JBiSE  Vol.9 No.7 , June 2016
Inhibition of Osteoarthritis in Rats by Electroporation with Interleukin-1 Receptor Antagonist
Abstract: Gene therapy constitutes a promising strategy for the treatment of osteoarthritis (OA). We assessed the use of electroporation (EP) of non-viral gene vectors, and compared its efficacy with that of adeno-associated virus (AAV) vectors. EP- and AAV-mediated delivery of human interleukin-1 receptor antagonist (hIL-1Ra) was localized performed in the joints of rats following induction of OA. mRNA levels for hIL-1Ra, IL-1β, TNF-α, MMP-13 and ADAMTS-4 in the cartilage and synovial tissues were analyzed. Structural analyses of the subchondral bone at the medial femoral condyle were performed by Micro-CT after treatment. Knee joint specimens were staining with hematoxylin and eosin and Saffron O. Induction of hIL-1Ra by both EP and AAV inhibited inflammatory-induced sub-chondral bone reconstruction, and effectively suppressed IL-1β activity, as evidenced by decreased expression of MMP-13 and ADAMTS-4. Histological analyses revealed significant protection of cartilage, proteoglycan by EP and AAV. hIL-1Ra expression was similar in both the EP and AAV groups. Notably, this gene is not easier degraded transduced by EP compared with AAV. Taken together, these results show that EP offers transfection efficiency comparable to that of AAV, with the potential for longer gene expression, making EP a promising candidate for efficient non-viral delivery of OA gene therapy.
Cite this paper: Sun, Z. , Yin, H. , Yu, X. , Sun, X. , Xiao, B. , Xu, Y. , Yuan, Z. , Meng, H. , Peng, J. , Yu, C. , Wang, Y. , Guo, Q. , Wang, A. and Lu, S. (2016) Inhibition of Osteoarthritis in Rats by Electroporation with Interleukin-1 Receptor Antagonist. Journal of Biomedical Science and Engineering, 9, 323-336. doi: 10.4236/jbise.2016.97027.

[1]   Iannone, F. and Lapadula, G (2003) The Pathophysiology of Osteoarthritis. Aging Clinical and Experimental Research, 15, 364-372.

[2]   Mankin, H.J., Johnson, M.E. and Lippiello, L. (1981) Biochemical and Metabolic Abnormalities in Articular Cartilage from Osteoarthritic Human Hips. III. Distribution and Metabolism of Amino Sugar-Containing Macromolecules. The Journal of Bone and Joint Surgery American Volume, 63, 131-139.

[3]   Zhang, X.L., Yu, C.L., Shi, X., Zhang, C., Tang, T.T. and Dai, K.R. (2006) Direct Chitosan-Mediated Gene Delivery to the Rabbit Knee Joints in Vitro and in Vivo. Biochemical and Biophysical Research Communications, 341, 202-208.

[4]   Evans, C.H., Robbins, P.D., Ghivizzani, S.C., Wasko, M.C., Tomaino, M.M., Kang, R., et al. (2005) Gene Transfer to Human Joints: Progress toward a Gene Therapy of Arthritis. Proceedings of the National Academy of Sciences of the United States of America, 102, 8698-8703.

[5]   Lang, A., Neuhaus, J., Pfeiffenberger, M., Schroder, E., Ponomarev, I., Weber, Y., et al. (2014) Optimization of A Nonviral Transfection System to Evaluate Cox-2 Controlled Interleukin-4 Expression for Osteoarthritis Gene Therapy in Vitro. The Journal of Gene Medicine, 16, 352-363.

[6]   Madry, H. and Cucchiarini, M. (2014) Tissue-Engineering Strategies to Repair Joint Tissue in Osteoarthritis: Nonviral Gene-Transfer Approaches. Current Rheumatology Reports, 16, 450.

[7]   Lu, H.D., Zhao, H.Q., Wang, K. and Lv, L.L. (2011) Novel Hyaluronic Acid-Chitosan Nanoparticles as Non-Viral Gene Delivery Vectors Targeting Osteoarthritis. International Journal of Pharmaceutics, 420, 358-365.

[8]   Goodrich, L.R., Phillips, J.N., McIlwraith, C.W., Foti, S.B., Grieger, J.C., Gray, S.J., et al. (2013) Optimization of scAAVIL-1ra in Vitro and in Vivo to Deliver High Levels of Therapeutic Protein for Treatment of Osteoarthritis. Molecular Therapy Nucleic Acids, 2, e70.

[9]   Chiu, W.C., Chen, C.M., Cheng, T.T., You, H.L., Yu, S.F., Weng, L.H., et al. (2013) EBV-Encoded Small RNA1 and Nonresolving Inflammation in Rheumatoid Arthritis. The Kaohsiung Journal of Medical Sciences, 29, 606-610.

[10]   Croia, C., Serafini, B., Bombardieri, M., Kelly, S., Humby, F., Severa, M., et al. (2013) Epstein-Barr Virus Persistence and Infection of Autoreactive Plasma Cells in Synovial Lymphoid Structures in Rheumatoid Arthritis. Annals of the Rheumatic Diseases, 72, 1559-1568.

[11]   Hsieh, J.L., Shen, P.C., Shiau, A.L., Jou, I.M., Lee, C.H., Teo, M.L., et al. (2009) Adenovirus-Mediated Kallistatin Gene Transfer Ameliorates Disease Progression in a Rat Model of Osteoarthritis Induced by Anterior Cruciate Ligament Transection. Human Gene Therapy, 20, 147-158.

[12]   Simon, R.H., Engelhardt, J.F., Yang, Y., Zepeda, M., Weber-Pendleton, S., Grossman, M., et al. (1993) Adenovirus- Mediated Transfer of the CFTR Gene to Lung of Nonhuman Primates: Toxicity Study. Human Gene Therapy, 4, 771- 780.

[13]   Rothe, M., Modlich, U. and Schambach, A. (2013) Biosafety Challenges for Use of Lentiviral Vectors in Gene Therapy. Current Gene Therapy, 13, 453-468.

[14]   Heckl, D., Schwarzer, A., Haemmerle, R., Steinemann, D., Rudolph, C., Skawran, B., et al. (2012) Lentiviral Vector Induced Insertional Haploinsufficiency of Ebf1 Causes Murine Leukemia. Molecular Therapy: The Journal of the American Society of Gene Therapy, 20, 1187-1195.

[15]   Gao, Y., Xu, Z., Chen, S., Gu, W., Chen, L. and Li, Y. (2008) Arginine-Chitosan/DNA self-Assemble Nanoparticles for Gene Delivery: In Vitro Characteristics and Transfection Efficiency. International Journal of Pharmaceutics, 359, 241-246.

[16]   Hejazi, R. and Amiji, M. (2003) Chitosan-Based Gastrointestinal Delivery Systems. Journal of Controlled Release, 89, 151-165.

[17]   Li, Z. and Zhang, M. (2005) Chitosan-Alginate as Scaffolding Material for Cartilage Tissue Engineering. Journal of Biomedical Materials Research Part A, 75, 485-493.

[18]   Mao, S., Sun, W. and Kissel, T. (2010) Chitosan-Based Formulations for Delivery of DNA and siRNA. Advanced Drug Delivery Reviews, 62, 12-27.

[19]   Pelletier, J.P., Faure, M.P., DiBattista, J.A., Wilhelm, S., Visco, D. and Martel-Pelletier, J. (1993) Coordinate Synthesis of Stromelysin, Interleukin-1, and Oncogene Proteins in Experimental Osteoarthritis. An Immunohistochemical Study. The American Journal of Pathology, 142, 95-105.

[20]   Goldring, M.B. (1999) The Role of Cytokines as Inflammatory Mediators in Osteoarthritis: Lessons from Animal Models. Connective Tissue Research, 40, 1-11.

[21]   Zhu, S., Lu, P., Liu, H., Chen, P., Wu, Y., Wang, Y., et al. (2015) Inhibition of Rac1 Activity by Controlled Release of NSC23766 from Chitosan Microspheres Effectively Ameliorates Osteoarthritis Development in Vivo. Annals of the Rheumatic Diseases, 74, 285-293.

[22]   Bondeson, J., Wainwright, S.D., Lauder, S., Amos, N. and Hughes, C.E. (2006) The Role of Synovial Macrophages and Macrophage-Produced Cytokines in Driving Aggrecanases, Matrix Metalloproteinases, and Other Destructive and Inflammatory Responses in Osteoarthritis. Arthritis Research & Therapy, 8, R187.

[23]   Goldring, M.B., Sandell, L.J., Stephenson, M.L. and Krane, S.M. (1986) Immune Interferon Suppresses Levels of Procollagen mRNA and Type II Collagen Synthesis in Cultured Human Articular and Costal Chondrocytes. The Journal of Biological Chemistry, 261, 9049-9055.

[24]   Eisenberg, S.P., Evans, R.J., Arend, W.P., Verderber, E., Brewer, M.T., Hannum, C.H., et al. (1990) Primary Structure and Functional Expression from Complementary DNA of a Human Interleukin-1 Receptor Antagonist. Nature, 343, 341-346.

[25]   Dhaneshwar, S., Dipmala, P., Abhay, H. and Prashant, B. (2013) Dis-ease-Modifying Effect of Anthraquinone Prodrug with Boswellic Acid on Collagenase-Induced Osteoarthritis in Wistar Rats. Inflammation & Allergy Drug Targets, 12, 288-295.

[26]   Frisbie, D.D., Ghivizzani, S.C., Robbins, P.D., Evans, C.H. and McIlwraith, C.W. (2002) Treatment of Experimental Equine Osteoarthritis by in Vivo Delivery of the Equine Interleukin-1 Receptor Antagonist Gene. Gene Therapy, 9, 12- 20.

[27]   Pelletier, J.P., Caron, J.P., Evans, C., Robbins, P.D., Georgescu, H.I., Jo-vanovic, D., et al. (1997) In Vivo Suppression of Early Experimental Osteoarthritis by Interleukin-1 Receptor Antagonist Using Gene Therapy. Arthritis and Rheumatism, 40, 1012-1019.

[28]   Choi, S.A., Hwang, S.K., Wang, K.C., Cho, B.K., Phi, J.H., Lee, J.Y., et al. (2011) Therapeutic Efficacy and Safety of TRAIL-Producing Human Adipose Tissue-Derived Mesenchymal Stem Cells against Experimental Brainstem Glioma. Neuro-Oncology, 13, 61-69.

[29]   Kimelman-Bleich, N., Pelled, G., Zilberman, Y., Kallai, I., Mizrahi, O., Tawackoli, W., et al. (2011) Targeted Gene- and-Host Progenitor Cell Therapy for Nonunion Bone Fracture Repair. Molecular Therapy, 19, 53-59.

[30]   Gehl, J. (2003) Electroporation, Theory and Methods, Perspectives for Drug Delivery, Gene Therapy and Research. Acta Physiologica Scandinavica, 177, 437-447.

[31]   Sukedai, M., Ariyoshi, W., Okinaga, T., Iwanaga, K., Habu, M., Yoshioka, I., et al. (2011) Inhibition of Adjuvant Arthritis in Rats by Electroporation with Interleukin-1 Receptor Antago-nist. Journal of Interferon & Cytokine Research, 31, 839-846.

[32]   Grossin, L., Cournil-Henrionnet, C., Mir, L.M., Liagre, B., Dumas, D., Etienne, S., et al. (2003) Direct Gene Transfer into Rat Articular Cartilage by in Vivo Electroporation. FASEB Journal, 17, 829-835.

[33]   Bloquel, C., Trollet, C., Pradines, E., Seguin, J., Scherman, D. and Bureau, M.F. (2006) Optical Imaging of Luminescence for in Vivo Quantification of Gene Electrotransfer in Mouse Muscle and Knee. BMC Biotechnology, 6, 16.

[34]   Ohashi, S., Kubo, T., Kishida, T., Ikeda, T., Takahashi, K., Arai, Y., et al. (2002) Successful Genetic Transduction in Vivo into Synovium by Means of Electroporation. Biochemical and Biophysical Research Communications, 293, 1530- 1535.

[35]   Seguin, C.A. and Bernier, S.M. (2003) TNFalpha Suppresses Link Protein and Type II Collagen Expression in Chondrocytes, Role of MEK1/2 and NF-KappaB Signaling Pathways. Journal of Cellular Physiology, 197, 356-369.

[36]   Verma, P. and Dalal, K. (2011) ADAMTS-4 and ADAMTS-5, Key Enzymes in Osteoarthritis. Journal of Cellular Biochemistry, 112, 3507-3514.

[37]   Madry, H., van Dijk, C.N. and Mueller-Gerbl, M. (2010) The Basic Science of the Subchondral Bone. Knee Surgery, Sports Traumatology, Arthroscopy, 18, 419-433.

[38]   Muraoka, T., Hagino, H., Okano, T., Enokida, M. and Teshima, R. (2007) Role of Subchondral Bone in Osteoarthritis Development: A Comparative Study of Two Strains of Guinea Pigs with and without Spontaneously Occurring Osteoarthritis. Arthritis and Rheumatism, 56, 3366-3374.

[39]   Zhang, P., Zhong, Z.H., Yu, H.T. and Liu, B. (2015) Exogenous Expression of IL-1Ra and TGF-Beta1 Promotes in Vivo Repair in Experimental Rabbit Osteoarthritis. Scandinavian Journal of Rheumatology, 44, 404-411.

[40]   Chen, B., Qin, J., Wang, H., Magdalou, J. and Chen, L. (2010) Effects of Adenovirus-Mediated bFGF, IL-1Ra and IGF-1 Gene Transfer on Human Osteoarthritic Chondro-cytes and Osteoarthritis in Rabbits. Experimental & Molecular medicine, 42, 684-695.

[41]   Watson, R.S., Broome, T.A., Levings, P.P., Rice, B.L., Kay, J.D., Smith, A.D., et al. (2013) ScAAV-Mediated Gene Transfer of Interleukin-1-Receptor Antagonist to Synovium and Articular Cartilage in Large Mammalian Joints. Gene Therapy, 20, 670-677.

[42]   Buckley, S.M., Delhove, J.M., Perocheau, D.P., Karda, R., Rahim, A.A., Howe, S.J., et al. (2015) In Vivo Bioimaging with Tissue-Specific Transcription Factor Activated Luciferase Reporters. Scientific Reports, 5, Article Number: 11842.

[43]   Goodrich, L.R., Grieger, J.C., Phillips, J.N., Khan, N., Gray, S.J., McIlwraith, C.W., et al. (2015) ScAAVIL-1ra Dosing Trial in a Large Animal Model and Valida-tion of Long-Term Expression with Repeat Administration for Osteoarthritis Therapy. Gene Therapy, 22, 536-545.

[44]   Deng, W.T., Dyka, F.M., Dinculescu, A., Li, J., Zhu, P., Chiodo, V.A., et al. (2015) Stability and Safety of an AAV Vector for Treating RPGR-ORF15 X-Linked Retinitis Pigmentosa. Human Gene Therapy, 26, 593-602.

[45]   Evans, C.H., Ghivizzani, S.C. and Robbins, P.D. (2013) Arthritis Gene Therapy and Its Tortuous Path into the Clinic. Translational Research, 161, 205-216.

[46]   Ishihara, A., Bartlett, J.S. and Bertone, A.L. (2012) Inflammation and Immune Response of Intra-Articular Serotype 2 Adeno-Associated Virus or Adenovirus Vectors in a Large Animal Model. Arthritis, 2012, Article ID: 735472

[47]   Onuora, S. (2014) Osteoarthritis, Targeting Rac1 via Microparticle-Based Drug Delivery System Protects OA Cartilage in Vivo. Nature Reviews Rheumatology, 10, 1.

[48]   Brama, P.A., Firth, E.C., van Weeren, P.R., Tuukkanen, J., Holopainen, J., Helminen, H.J., et al. (2009) Influence of Intensity and Changes of Physical Activity on Bone Mineral Density of Immature Equine Subchondral Bone. Equine Veterinary Journal, 41, 564-571.

[49]   Mengshol, J.A., Vincenti, M.P., Coon, C.I., Barchowsky, A. and Brinckerhoff, C.E. (2000) Interleukin-1 Induction of Collagenase 3 (Matrix Metalloproteinase 13) Gene Expression in Chondrocytes Requires p38, c-Jun N-Terminal Kinase, and Nuclear Factor KappaB, Differential Regulation of Collagenase 1 and Collagenase 3. Arthritis and Rheumatism, 43, 801-811.<801::AID-ANR10>3.0.CO;2-4

[50]   Meszaros, E. and Malemud, C.J. (2012) Prospects for Treating Osteoarthritis, Enzyme-Protein Interactions Regulating Matrix Metalloproteinase Activity. Therapeutic Advances in Chronic Disease, 3, 219-229.

[51]   Raina, A., Kumar, S., Shrivastava, R. and Mitra, A. (2015) Testis Mediated Gene Transfer, in Vitro Transfection in Goat Testis by Electroporation. Gene, 554, 96-100.

[52]   Zhang, X., Mao, Z. and Yu, C. (2004) Suppression of Early Experimental Osteoarthritis by Gene Transfer of Interleukin-1 Receptor Antagonist and Interleukin-10. Journal of Orthopaedic Research, 22, 742-750.