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Gene therapy for osteoporosis: evaluation in a murine ovariectomy model

Gene Therapy volume 8, pages 1770–1776 (2001)Cite this article

Abstract

Various cytokines and cytokine antagonists hold promise as new therapeutic agents for osteoporosis, but their application is hindered by delivery problems. Gene transfer offers an attractive technology with which to obviate these restrictions. Its utility was evaluated in an animal model of osteoporosis. Disease was induced by surgical ovariectomy and monitored by measuring bone weight after 12 days, and by histomorphometry after 5 weeks. Genes were transferred to the mice by intramedullary injection of adenoviral vectors. LacZ and luciferase marker genes were used to identify the bone marrow cells transduced by this procedure, and to track the possible spread of transgenes to other organs. The effect on bone loss of transferring a cDNA encoding the human interleukin-1 receptor antagonist (IL-1Ra) was then evaluated. The intramedullary injection of adenoviral vectors transduced lining osteoblasts, osteocytes and cells within the bone marrow. Luciferase activity persisted within the injected femora and adjacent musculature for at least 3 weeks, and in the draining lymph nodes for 2 weeks. Transient, low level expression was present in the liver, but no luciferase was detected at any time in the lung or spleen. Intramedullary introduction of the IL-1Ra gene resulted in circulation of the corresponding protein at concentrations that peaked on day 3, and returned to baseline by day 12. Transfer of the IL-1Ra gene strongly reduced the early loss of bone mass occurring in response to ovariectomy. Furthermore, it completely inhibited the loss of matrix detected by histomorphometry at 5 weeks. The protective effect of this gene was not restricted to bones receiving intramedullary injection of the vector, but occurred in all bones that were evaluated. This proof of concept encourages further development of gene therapy approaches to the treatment of osteoporosis.

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References

  1. Pacifici R . Estrogen, cytokines, and pathogenesis of postmenopausal osteoporosis J Bone Miner Res 1996 11: 1043–1051

    Article  CAS  PubMed  Google Scholar 

  2. Gowen M et al. An interleukin 1 like factor stimulates bone resorption in vitro Nature 1983 306: 378–380

    Article  CAS  PubMed  Google Scholar 

  3. Boyce BF et al. Effects of interleukin-1 on bone turnover in normal mice Endocrinology 1989 125: 1142–1150

    Article  CAS  PubMed  Google Scholar 

  4. Lerner UH, Ohlin A . Tumor necrosis factors alpha and beta can stimulate bone resorption in cultured mouse calvariae by a prostaglandin-independent mechanism J Bone Miner Res 1993 8: 147–155

    Article  CAS  PubMed  Google Scholar 

  5. Pacifici R et al. Effect of surgical menopause and estrogen replacement on cytokine release from human blood mononuclear cells Proc Natl Acad Sci USA 1991 88: 5134–5138

    Article  CAS  PubMed  Google Scholar 

  6. Pacifici R et al. Ovarian steroid treatment blocks a postmenopausal increase in blood monocyte interleukin 1 release Proc Natl Acad Sci USA 1989 86: 2398–2402

    Article  CAS  PubMed  Google Scholar 

  7. Ralston SH . Analysis of gene expression in human bone biopsies by polymerase chain reaction: evidence for enhanced cytokine expression in postmenopausal osteoporosis J Bone Miner Res 1994 9: 883–890

    Article  CAS  PubMed  Google Scholar 

  8. Ralston SH, Russell RG, Gowen M . Estrogen inhibits release of tumor necrosis factor from peripheral blood mononuclear cells in postmenopausal women J Bone Miner Res 1990 5: 983–988

    Article  CAS  PubMed  Google Scholar 

  9. Pfeilschifter J et al. Interleukin-1 and tumor necrosis factor stimulate the formation of human osteoclastlike cells in vitro J Bone Miner Res 1989 4: 113–118

    Article  CAS  PubMed  Google Scholar 

  10. van der Pluijm G et al. Two distinct effects of recombinant human tumor necrosis factor-alpha on osteoclast development and subsequent resorption of mineralized matrix Endocrinology 1991 129: 1596–1604

    Article  CAS  PubMed  Google Scholar 

  11. Suda T, Takahashi N, Martin TJ . Modulation of osteoclast differentiation Endocr Rev 1992 13: 66–80

    CAS  PubMed  Google Scholar 

  12. Kitazawa R et al. Interleukin-1 receptor antagonist and tumor necrosis factor binding protein decrease osteoclast formation and bone resorption in ovariectomized mice J Clin Invest 1994 94: 2397–2406

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kimble RB et al. Interleukin-1 receptor antagonist decreases bone loss and bone resorption in ovariectomized rats J Clin Invest 1994 93: 1959–1967

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kimble RB, Bain S, Pacifici R . The functional block of TNF but not of IL-6 prevents bone loss in ovariectomized mice J Bone Miner Res 1997 12: 935–941

    Article  CAS  PubMed  Google Scholar 

  15. Ammann P et al. Transgenic mice expressing soluble tumor necrosis factor-receptor are protected against bone loss caused by estrogen deficiency J Clin Invest 1997 99: 1699–1703

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lorenzo JA et al. Mice lacking the type I interleukin-1 receptor do not lose bone mass after ovariectomy Endocrinology 1998 139: 3022–3025

    Article  CAS  PubMed  Google Scholar 

  17. Kimble RB et al. Simultaneous block of interleukin-1 and tumor necrosis factor is required to completely prevent bone loss in the early postovariectomy period Endocrinology 1995 136: 3054–3061

    Article  CAS  PubMed  Google Scholar 

  18. Evans CH, Robbins PD . Possible orthopaedic applications of gene therapy J Bone Joint Surg Am 1995 77: 1103–1114

    Article  CAS  PubMed  Google Scholar 

  19. Evans CH, Robbins PD . Gene therapy in orthopaedics Orthop Nursing 2000 19: 16–22

    Article  CAS  Google Scholar 

  20. Bandara G et al. Intraarticular expression of biologically active interleukin 1-receptor- antagonist protein by ex vivo gene transfer Proc Natl Acad Sci USA 1993 90: 10764–10768

    Article  CAS  Google Scholar 

  21. Gerich TG et al. Gene transfer to the rabbit patellar tendon: potential for genetic enhancement of tendon and ligament healing Gene Therapy 1996 3: 1089–1093

    CAS  PubMed  Google Scholar 

  22. Kang R et al. Ex vivo gene transfer to chondrocytes in full-thickness articular cartilage defects: a feasibility study Osteoarthritis Cartilage 1997 5: 139–143

    Article  CAS  PubMed  Google Scholar 

  23. Balk ML et al. Effect of rhBMP-2 on the osteogenic potential of bone marrow stromal cells from an osteogenesis imperfecta mouse (oim) Bone 1997 21: 7–15

    Article  CAS  Google Scholar 

  24. Baltzer AW et al. Genetic enhancement of fracture repair: healing of an experimental segmental defect by adenoviral transfer of the BMP-2 gene Gene Therapy 2000 7: 734–739

    Article  CAS  PubMed  Google Scholar 

  25. Goto H et al. Transfer of lacZ marker gene to the meniscus J Bone Joint Surg Am 1999 81: 918–925

    Article  CAS  PubMed  Google Scholar 

  26. Evans CH et al. Clinical trial to assess the safety, feasibility, and efficacy of transferring a potentially anti-arthritic cytokine gene to human joints with rheumatoid arthritis Hum Gene Ther 1996 7: 1261–1280

    Article  CAS  Google Scholar 

  27. Gough A et al. Osteoclastic activation is the principal mechanism leading to secondary osteoporosis in rheumatoid arthritis J Rheumatol 1998 25: 1282–1289

    CAS  PubMed  Google Scholar 

  28. Oyama M et al. Retrovirally transduced bone marrow stromal cells isolated from a mouse model of human osteogenesis imperfecta (oim) persist in bone and retain the ability to form cartilage and bone after extended passaging Gene Therapy 1999 6: 321–329

    Article  CAS  PubMed  Google Scholar 

  29. Baltzer AW et al. Adenoviral transduction of human osteoblastic cell cultures: a new perspective for gene therapy of bone diseases Acta Orthop Scand 1999 70: 419–424

    Article  CAS  PubMed  Google Scholar 

  30. Takahashi T et al. A potential molecular approach to ex vivo hematopoietic expansion with recombinant epidermal growth factor receptor-expressing adenovirus vector Blood 1998 91: 4509–4515

    CAS  PubMed  Google Scholar 

  31. Foley R et al. Intramarrow cytokine gene transfer by adenoviral vectors in dogs Hum Gene Ther 1997 8: 545–553

    Article  CAS  PubMed  Google Scholar 

  32. Bolon B et al. Adenoviral delivery of osteoprotegerin ameliorates bone resorption in a mouse ovariectomy model of osteoporosis Mol Ther 2001 3: 197–205

    Article  CAS  PubMed  Google Scholar 

  33. Fang J et al. Stimulation of new bone formation by direct transfer of osteogenic plasmid genes Proc Natl Acad Sci USA 1996 93: 5753–5758

    Article  CAS  Google Scholar 

  34. Bonadio J, Smiley E, Patil P, Goldstein S . Localized direct plasmid gene delivery in vivo: prolonged therapy results in reproducible tissue regeneration Nat Med 1999 5: 753–759

    Article  CAS  Google Scholar 

  35. Lieberman JR et al. Regional gene therapy with a BMP-2-producing murine stromal cell line induces heterotopic and orthotopic bone formation in rodents J Orthop Res 1998 16: 330–339

    Article  CAS  Google Scholar 

  36. Lieberman JR et al. The effect of regional gene therapy with bone morphogenetic protein-2- producing bone-marrow cells on the repair of segmental femoral defects in rats J Bone Joint Surg Am 1999 81: 905–917

    Article  CAS  PubMed  Google Scholar 

  37. Baltzer AW et al. A gene therapy approach to accelerating bone healing. Evaluation of gene expression in a New Zealand white rabbit model Knee Surg Sports Traumatol Arthrosc 1999 7: 197–202

    Article  CAS  PubMed  Google Scholar 

  38. Caplan AI . Mesenchymal stem cells J Orthop Res 1991 9: 641–650

    Article  CAS  Google Scholar 

  39. Pittenger MF et al. Multilineage potential of adult human mesenchymal stem cells Science 1999 284: 143–147

    Article  CAS  Google Scholar 

  40. Vesterby A et al. Biologically meaningful determinants of the in vitro strength of lumbar vertebrae Bone 1991 12: 219–224

    Article  CAS  PubMed  Google Scholar 

  41. Castellote A, Torres A, Whyte J, Sarrat R . Contribution to the morphological knowledge of the articulations of the human tympanic ossicular chain Acta Otorrinolaringol Esp 1997 48: 269–274

    CAS  PubMed  Google Scholar 

  42. Ghivizzani SC et al. Direct adenovirus-mediated gene transfer of interleukin 1 and tumor necrosis factor alpha soluble receptors to rabbit knees with experimental arthritis has local and distal anti-arthritic effects Proc Natl Acad Sci USA 1998 95: 4613–4618

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Orthopädische Universitätsklinik, Heinrich Heine Universität, Düsseldorf, Germany

    AWA Baltzer

  2. Department of Orthopedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    JD Whalen & C Latterman

  3. Department of Orthopedic Surgery, Wayne State University, Detroit, MI, USA

    P Wooley & LM Truchan

  4. Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    PD Robbins

  5. Center for Molecular Orthopedics, Harvard Medical School, Boston, MA, USA

    CH Evans

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  1. AWA Baltzer
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  2. JD Whalen
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  4. C Latterman
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  7. CH Evans
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Baltzer, A., Whalen, J., Wooley, P. et al. Gene therapy for osteoporosis: evaluation in a murine ovariectomy model. Gene Ther 8, 1770–1776 (2001). https://doi.org/10.1038/sj.gt.3301594

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