Recombinant Adeno-Associated Virus-Mediated Osteoprotegerin Gene Therapy Inhibits Wear Debris-Induced Osteolysis

Kato, Hiroyuki; Hirayama, Takuya; Minami, Akio; Iwasaki, Norimasa; Hirachi, Kazuhiko

doi:10.2106/00004623-200208000-00017

Cited by 147 publications

(79 citation statements)

References 4 publications

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“…This ex vivo OPG gene therapy effectively blocked titanium particle-stimulated osteoclastogenesis as evaluated three days after particle implantation. Similarly, the same group using this in vivo murinc model reported effective blockadc of wear debris-induced osteoclastogenesis and osteolysis by adeno-associated virus-mediated OPG gene therapy [35].…”

Section: Discussionmentioning

confidence: 76%

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NF‐kB signaling blockade abolishes implant particle‐induced osteoclastogenesis

Clohisy

Hirayama

Frazier

et al. 2004

Journal Orthopaedic Research

106

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In this study we investigated the effect of NF‐kB signaling blockade on polymethylmethacrylate (PMMA) particle‐induced osteoclastogenesis in vitro. We first established effective blockade of NF‐kB activity as tested by electrophoretic mobility shift assays (EMSA). Particle‐induced NF‐kB activation in murine osteoclast precursor cells (CSF‐1‐dependent bone marrow macrophages) was markedly reduced by co‐treatment of the cells with the NF‐kB inhibitors N‐tosyl‐L‐phenylalanine chloromethyl ketone (TPCK) and Calpain Inhibitor I (CPI). This inhibition of NF‐kB activity was associated with blockade of p50 NF‐kB subunit nuclear trans‐location. We then established a direct NF‐kB inhibition approach by utilizing a TAT‐bound, mutant IkB (TAT:IkB46‐317), and demonstrated an inhibitory effect evidenced by decreased NF‐kB DNA binding activity. Having established that these strategies (TPCK, CPI, TAT: IkB46‐317) effectively block NF‐kB activation, we next investigated the effect of these agents on particle‐stimulated osteoclast formation. PMMA particle stimulation of mature osteoclast formation from RANKL‐primed osteoclast precursor cells was blocked by all three inhibitors. To further test the efficacy of NF‐kB blockade, experiments were performed with the TAT:IkB46‐317 mutant peptide in whole bone marrow cultures that contain supporting stromal cells. Again, this inhibitor efficiently blocked particle‐induced osteoclastogenesis. Thus, we have shown that pharmaceutical and molecular blockade of NF‐kB activation inhibits PMMA particle‐directed osteoclastogenesis in vitro. © 2003 Orthopaedic Research Society. Published by Elsevier Ltd. All rights reserved.

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Section: Discussionmentioning

confidence: 76%

“…lysis [11,12,15,27,30,35]. The osteoclastogenic action of these cytokines is thought to be primarily mediated through induction of the nuclear transcription factor NF-kB which is known to be essential for osteoclastogenesis [20].…”

mentioning

confidence: 99%

NF‐kB signaling blockade abolishes implant particle‐induced osteoclastogenesis

Clohisy

Hirayama

Frazier

et al. 2004

Journal Orthopaedic Research

106

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“…Computerized image analysis revealed that expression of OPG significantly protected against bone collagen loss. We also evaluated the effects of ex vivo 88 and in vivo 89 OPG gene therapy in the calvaria model of wear debris-induced osteolysis. Again the results were similar to the data obtained in the air pouch model and support the hypothesis that RANKL is the final effector of osteoclastogenesis and bone resorption.…”

Section: Gene Therapymentioning

confidence: 99%

Aseptic loosening

2004

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“…4,26 New generations of vectors have been generated to address these limitations. Among these, adeno-associated viruses appear promising as they do not encode for inflammatory viral proteins 26,[42][43][44] and have successfully been applied to stimulate osteogenesis in vivo. 8,9 However, they do not integrate the host genome and are difficult to generate at high titers.…”

Section: Discussionmentioning

confidence: 99%

Local gene transfer to calcified tissue cells using prolonged infusion of a lentiviral vector

et al. 2006

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Gene transfer using viral vectors offers the potential for the sustained expression of proteins in specific target tissues. However, in the case of calcified tissues, in vivo delivery remains problematic because of limited accessibility. The aim of this study was to test the efficiency of lentiviral vectors (LVs) on osteogenic cells in vitro, and determine the feasibility of directly transducing resident bone cells in vivo. LVs encoding for green fluorescent protein (GFP) and ameloblastin (AMBN), a protein associated with mineralization not reported in bone, were generated. The transduction efficiency of the LVs was evaluated using the MC3T3 cell line and primary calvaria-derived osteogenic cells. For in vivo delivery, the LVs were infused using osmotic minipumps through holes created in the bone of the rat hemimandible and tibia. The production of GFP and AMBN in vitro and in vivo was monitored using fluorescence microscopy. Both transgenes were expressed in MC3T3 and primary osteogenic cells. In vivo, GFP was detected at the infusion site and fibroblast-like cells, osteoblasts, osteocytes and osteoclasts expressed AMBN. Our data demonstrate, for the first time, that primary osteogenic cells are efficiently transduced with LVs and that their infusion is advantageous for locally delivering DNA to bone cells.

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Recombinant Adeno-Associated Virus-Mediated Osteoprotegerin Gene Therapy Inhibits Wear Debris-Induced Osteolysis

Cited by 147 publications

References 4 publications

NF‐kB signaling blockade abolishes implant particle‐induced osteoclastogenesis

NF‐kB signaling blockade abolishes implant particle‐induced osteoclastogenesis

Aseptic loosening

Local gene transfer to calcified tissue cells using prolonged infusion of a lentiviral vector

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