasing the bone loss and the osteoclastogenesis, demonstrated by the significant increase in the bone volume (P<0.001) and by the reduction in both the number of TRAP(+) cells and osteoclast activity (P<0.01). A bone anabolic effect demonstrated by the formation of new trabecular bone was confirmed by the increased immunopositive staining for osteoblast-specific proteins. In addition, 5 and 10 μg of RANK siRNA downregulated the expression of pro-inflammatory cytokines (P<0.01) without depletion of macrophages. Our findings show that RANK siRNA delivered locally by a synthetic vector may be an effective approach for reducing osteolysis and may even stimulate bone formation in aseptic loosening of prosthetic implants.
authors.affiliation: INSERM, UMR 957, 1 rue Gaston Veil, 44035 Nantes Cedex 1, France; University of Nantes, Nantes Atlantique Universities, Laboratory of Pathophysiology of Bone Resorption and Therapy of Primary Bone Tumours, 1 rue Gaston Veil, 44035 Nantes Cedex 1, France; Department of Oral and Maxillofacial Surgery, San Borja Arriaran University Hospital, Faculty of Dentistry, University of Chile-CONICYT, Sergio Livingstone Polhammer 943, Independencia, Santiago, Chile. Electronic address: dominique.heymann@univ-nantes.fr.
authors.forename: L A
authors.initials: LA
authors.lastname: Córdova
authors.affiliation: INSERM, UMR 957, 1 rue Gaston Veil, 44035 Nantes Cedex 1, France; University of Nantes, Nantes Atlantique Universities, Laboratory of Pathophysiology of Bone Resorption and Therapy of Primary Bone Tumours, 1 rue Gaston Veil, 44035 Nantes Cedex 1, France.
authors.forename: V
authors.initials: V
authors.lastname: Trichet
authors.affiliation: UTCBS CNRS UMR 8258 INSERM UMR-S 1022, 4 avenue de l'Observatoire, 75006 Paris, France.
authors.forename: V
authors.initials: V
authors.lastname: Escriou
authors.affiliation: INSERM, UMR 957, 1 rue Gaston Veil, 44035 Nantes Cedex 1, France; University of Nantes, Nantes Atlantique Universities, Laboratory of Pathophysiology of Bone Resorption and Therapy of Primary Bone Tumours, 1 rue Gaston Veil, 44035 Nantes Cedex 1, France; Tours University Hospital, François Rabelais, 37044 Tours Cedex 9, France.
authors.forename: P
authors.initials: P
authors.lastname: Rosset
authors.affiliation: INSERM, UMR 957, 1 rue Gaston Veil, 44035 Nantes Cedex 1, France; University of Nantes, Nantes Atlantique Universities, Laboratory of Pathophysiology of Bone Resorption and Therapy of Primary Bone Tumours, 1 rue Gaston Veil, 44035 Nantes Cedex 1, France.
authors.forename: J
authors.initials: J
authors.lastname: Amiaud
authors.affiliation: INSERM, UMR 957, 1 rue Gaston Veil, 44035 Nantes Cedex 1, France; University of Nantes, Nantes Atlantique Universities, Laboratory of Pathophysiology of Bone Resorption and Therapy of Primary Bone Tumours, 1 rue Gaston Veil, 44035 Nantes Cedex 1, France.
authors.forename: S
authors.initials: S
authors.lastname: Battaglia
authors.affiliation: INSERM, UMR 957, 1 rue Gaston Veil, 44035 Nantes Cedex 1, France; University of Nantes, Nantes Atlantique Universities, Laboratory of Pathophysiology of Bone Resorption and Therapy of Primary Bone Tumours, 1 rue Gaston Veil, 44035 Nantes Cedex 1, France.
authors.forename: C
authors.initials: C
authors.lastname: Charrier
authors.affiliation: INSERM, UMR 957, 1 rue Gaston Veil, 44035 Nantes Cedex 1, France; University of Nantes, Nantes Atlantique Universities, Laboratory of Pathophysiology of Bone Resorption and Therapy of Primary Bone Tumours, 1 rue Gaston Veil, 44035 Nantes Cedex 1, France.
authors.forename: M
authors.initials: M
authors.lastname: Berreur
authors.affiliation: INSERM, UMR 957, 1 rue Gaston Veil, 44035 Nantes Cedex 1, France; University of Nantes, Nantes Atlantique Universities, Laboratory of Pathophysiology of Bone Resorption and Therapy of Primary Bone Tumours, 1 rue Gaston Veil, 44035 Nantes Cedex 1, France; Nantes University Hospital, 1 place Alexis-Ricordeau, 44093 Nantes Cedex 1, France.
authors.forename: R
authors.initials: R
authors.lastname: Brion
authors.affiliation: INSERM, UMR 957, 1 rue Gaston Veil, 44035 Nantes Cedex 1, France; University of Nantes, Nantes Atlantique Universities, Laboratory of Pathophysiology of Bone Resorption and Therapy of Primary Bone Tumours, 1 rue Gaston Veil, 44035 Nantes Cedex 1, France; Nantes University Hospital, 1 place Alexis-Ricordeau, 44093 Nantes Cedex 1, France.
authors.forename: F
authors.initials: F
authors.lastname: Gouin
authors.affiliation: INSERM, UMR 957, 1 rue Gaston Veil, 44035 Nantes Cedex 1, France; University of Nantes, Nantes Atlantique Universities, Laboratory of Pathophysiology of Bone Resorption and Therapy of Primary Bone Tumours, 1 rue Gaston Veil, 44035 Nantes Cedex 1, France.
authors.forename: P
authors.initials: P
authors.lastname: Layrolle
authors.affiliation: INSERM, UMR 957, 1 rue Gaston Veil, 44035 Nantes Cedex 1, France; University of Nantes, Nantes Atlantique Universities, Laboratory of Pathophysiology of Bone Resorption and Therapy of Primary Bone Tumours, 1 rue Gaston Veil, 44035 Nantes Cedex 1, France; Nantes University Hospital, 1 place Alexis-Ricordeau, 44093 Nantes Cedex 1, France.
authors.forename: N
authors.initials: N
authors.lastname: Passuti
authors.affiliation: INSERM, UMR 957, 1 rue Gaston Veil, 44035 Nantes Cedex 1, France; University of Nantes, Nantes Atlantique Universities, Laboratory of Pathophysiology of Bone Resorption and Therapy of Primary Bone Tumours, 1 rue Gaston Veil, 44035 Nantes Cedex 1, France; Nantes University Hospital, 1 place Alexis-Ricordeau, 44093 Nantes Cedex 1, France.
authors.forename: D
authors.initials: D
authors.lastname: Heymann
mesh_terms: D000135:Acid Phosphatase / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects*; D005822:Genetic Vectors / Q000235:genetics / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008081:Liposomes; D051379:Mice; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D010014:Osteolysis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D020959:Polyethylene / Q000633:toxicity*; D034741:RNA, Small Interfering; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000096:biosynthesis / Q000235:genetics; D000071681:Tartrate-Resistant Acid Phosphatase
chemical_list: D007527:Isoenzymes; D008081:Liposomes; D034741:RNA, Small Interfering; D053246:Receptor Activator of Nuclear Factor-kappa B; C505687:Tnfrsf11a protein, mouse; D020959:Polyethylene; D000135:Acid Phosphatase; C000605511:Acp5 protein, mouse; D000071681:Tartrate-Resistant Acid Phosphatase
keywords: Osteoclast; Polyethylene particle-induced osteolysis; Wear debris; siRNA