title: Antisense oligonucleotide targeting TNF-alpha can suppress Co-Cr-Mo particle-induced osteolysis.
abstract: The most common cause of implant failure in joint replacement is aseptic loosening due to particle-induced osteolysis. TNF-alpha has been shown to be one of the key factors in the process of osteoclastogenesis. Anti-TNF agents are useful in the treatment of joint inflammation related to osteolysis. This study investigated the effect of a single subcutaneous dose of an antisense oligonucleotide (ASO) on particle-induced osteolysis. We utilized the murine calvaria osteolysis model in C57BL/J6 mice. Bone resorption was measured by the toluidine blue staining. Osteoclasts were detected by tartrate resistant acid phosphatase (TRAP) staining assay and were quantified by a TRAP quantification kit. Results show that bone resorption is 0.347 +/- 0.09 mm(2) in mice with particle implantation, and decreased to 0.123 +/- 0.05 mm(2) and 0.052 +/- 0.02 mm(2) after ASO treatment with low and high doses, respectively. The number of osteoclasts in animal calvaria treated with ASO is reduced compared with that of untreated animals, and the quantification results indicate that about 90% of osteoclastogenesis is suppressed by the ASO. In addition, the osteoclastogenesis can be reestablished by the addition of TNF-alpha. In conclusion, we demonstrate that the antisense oligonucleotide targeting to TNF-alpha can suppress osteolysis induced by metal particles in a murine calvaria model. This new finding may be of value in the search for novel therapeutic methods for implant loosening.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, and Department of Orthopaedics, Jinling Hospital, School of Medicine, Nanjing University, Nanjing 210093, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Dong
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.forename: Yi-An
authors.initials: YA
authors.lastname: Zhu
authors.forename: Chunming
authors.initials: C
authors.lastname: Wang
authors.forename: Huajia
authors.initials: H
authors.lastname: Diao
authors.forename: Chenyu
authors.initials: C
authors.lastname: Zhang
authors.forename: Jianning
authors.initials: J
authors.lastname: Zhao
authors.forename: Junfeng
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002858:Chromium Alloys / Q000633:toxicity*; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression / Q000276:immunology; D015316:Genetic Therapy / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D020320:Oligoribonucleotides, Antisense / Q000494:pharmacology*; D010010:Osteoclasts / Q000473:pathology; D010014:Osteolysis / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D011475:Prosthesis Failure; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012886:Skull; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
chemical_list: D002858:Chromium Alloys; D020320:Oligoribonucleotides, Antisense; D014409:Tumor Necrosis Factor-alpha; C103771:cobalt-chromium-molybdenum-carbon alloy