Viral interleukin-10 gene inhibition of inflammation, osteoclastogenesis, and bone resorption in response to titanium particles.

OBJECTIVE To evaluate the potential of viral interleukin-10 (vIL-10) gene therapy as an approach to prevent wear debris-induced inflammation, osteoclastogenesis, and bone resorption as it relates to periprosthetic osteolysis in patients with total joint replacements. METHODS Replication-defective adenovirus vectors expressing vIL-10 (AdvIL-10) or LacZ (AdLacZ) target genes were used to transduce fibroblast-like synoviocytes (FLS) in vitro, and the effects of these cells on wear debris-induced proinflammatory cytokine production and receptor activator of nuclear factor kappaB ligand + macrophage colony-stimulating factor splenocyte osteoclastogenesis were assessed by enzyme-linked immunosorbent assay and tartrate-resistant acid phosphatase assay. The effects of AdvIL-10 administration on wear debris-induced osteolysis in vivo were analyzed using the mouse calvaria model, in which AdLacZ was used as the control. RESULTS In the presence of AdLacZ-infected FLS, titanium particle-stimulated macrophages exhibited a marked increase in secretion of tumor necrosis factor alpha (TNFalpha) (6.5-fold), IL-6 (13-fold), and IL-1 (5-fold). Coculture with AdvIL-10-transduced FLS suppressed cytokine secretion to basal levels, while addition of an anti-IL-10 neutralizing antibody completely blocked this effect. The vIL-10-transduced FLS also inhibited osteoclastogenesis 10-fold in an anti-IL-10-sensitive manner. In vivo, titanium implantation resulted in a 2-fold increase in osteoclasts (P < 0.05) and in a 2-fold increase in sagittal suture area (P < 0.05). This increase over control levels was completely blocked in mice receiving intraperitoneal injections of AdvIL-10, all of whom had measurable serum vIL-10 levels for the duration of the experiment. Immunohistochemistry demonstrated reduced cyclooxygenase 2 and TNFalpha expression in AdvIL-10-infected animals. CONCLUSION This study demonstrates that gene delivery of vIL-10 inhibits 3 processes critically involved in periprosthetic osteolysis: 1) wear debris-induced proinflammatory cytokine production, 2) osteoclastogenesis, and 3) osteolysis.

[1]  E. Schwarz,et al.  Effect of Anti‐Tumor Necrosis Factor-&agr; Gene Therapy on Wear Debris‐Induced Osteolysis , 2001, The Journal of bone and joint surgery. American volume.

[2]  E. Schwarz,et al.  Evidence for a Direct Role of Cyclo‐Oxygenase 2 in Implant Wear Debris‐Induced Osteolysis , 2001, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[3]  P. Robbins,et al.  Future of adenoviruses in the gene therapy of arthritis , 2001, Arthritis research.

[4]  E. Schwarz,et al.  Efficacy of Etanercept for Wear Debris‐Induced Osteolysis , 2001, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[5]  F. Breedveld,et al.  Are differences in interleukin 10 production associated with joint damage? , 2000, Rheumatology.

[6]  R. Gay,et al.  Expression of osteoclast differentiation factor in rheumatoid arthritis. , 2000, Arthritis and rheumatism.

[7]  E M Schwarz,et al.  Quantitative small‐animal surrogate to evaluate drug efficacy in preventing wear debris‐induced osteolysis , 2000, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[8]  E. Schwarz.  The adeno-associated virus vector for orthopaedic gene therapy. , 2000, Clinical orthopaedics and related research.

[9]  E. Schwarz,et al.  Breakthrough in bone: the molecular mechanism of osteoclast/osteoblast coupling revealed , 2000 .

[10]  T. Shanley,et al.  Regulation of chemokine expression by IL-10 in lung inflammation. , 2000, Cytokine.

[11]  E. Schwarz,et al.  NF-κB Regulates VCAM-1 Expression on Fibroblast-Like Synoviocytes1 , 2000, The Journal of Immunology.

[12]  T. L. Nagabhushan,et al.  Design and Analysis of an Engineered Human Interleukin-10 Monomer* , 2000, The Journal of Biological Chemistry.

[13]  G. Kollias,et al.  Tumor necrosis factor‐α/nuclear transcription factor‐κB signaling in periprosthetic osteolysis , 2000 .

[14]  G. Kollias,et al.  Empirical advantages of adeno associated viral vectors in vivo gene therapy for arthritis. , 2000, The Journal of rheumatology.

[15]  R. Strieter,et al.  Viral IL-10 Gene Transfer Decreases Inflammation and Cell Adhesion Molecule Expression in a Rat Model of Venous Thrombosis1 2 , 2000, The Journal of Immunology.

[16]  E. Giannini,et al.  Viral IL-10 and Soluble TNF Receptor Act Synergistically to Inhibit Collagen-Induced Arthritis Following Adenovirus- Mediated Gene Transfer1 , 2000, The Journal of Immunology.

[17]  S. Pestka,et al.  A Single Amino Acid Determines the Immunostimulatory Activity of Interleukin 10 , 2000, The Journal of experimental medicine.

[18]  L. Moldawer,et al.  TNF-α Receptor Signaling and IL-10 Gene Therapy Regulate the Innate and Humoral Immune Responses to Recombinant Adenovirus in the Lung1 , 2000, The Journal of Immunology.

[19]  J. S. Kim,et al.  Primary total hip arthroplasty with a cementless porous-coated anatomic total hip prosthesis: 10- to 12-year results of prospective and consecutive series. , 1999, The Journal of arthroplasty.

[20]  Jeffrey Bonadio,et al.  Localized, direct plasmid gene delivery in vivo: prolonged therapy results in reproducible tissue regeneration , 1999, Nature Medicine.

[21]  P J Gregg,et al.  Outcome of Charnley total hip replacement across a single health region in England: the results at five years from a regional hip register. , 1999, The Journal of bone and joint surgery. British volume.

[22]  S. Akira,et al.  Interleukin-10 Receptor Signaling through the JAK-STAT Pathway , 1999, The Journal of Biological Chemistry.

[23]  S Hukuda,et al.  Gene expressions of antiinflammatory mediators in THR retrieved interfacial membranes. , 1999, Acta orthopaedica Scandinavica.

[24]  P. Robbins,et al.  Adenoviral transfer of the viral IL-10 gene periarticularly to mouse paws suppresses development of collagen-induced arthritis in both injected and uninjected paws. , 1999, Journal of immunology.

[25]  P. Robbins,et al.  Gene transfer of cytokine inhibitors into human synovial fibroblasts in the SCID mouse model. , 1999, Arthritis and rheumatism.

[26]  M. Perretti,et al.  Role of resident peritoneal macrophages and mast cells in chemokine production and neutrophil migration in acute inflammation: evidence for an inhibitory loop involving endogenous IL-10. , 1999, Journal of immunology.

[27]  B. Davidson,et al.  Interleukin-10 modulates the severity of hypersensitivity pneumonitis in mice. , 1998, American journal of respiratory cell and molecular biology.

[28]  J. Puzas,et al.  Interleukin‐10 inhibits cytokine synthesis in monocytes stimulated by titanium particles: Evidence of an anti‐inflammatory regulatory pathway , 1998, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[29]  L. Leon,et al.  Role of IL‐10 in Inflammation: Studies Using Cytokine Knockout Mice a , 1998, Annals of the New York Academy of Sciences.

[30]  G. Boivin,et al.  Inhibition of collagen-induced arthritis in mice by viral IL-10 gene transfer. , 1998, Journal of immunology.

[31]  J. Callaghan,et al.  Charnley Total Hip Arthroplasty in Patients Less Than Fifty Years Old. A Twenty to Twenty-five-Year Follow-up Note* , 1998, The Journal of bone and joint surgery. American volume.

[32]  Y. Liu,et al.  IL‐10 inhibits macrophage activation and proliferation by distinct signaling mechanisms: evidence for Stat3‐dependent and ‐independent pathways , 1998, The EMBO journal.

[33]  I. Verma,et al.  Gene therapy - promises, problems and prospects , 1997, Nature.

[34]  W H Harris,et al.  Wear of Polyethylene Acetabular Components in Total Hip Arthroplasty. An Analysis of One Hundred and Twenty-eight Components Retrieved at Autopsy or Revision Operations* , 1997, The Journal of bone and joint surgery. American volume.

[35]  I. Verma,et al.  Immunological defects in mice with a targeted disruption in Bcl-3. , 1997, Genes & development.

[36]  J. Banchereau,et al.  The EBV IL-10 homologue is a selective agonist with impaired binding to the IL-10 receptor. , 1997, Journal of immunology.

[37]  T. Glant,et al.  Human monocyte/macrophage response to cobalt‐chromium corrosion products and titanium particles in patients with total joint replacements , 1997, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[38]  Gregory J. Goodall,et al.  Differential Regulation of the Stability of Cytokine mRNAs in Lipopolysaccharide-activated Blood Monocytes in Response to Interleukin-10* , 1996, The Journal of Biological Chemistry.

[39]  J. Puzas,et al.  Increased Levels of Tumor Necrosis Factor-&agr; and Interleukin-6 Protein and Messenger RNA in Human Peripheral Blood Monocytes due to Titanium Particles* , 1996, The Journal of bone and joint surgery. American volume.

[40]  K. Drazan,et al.  Viral IL-10 gene therapy inhibits TNF-α and IL-1β, not IL-6, in the newborn endotoxemic mouse , 1996 .

[41]  A. Kukita,et al.  Interleukin‐10 selectively inhibits osteoclastogenesis by inhibiting differentiation of osteoclast progenitors into preosteoclast‐like cells in rat bone marrow culture system , 1995, Journal of cellular physiology.

[42]  J. Vries.  Immunosuppressive and anti-inflammatory properties of interleukin 10. , 1995, Annals of medicine.

[43]  H. Niiro,et al.  Inhibition by interleukin-10 of inducible cyclooxygenase expression in lipopolysaccharide-stimulated monocytes: its underlying mechanism in comparison with interleukin-4. , 1995, Blood.

[44]  L. Shapiro,et al.  A randomized, controlled trial of IL-10 in humans. Inhibition of inflammatory cytokine production and immune responses. , 1995, Journal of immunology.

[45]  N. Sarvetnick,et al.  Cellular and humoral immune responses to adenoviral vectors containing factor IX gene: tolerization of factor IX and vector antigens allows for long-term expression. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[46]  W. Harris,et al.  The problem is osteolysis. , 1995, Clinical orthopaedics and related research.

[47]  J. Galante,et al.  Wear Debris in Total Joint Replacements , 1994, The Journal of the American Academy of Orthopaedic Surgeons.

[48]  P. Revell,et al.  Interleukin-1 production by activated macrophages surrounding loosened orthopaedic implants: a potential role in osteolysis. , 1994, British journal of rheumatology.

[49]  H. Rubash,et al.  The characterization of cytokines in the interface tissue obtained from failed cementless total hip arthroplasty with and without femoral osteolysis. , 1994, Clinical orthopaedics and related research.

[50]  T. Wright,et al.  The problem in total joint arthroplasty: aseptic loosening. , 1993, The Journal of bone and joint surgery. American volume.

[51]  W H Harris,et al.  Production of cytokines around loosened cemented acetabular components. Analysis with immunohistochemical techniques and in situ hybridization. , 1993, The Journal of bone and joint surgery. American volume.

[52]  Y. Vodovotz,et al.  Macrophage deactivation by interleukin 10 , 1991, The Journal of experimental medicine.

[53]  C G Figdor,et al.  Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes , 1991, The Journal of experimental medicine.

[54]  T. Mosmann,et al.  Expression of interleukin-10 activity by Epstein-Barr virus protein BCRF1. , 1990, Science.

[55]  T. Mosmann,et al.  Homology of cytokine synthesis inhibitory factor (IL-10) to the Epstein-Barr virus gene BCRFI. , 1990, Science.

[56]  D. Radzioch,et al.  Heterogeneity of hematopoietic cells immortalized by v-myc/v-raf recombinant retrovirus infection of bone marrow or fetal liver. , 1989, Journal of the National Cancer Institute.

[57]  R. Coffman,et al.  Interleukin-10 and the interleukin-10 receptor. , 2001, Annual review of immunology.

[58]  G. Firestein.  Cytokine networks in rheumatoid arthritis: implications for therapy. , 1995, Agents and actions. Supplements.

[59]  J O Galante,et al.  Composition and morphology of wear debris in failed uncemented total hip replacement. , 1994, The Journal of bone and joint surgery. British volume.