title: Adenovirus-mediated expression of bone morphogenetic protein-2 activates titanium particle-induced osteoclastogenesis and this effect occurs in spite of the suppression of TNF-α expression by siRNA.
abstract: The phagocytosis of wear particles by macrophages results in the secretion of pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), which play a major role in promoting osteoclast recruitment. The inhibition of TNF-α expression decreases osteoclastogenesis. In a previous study, we demonstrated that bone morphogenetic protein-2 (BMP-2) can activate wear debris-induced osteoclast recruitment in the presence of receptor activator of nuclear factor (NF)-κB ligand (RANKL); however, whether these effects are associated with pro-inflammatory cytokines remains unclear. In this study, we constructed an adenoviral vector carrying TNF-small interfering RNA (siRNA) (Ad-TNF-siRNA), as well as a vector carrying both the BMP-2 gene and TNF-α-siRNA (Ad-BMP-2-TNF-siRNA). The two adenoviral vectors significantly suppressed the expression of TNF-α; however, only treatment with Ad-TNF-siRNA significantly inhibited osteoclastogenesis. We demonstrate that the overexpression of BMP-2, despite the suppression of TNF-α expression by Ad-BMP-2-TNF-siRNA, increases the size and number of titanium (Ti) particle-induced multinuclear osteoclasts, the expression of osteoclast genes, as well as the resorption area. There were no differences observed between Ti particle-induced and Ad-BMP-2-TNF-siRNA-induced osteoclast formation. Moreover, Ad-BMP-2-TNF-siRNA directly acted upon osteoclast precursors by increasing the level of c-Fos, regulating other signaling pathways, such as p38 phosphorylated c-Jun N-terminal kinase (p-JNK) and phosphorylated IκB (p‑IκB). Taken together, these data demonstrate that treatment with Ad-BMP-2-TNF-siRNA increases wear debris-induced osteoclast formation by activating c-Fos and that these effects are not associated with pro-inflammatory cytokines.
authors.affiliation: Department of Orthopedics, Affiliated Hospital of Ningxia Medical University, Ningxia 750004, P.R. China.
authors.forename: Shouxuan
authors.initials: S
authors.lastname: Sun
authors.forename: Haohui
authors.initials: H
authors.lastname: Guo
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Bo
authors.initials: B
authors.lastname: Yu
authors.forename: Kening
authors.initials: K
authors.lastname: Sun
authors.forename: Qunhua
authors.initials: Q
authors.lastname: Jin
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics*; D001862:Bone Resorption / Q000209:etiology* / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation; D015870:Gene Expression; D005822:Genetic Vectors / Q000235:genetics; D051379:Mice; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics*; D014025:Titanium / Q000009:adverse effects*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
chemical_list: D055396:Bone Morphogenetic Protein 2; D016760:Proto-Oncogene Proteins c-fos; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D014025:Titanium