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Erschienen in: Osteoporosis International 2/2005

01.03.2005 | Review

The potential of gene therapy for fracture healing in osteoporosis

verfasst von: M. Egermann, E. Schneider, C. H. Evans, A. W. Baltzer

Erschienen in: Osteoporosis International | Sonderheft 2/2005

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Abstract

Osteoporosis-associated fractures impair a patient’s function and quality of life and represent one of the major public health burdens. Demographic changes predict a dramatic increase in osteoporotic fractures. Experimental data have shown that osteoporosis impairs fracture healing. Clinical observations demonstrate high failure rates of implant fixation in osteoporosis. The reduced healing capacity, including impaired bone formation, in osteoporotic humans might be due to defects in mesenchymal stem cells that lead to reduced proliferation and osteoblastic differentiation. Growth factors show remarkable promise as agents that can improve the healing of bone or increase the proliferation and differentiation capacities of mesenchymal stem cells. Their clinical utility is limited by delivery problems. The attraction of gene-transfer approaches is the unique ability to deliver authentically processed gene products to precise anatomical locations at therapeutic levels for sustained periods of time. Unlike the treatment of chronic diseases, it is neither necessary nor desirable for transgene expression to persist beyond the few weeks or months needed to achieve healing. This review presents different approaches of gene therapy to enhance fracture healing and summarizes the promising results of preclinical studies. It focuses on applications of this new technique to fracture healing in osteoporosis. In our opinion, these applications represent some of the few examples in which gene therapy has a good chance of early clinical success.
Literatur
1.
Zurück zum Zitat Riggs BL, Melton LJ 3rd (1995) The worldwide problem of osteoporosis: insights afforded by epidemiology. Bone 17:505S–511SCrossRefPubMed Riggs BL, Melton LJ 3rd (1995) The worldwide problem of osteoporosis: insights afforded by epidemiology. Bone 17:505S–511SCrossRefPubMed
2.
Zurück zum Zitat Cummings SR, Black DM, Rubin SM (1989) Lifetime risks of hip, Colles’, or vertebral fracture and coronary heart disease among white postmenopausal women. Arch Intern Med 149:2445–2448CrossRefPubMed Cummings SR, Black DM, Rubin SM (1989) Lifetime risks of hip, Colles’, or vertebral fracture and coronary heart disease among white postmenopausal women. Arch Intern Med 149:2445–2448CrossRefPubMed
3.
Zurück zum Zitat Adachi JD, Ioannidis G, Pickard L, Berger C, Prior JC, Joseph L, Hanley DA, Olszynski WP, Murray TM, Anastassiades T, Hopman W, Brown JP, Kirkland S, Joyce C, Papaioannou A, Poliquin S, Tenenhouse A, Papadimitropoulos EA (2003) The association between osteoporotic fractures and health-related quality of life as measured by the Health Utilities Index in the Canadian Multicentre Osteoporosis Study (CaMos). Osteoporos Int Adachi JD, Ioannidis G, Pickard L, Berger C, Prior JC, Joseph L, Hanley DA, Olszynski WP, Murray TM, Anastassiades T, Hopman W, Brown JP, Kirkland S, Joyce C, Papaioannou A, Poliquin S, Tenenhouse A, Papadimitropoulos EA (2003) The association between osteoporotic fractures and health-related quality of life as measured by the Health Utilities Index in the Canadian Multicentre Osteoporosis Study (CaMos). Osteoporos Int
4.
Zurück zum Zitat Boyle P, Leon ME, Autier P (2001) Epidemiology of osteoporosis. J Epidemiol Biostat 6:185–192CrossRef Boyle P, Leon ME, Autier P (2001) Epidemiology of osteoporosis. J Epidemiol Biostat 6:185–192CrossRef
6.
Zurück zum Zitat Namkung-Matthai H, Appleyard R, Jansen J, Hao LJ, Maastricht S, Swain M, Mason RS, Murrell GA, Diwan AD, Diamond T (2001) Osteoporosis influences the early period of fracture healing in a rat osteoporotic model. Bone 28:80–86CrossRefPubMed Namkung-Matthai H, Appleyard R, Jansen J, Hao LJ, Maastricht S, Swain M, Mason RS, Murrell GA, Diwan AD, Diamond T (2001) Osteoporosis influences the early period of fracture healing in a rat osteoporotic model. Bone 28:80–86CrossRefPubMed
7.
Zurück zum Zitat Walsh WR, Sherman P, Howlett CR, Sonnabend DH, Ehrlich MG (1997) Fracture healing in a rat osteopenia model. Clin Orthop 218–227 Walsh WR, Sherman P, Howlett CR, Sonnabend DH, Ehrlich MG (1997) Fracture healing in a rat osteopenia model. Clin Orthop 218–227
8.
Zurück zum Zitat Lill CA, Hesseln J, Schlegel U, Eckhardt C, Goldhahn J, Schneider E (2003) Biomechanical evaluation of healing in a non-critical defect in a large animal model of osteoporosis. J Orthop Res 21:836–842CrossRefPubMed Lill CA, Hesseln J, Schlegel U, Eckhardt C, Goldhahn J, Schneider E (2003) Biomechanical evaluation of healing in a non-critical defect in a large animal model of osteoporosis. J Orthop Res 21:836–842CrossRefPubMed
9.
Zurück zum Zitat Meyer RA Jr, Tsahakis PJ, Martin DF, Banks DM, Harrow ME, Kiebzak GM (2001) Age and ovariectomy impair both the normalization of mechanical properties and the accretion of mineral by the fracture callus in rats. J Orthop Res 19:428–435CrossRefPubMed Meyer RA Jr, Tsahakis PJ, Martin DF, Banks DM, Harrow ME, Kiebzak GM (2001) Age and ovariectomy impair both the normalization of mechanical properties and the accretion of mineral by the fracture callus in rats. J Orthop Res 19:428–435CrossRefPubMed
10.
Zurück zum Zitat Xu SW, Yu R, Zhao GF, Wang JW (2003) Early period of fracture healing in ovariectomized rats. Chin J Traumatol 6:160–166 Xu SW, Yu R, Zhao GF, Wang JW (2003) Early period of fracture healing in ovariectomized rats. Chin J Traumatol 6:160–166
11.
Zurück zum Zitat Kubo T, Shiga T, Hashimoto J, Yoshioka M, Honjo H, Urabe M, Kitajima I, Semba I, Hirasawa Y (1999) Osteoporosis influences the late period of fracture healing in a rat model prepared by ovariectomy and low calcium diet. J Steroid Biochem Mol Biol 68:197–202CrossRefPubMed Kubo T, Shiga T, Hashimoto J, Yoshioka M, Honjo H, Urabe M, Kitajima I, Semba I, Hirasawa Y (1999) Osteoporosis influences the late period of fracture healing in a rat model prepared by ovariectomy and low calcium diet. J Steroid Biochem Mol Biol 68:197–202CrossRefPubMed
12.
Zurück zum Zitat Barrios C, Brostrom LA, Stark A, Walheim G (1993) Healing complications after internal fixation of trochanteric hip fractures: the prognostic value of osteoporosis. J Orthop Trauma 7:438–442PubMed Barrios C, Brostrom LA, Stark A, Walheim G (1993) Healing complications after internal fixation of trochanteric hip fractures: the prognostic value of osteoporosis. J Orthop Trauma 7:438–442PubMed
13.
Zurück zum Zitat Cornell CN (2003) Internal fracture fixation in patients with osteoporosis. J Am Acad Orthop Surg 11:109–119 Cornell CN (2003) Internal fracture fixation in patients with osteoporosis. J Am Acad Orthop Surg 11:109–119
14.
Zurück zum Zitat Kim WY, Han CH, Park JI, Kim JY (2001) Failure of intertrochanteric fracture fixation with a dynamic hip screw in relation to pre-operative fracture stability and osteoporosis. Int Orthop 25:360–362CrossRefPubMed Kim WY, Han CH, Park JI, Kim JY (2001) Failure of intertrochanteric fracture fixation with a dynamic hip screw in relation to pre-operative fracture stability and osteoporosis. Int Orthop 25:360–362CrossRefPubMed
15.
Zurück zum Zitat Bergman RJ, Gazit D, Kahn AJ, Gruber H, McDougall S, Hahn TJ (1996) Age-related changes in osteogenic stem cells in mice. J Bone Miner Res 11:568–577PubMed Bergman RJ, Gazit D, Kahn AJ, Gruber H, McDougall S, Hahn TJ (1996) Age-related changes in osteogenic stem cells in mice. J Bone Miner Res 11:568–577PubMed
16.
Zurück zum Zitat Rodriguez JP, Garat S, Gajardo H, Pino AM, Seitz G (1999) Abnormal osteogenesis in osteoporotic patients is reflected by altered mesenchymal stem cell dynamics. J Cell Biochem 75:414–423 Rodriguez JP, Garat S, Gajardo H, Pino AM, Seitz G (1999) Abnormal osteogenesis in osteoporotic patients is reflected by altered mesenchymal stem cell dynamics. J Cell Biochem 75:414–423
17.
Zurück zum Zitat Rodriguez JP, Montecinos L, Rios S, Reyes P, Martinez J (2000) Mesenchymal stem cells from osteoporotic patients produce a type I collagen-deficient extracellular matrix favoring adipogenic differentiation. J.Cell Biochem. 79:557–565 Rodriguez JP, Montecinos L, Rios S, Reyes P, Martinez J (2000) Mesenchymal stem cells from osteoporotic patients produce a type I collagen-deficient extracellular matrix favoring adipogenic differentiation. J.Cell Biochem. 79:557–565
18.
Zurück zum Zitat D’Ippolito G, Schiller PC, Ricordi C, Roos BA, Howard GA (1999) Age-related osteogenic potential of mesenchymal stromal stem cells from human vertebral bone marrow. J Bone Miner Res 14:1115–1122 D’Ippolito G, Schiller PC, Ricordi C, Roos BA, Howard GA (1999) Age-related osteogenic potential of mesenchymal stromal stem cells from human vertebral bone marrow. J Bone Miner Res 14:1115–1122
19.
Zurück zum Zitat Sterck JG, Klein-Nulend J, Lips P, Burger EH (1998) Response of normal and osteoporotic human bone cells to mechanical stress in vitro. Am J Physiol 274:E1113–E1120PubMed Sterck JG, Klein-Nulend J, Lips P, Burger EH (1998) Response of normal and osteoporotic human bone cells to mechanical stress in vitro. Am J Physiol 274:E1113–E1120PubMed
20.
Zurück zum Zitat Arrington ED, Smith WJ, Chambers HG, Bucknell AL, Davino NA (1996) Complications of iliac crest bone graft harvesting. Clin Orthop 300–309 Arrington ED, Smith WJ, Chambers HG, Bucknell AL, Davino NA (1996) Complications of iliac crest bone graft harvesting. Clin Orthop 300–309
21.
Zurück zum Zitat Banwart JC, Asher MA, Hassanein RS (1995) Iliac crest bone graft harvest donor site morbidity. A statistical evaluation. Spine 20:1055–1060PubMed Banwart JC, Asher MA, Hassanein RS (1995) Iliac crest bone graft harvest donor site morbidity. A statistical evaluation. Spine 20:1055–1060PubMed
22.
Zurück zum Zitat Summers BN, Eisenstein SM (1989) Donor site pain from the ilium. A complication of lumbar spine fusion. J Bone Joint Surg Br 71:677–680 Summers BN, Eisenstein SM (1989) Donor site pain from the ilium. A complication of lumbar spine fusion. J Bone Joint Surg Br 71:677–680
23.
Zurück zum Zitat Urist MR (1965) Bone: formation by autoinduction. Science 150:893–899PubMed Urist MR (1965) Bone: formation by autoinduction. Science 150:893–899PubMed
24.
Zurück zum Zitat Reddi AH (2001) Bone morphogenetic proteins: from basic science to clinical applications. J Bone Joint Surg Am 83 [Suppl 1]:S1–S6 Reddi AH (2001) Bone morphogenetic proteins: from basic science to clinical applications. J Bone Joint Surg Am 83 [Suppl 1]:S1–S6
25.
Zurück zum Zitat Schmitt JM, Hwang K, Winn SR, Hollinger JO (1999) Bone morphogenetic proteins: an update on basic biology and clinical relevance. J Orthop Res 17:269–278 Schmitt JM, Hwang K, Winn SR, Hollinger JO (1999) Bone morphogenetic proteins: an update on basic biology and clinical relevance. J Orthop Res 17:269–278
26.
Zurück zum Zitat Styrkarsdottir U, Cazier JB, Kong A, Rolfsson O, Larsen H, Bjarnadottir E, Johannsdottir VD, Sigurdardottir MS, Bagger Y, Christiansen C, Reynisdottir I, Grant SF, Jonasson K, Frigge ML, Gulcher JR, Sigurdsson G, Stefansson K (2003) Linkage of Osteoporosis to Chromosome 20p12 and Association to BMP2. PLoS Biol 1:E69CrossRef Styrkarsdottir U, Cazier JB, Kong A, Rolfsson O, Larsen H, Bjarnadottir E, Johannsdottir VD, Sigurdardottir MS, Bagger Y, Christiansen C, Reynisdottir I, Grant SF, Jonasson K, Frigge ML, Gulcher JR, Sigurdsson G, Stefansson K (2003) Linkage of Osteoporosis to Chromosome 20p12 and Association to BMP2. PLoS Biol 1:E69CrossRef
27.
Zurück zum Zitat Turgeman G, Zilberman Y, Zhou S, Kelly P, Moutsatsos IK, Kharode YP, Borella LE, Bex FJ, Komm BS, Bodine PV, Gazit D (2002) Systemically administered rhBMP-2 promotes MSC activity and reverses bone and cartilage loss in osteopenic mice. J Cell Biochem 86:461–474CrossRef Turgeman G, Zilberman Y, Zhou S, Kelly P, Moutsatsos IK, Kharode YP, Borella LE, Bex FJ, Komm BS, Bodine PV, Gazit D (2002) Systemically administered rhBMP-2 promotes MSC activity and reverses bone and cartilage loss in osteopenic mice. J Cell Biochem 86:461–474CrossRef
28.
Zurück zum Zitat Friedlaender GE, Perry CR, Cole JD, Cook SD, Cierny G, Muschler GF, Zych GA, Calhoun JH, LaForte AJ, Yin S (2001) Osteogenic protein-1 (bone morphogenetic protein-7) in the treatment of tibial nonunions. J Bone Joint Surg Am 83 [Suppl 1]:S151–S158 Friedlaender GE, Perry CR, Cole JD, Cook SD, Cierny G, Muschler GF, Zych GA, Calhoun JH, LaForte AJ, Yin S (2001) Osteogenic protein-1 (bone morphogenetic protein-7) in the treatment of tibial nonunions. J Bone Joint Surg Am 83 [Suppl 1]:S151–S158
29.
Zurück zum Zitat Govender S, Csimma C, Genant HK, Valentin-Opran A, Amit Y, Arbel R, Aro H, Atar D, Bishay M, Borner MG, Chiron P, Choong P, Cinats J, Courtenay B, Feibel R, Geulette B, Gravel C, Haas N, Raschke M, Hammacher E, van der Velde D, Hardy P, Holt M, Josten C, Ketterl RL, Lindeque B, Lob G, Mathevon H, McCoy G, Marsh D, Miller R, Munting E, Oevre S, Nordsletten L, Patel A, Pohl A, Rennie W, Reynders P, Rommens PM, Rondia J, Rossouw WC, Daneel PJ, Ruff S, Ruter A, Santavirta S, Schildhauer TA, Gekle C, Schnettler R, Segal D, Seiler H, Snowdowne RB, Stapert J, Taglang G, Verdonk R, Vogels L, Weckbach A, Wentzensen A, Wisniewski T (2002) Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients. J Bone Joint Surg Am 84-A:2123–2134 Govender S, Csimma C, Genant HK, Valentin-Opran A, Amit Y, Arbel R, Aro H, Atar D, Bishay M, Borner MG, Chiron P, Choong P, Cinats J, Courtenay B, Feibel R, Geulette B, Gravel C, Haas N, Raschke M, Hammacher E, van der Velde D, Hardy P, Holt M, Josten C, Ketterl RL, Lindeque B, Lob G, Mathevon H, McCoy G, Marsh D, Miller R, Munting E, Oevre S, Nordsletten L, Patel A, Pohl A, Rennie W, Reynders P, Rommens PM, Rondia J, Rossouw WC, Daneel PJ, Ruff S, Ruter A, Santavirta S, Schildhauer TA, Gekle C, Schnettler R, Segal D, Seiler H, Snowdowne RB, Stapert J, Taglang G, Verdonk R, Vogels L, Weckbach A, Wentzensen A, Wisniewski T (2002) Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients. J Bone Joint Surg Am 84-A:2123–2134
30.
Zurück zum Zitat Valentin-Opran A, Wozney J, Csimma C, Lilly L, Riedel GE (2002) Clinical evaluation of recombinant human bone morphogenetic protein-2. Clin Orthop 110–120 Valentin-Opran A, Wozney J, Csimma C, Lilly L, Riedel GE (2002) Clinical evaluation of recombinant human bone morphogenetic protein-2. Clin Orthop 110–120
31.
Zurück zum Zitat Evans CH, Robbins PD (1995) Possible orthopaedic applications of gene therapy. J Bone Joint Surg Am 77:1103–1114 Evans CH, Robbins PD (1995) Possible orthopaedic applications of gene therapy. J Bone Joint Surg Am 77:1103–1114
32.
Zurück zum Zitat Scaduto AA, Lieberman JR (1999) Gene therapy for osteoinduction. Orthop Clin North Am 30:625–633 Scaduto AA, Lieberman JR (1999) Gene therapy for osteoinduction. Orthop Clin North Am 30:625–633
33.
Zurück zum Zitat Bonadio J, Smiley E, Patil P, Goldstein S (1999) Localized, direct plasmid gene delivery in vivo: prolonged therapy results in reproducible tissue regeneration. Nat Med 5:753–759CrossRef Bonadio J, Smiley E, Patil P, Goldstein S (1999) Localized, direct plasmid gene delivery in vivo: prolonged therapy results in reproducible tissue regeneration. Nat Med 5:753–759CrossRef
34.
Zurück zum Zitat Goldstein SA (2000) In vivo nonviral delivery factors to enhance bone repair. Clin Orthop S113–S119 Goldstein SA (2000) In vivo nonviral delivery factors to enhance bone repair. Clin Orthop S113–S119
35.
Zurück zum Zitat Fang J, Zhu YY, Smiley E, Bonadio J, Rouleau JP, Goldstein SA, McCauley LK, Davidson BL, Roessler BJ (1996) Stimulation of new bone formation by direct transfer of osteogenic plasmid genes. Proc Natl Acad Sci U S A 93:5753–5758CrossRef Fang J, Zhu YY, Smiley E, Bonadio J, Rouleau JP, Goldstein SA, McCauley LK, Davidson BL, Roessler BJ (1996) Stimulation of new bone formation by direct transfer of osteogenic plasmid genes. Proc Natl Acad Sci U S A 93:5753–5758CrossRef
36.
Zurück zum Zitat Jahng JS, Kim HW (2000) Effect of intermittent administration of parathyroid hormone on fracture healing in ovariectomized rats. Orthopedics 23:1089–1094 Jahng JS, Kim HW (2000) Effect of intermittent administration of parathyroid hormone on fracture healing in ovariectomized rats. Orthopedics 23:1089–1094
37.
Zurück zum Zitat Christ M, Lusky M, Stoeckel F, Dreyer D, Dieterle A, Michou AI, Pavirani A, Mehtali M (1997) Gene therapy with recombinant adenovirus vectors: evaluation of the host immune response. Immunol Lett 57:19–25CrossRefPubMed Christ M, Lusky M, Stoeckel F, Dreyer D, Dieterle A, Michou AI, Pavirani A, Mehtali M (1997) Gene therapy with recombinant adenovirus vectors: evaluation of the host immune response. Immunol Lett 57:19–25CrossRefPubMed
38.
Zurück zum Zitat Crystal RG (1995) Transfer of genes to humans: early lessons and obstacles to success. Science 270:404–410PubMed Crystal RG (1995) Transfer of genes to humans: early lessons and obstacles to success. Science 270:404–410PubMed
39.
Zurück zum Zitat Wilson JM (1996) Adenoviruses as gene-delivery vehicles. N Engl J Med 334:1185–1187CrossRef Wilson JM (1996) Adenoviruses as gene-delivery vehicles. N Engl J Med 334:1185–1187CrossRef
40.
Zurück zum Zitat Ito T, Tokunaga K, Maruyama H, Kawashima H, Kitahara H, Horikoshi T, Ogose A, Hotta Y, Kuwano R, Katagiri H, Endo N (2003) Coxsackievirus and adenovirus receptor (CAR)-positive immature osteoblasts as targets of adenovirus-mediated gene transfer for fracture healing. Gene Ther 10:1623–1628CrossRef Ito T, Tokunaga K, Maruyama H, Kawashima H, Kitahara H, Horikoshi T, Ogose A, Hotta Y, Kuwano R, Katagiri H, Endo N (2003) Coxsackievirus and adenovirus receptor (CAR)-positive immature osteoblasts as targets of adenovirus-mediated gene transfer for fracture healing. Gene Ther 10:1623–1628CrossRef
41.
Zurück zum Zitat Alden TD, Pittman DD, Hankins GR, Beres EJ, Engh JA, Das S, Hudson SB, Kerns KM, Kallmes DF, Helm GA (1999) In vivo endochondral bone formation using a bone morphogenetic protein 2 adenoviral vector. Hum Gene Ther 10:2245–2253CrossRef Alden TD, Pittman DD, Hankins GR, Beres EJ, Engh JA, Das S, Hudson SB, Kerns KM, Kallmes DF, Helm GA (1999) In vivo endochondral bone formation using a bone morphogenetic protein 2 adenoviral vector. Hum Gene Ther 10:2245–2253CrossRef
42.
Zurück zum Zitat Musgrave DS, Bosch P, Ghivizzani S, Robbins PD, Evans CH, Huard J (1999) Adenovirus-mediated direct gene therapy with bone morphogenetic protein-2 produces bone. Bone 24:541–547CrossRef Musgrave DS, Bosch P, Ghivizzani S, Robbins PD, Evans CH, Huard J (1999) Adenovirus-mediated direct gene therapy with bone morphogenetic protein-2 produces bone. Bone 24:541–547CrossRef
43.
Zurück zum Zitat Alden TD, Beres EJ, Laurent JS, Engh JA, Das S, London SD, Jane JA Jr, Hudson SB, Helm GA (2000) The use of bone morphogenetic protein gene therapy in craniofacial bone repair. J Craniofac Surg 11:24–30 Alden TD, Beres EJ, Laurent JS, Engh JA, Das S, London SD, Jane JA Jr, Hudson SB, Helm GA (2000) The use of bone morphogenetic protein gene therapy in craniofacial bone repair. J Craniofac Surg 11:24–30
44.
Zurück zum Zitat Okubo Y, Bessho K, Fujimura K, Iizuka T, Miyatake SI (2000) Osteoinduction by bone morphogenetic protein-2 via adenoviral vector under transient immunosuppression. Biochem Biophys Res Commun 267:382–387CrossRef Okubo Y, Bessho K, Fujimura K, Iizuka T, Miyatake SI (2000) Osteoinduction by bone morphogenetic protein-2 via adenoviral vector under transient immunosuppression. Biochem Biophys Res Commun 267:382–387CrossRef
45.
Zurück zum Zitat Harvey BG, Hackett NR, El Sawy T, Rosengart TK, Hirschowitz EA, Lieberman MD, Lesser ML, Crystal RG (1999) Variability of human systemic humoral immune responses to adenovirus gene transfer vectors administered to different organs. J Virol 73:6729–6742 Harvey BG, Hackett NR, El Sawy T, Rosengart TK, Hirschowitz EA, Lieberman MD, Lesser ML, Crystal RG (1999) Variability of human systemic humoral immune responses to adenovirus gene transfer vectors administered to different organs. J Virol 73:6729–6742
46.
Zurück zum Zitat Harvey BG, Worgall S, Ely S, Leopold PL, Crystal RG (1999) Cellular immune responses of healthy individuals to intradermal administration of an E1-E3- adenovirus gene transfer vector. Hum Gene Ther 10:2823–2837CrossRef Harvey BG, Worgall S, Ely S, Leopold PL, Crystal RG (1999) Cellular immune responses of healthy individuals to intradermal administration of an E1-E3- adenovirus gene transfer vector. Hum Gene Ther 10:2823–2837CrossRef
47.
Zurück zum Zitat Baltzer AW, Lattermann C, Whalen JD, Wooley P, Weiss K, Grimm M, Ghivizzani SC, Robbins PD, Evans CH (2000) Genetic enhancement of fracture repair: healing of an experimental segmental defect by adenoviral transfer of the BMP-2 gene. Gene Ther 7:734–739CrossRef Baltzer AW, Lattermann C, Whalen JD, Wooley P, Weiss K, Grimm M, Ghivizzani SC, Robbins PD, Evans CH (2000) Genetic enhancement of fracture repair: healing of an experimental segmental defect by adenoviral transfer of the BMP-2 gene. Gene Ther 7:734–739CrossRef
48.
Zurück zum Zitat Baltzer AW, Lattermann C, Whalen JD, Braunstein S, Robbins PD, Evans CH (1999) A gene therapy approach to accelerating bone healing. Evaluation of gene expression in a New Zealand white rabbit model. Knee Surg Sports Traumatol Arthrosc 7:197–202CrossRef Baltzer AW, Lattermann C, Whalen JD, Braunstein S, Robbins PD, Evans CH (1999) A gene therapy approach to accelerating bone healing. Evaluation of gene expression in a New Zealand white rabbit model. Knee Surg Sports Traumatol Arthrosc 7:197–202CrossRef
49.
Zurück zum Zitat Egermann M, Lill C, Alini M, Evans CH, Robbins P, Schneider E, Baltzer A (2003) Host immune response does not impair gene expression after local delivery of adenoviral vector. ORS Abstractbook 2003 (abstract) Egermann M, Lill C, Alini M, Evans CH, Robbins P, Schneider E, Baltzer A (2003) Host immune response does not impair gene expression after local delivery of adenoviral vector. ORS Abstractbook 2003 (abstract)
50.
Zurück zum Zitat Betz OB, Betz VM, Gouze E, Gouze JN, Palmer GD, Pascher A, von Stechow D, Liew V, Schultz K, Gerstenfeld LC, Vrahas MS, Ghivizzani SC, Einhorn TA, Evans CH (2003) Use of direct BMP-2 gene delivery to enhance the healing of segmental bone defects: Evaluation in the rat model. ORS 2003 Abstractbook (#0890, conference proceeding) Betz OB, Betz VM, Gouze E, Gouze JN, Palmer GD, Pascher A, von Stechow D, Liew V, Schultz K, Gerstenfeld LC, Vrahas MS, Ghivizzani SC, Einhorn TA, Evans CH (2003) Use of direct BMP-2 gene delivery to enhance the healing of segmental bone defects: Evaluation in the rat model. ORS 2003 Abstractbook (#0890, conference proceeding)
51.
Zurück zum Zitat Franceschi RT, Wang D, Krebsbach PH, Rutherford RB (2000) Gene therapy for bone formation: in vitro and in vivo osteogenic activity of an adenovirus expressing BMP7. J Cell Biochem 78:476–486CrossRef Franceschi RT, Wang D, Krebsbach PH, Rutherford RB (2000) Gene therapy for bone formation: in vitro and in vivo osteogenic activity of an adenovirus expressing BMP7. J Cell Biochem 78:476–486CrossRef
52.
Zurück zum Zitat Sonobe J et al (2004) Osteoinduction by bone morphogenetic protein-2 expressing adenoviral vector: application of biomaterial to mask the host immune response. Hum Gene Ther 15(7):659–668CrossRef Sonobe J et al (2004) Osteoinduction by bone morphogenetic protein-2 expressing adenoviral vector: application of biomaterial to mask the host immune response. Hum Gene Ther 15(7):659–668CrossRef
53.
Zurück zum Zitat Mack CA, Song WR, Carpenter H, Wickham TJ, Kovesdi I, Harvey BG, Magovern CJ, Isom OW, Rosengart T, Falck-Pedersen E, Hackett NR, Crystal RG, Mastrangeli A (1997) Circumvention of anti-adenovirus neutralizing immunity by administration of an adenoviral vector of an alternate serotype. Hum Gene Ther 8:99–109 Mack CA, Song WR, Carpenter H, Wickham TJ, Kovesdi I, Harvey BG, Magovern CJ, Isom OW, Rosengart T, Falck-Pedersen E, Hackett NR, Crystal RG, Mastrangeli A (1997) Circumvention of anti-adenovirus neutralizing immunity by administration of an adenoviral vector of an alternate serotype. Hum Gene Ther 8:99–109
54.
Zurück zum Zitat Olmsted-Davis EA, Gugala Z, Gannon FH, Yotnda P, McAlhany RE, Lindsey RW, Davis AR (2002) Use of a chimeric adenovirus vector enhances BMP2 production and bone formation. Hum Gene Ther 13:1337–1347CrossRef Olmsted-Davis EA, Gugala Z, Gannon FH, Yotnda P, McAlhany RE, Lindsey RW, Davis AR (2002) Use of a chimeric adenovirus vector enhances BMP2 production and bone formation. Hum Gene Ther 13:1337–1347CrossRef
55.
Zurück zum Zitat Chen Y, Luk KD, Cheung KM, Xu R, Lin MC, Lu WW, Leong JC, Kung HF (2003) Gene therapy for new bone formation using adeno-associated viral bone morphogenetic protein-2 vectors. Gene Ther 10:1345–1353CrossRefPubMed Chen Y, Luk KD, Cheung KM, Xu R, Lin MC, Lu WW, Leong JC, Kung HF (2003) Gene therapy for new bone formation using adeno-associated viral bone morphogenetic protein-2 vectors. Gene Ther 10:1345–1353CrossRefPubMed
56.
Zurück zum Zitat Luk KD, Chen Y, Cheung KM, Kung HF, Lu WW, Leong JC (2003) Adeno-associated virus-mediated bone morphogenetic protein-4 gene therapy for in vivo bone formation. Biochem Biophys Res Commun 308:636–645CrossRef Luk KD, Chen Y, Cheung KM, Kung HF, Lu WW, Leong JC (2003) Adeno-associated virus-mediated bone morphogenetic protein-4 gene therapy for in vivo bone formation. Biochem Biophys Res Commun 308:636–645CrossRef
57.
Zurück zum Zitat Ulrich-Vinther M, Carmody EE, Goater JJ, Balle S, O’Keefe RJ, Schwarz EM (2002) Recombinant adeno-associated virus-mediated osteoprotegerin gene therapy inhibits wear debris-induced osteolysis. J Bone Joint Surg Am 84-A:1405–1412 Ulrich-Vinther M, Carmody EE, Goater JJ, Balle S, O’Keefe RJ, Schwarz EM (2002) Recombinant adeno-associated virus-mediated osteoprotegerin gene therapy inhibits wear debris-induced osteolysis. J Bone Joint Surg Am 84-A:1405–1412
58.
Zurück zum Zitat Kostenuik PJ, Bolon B, Morony S, Daris M, Geng Z, Carter C, Sheng J (2004) Gene therapy with human recombinant osteoprotegerin reverses established osteopenia in ovariectomized mice. Bone 34:656–664CrossRef Kostenuik PJ, Bolon B, Morony S, Daris M, Geng Z, Carter C, Sheng J (2004) Gene therapy with human recombinant osteoprotegerin reverses established osteopenia in ovariectomized mice. Bone 34:656–664CrossRef
59.
Zurück zum Zitat Flick LM, Weaver JM, Ulrich-Vinther M, Abuzzahab F, Zhang X, Dougall WC, Anderson D, O’Keefe RJ, Schwarz EM (2003) Effects of receptor activator of NFkappaB (RANK) signaling blockade on fracture healing. J Orthop Res 21:676–684CrossRef Flick LM, Weaver JM, Ulrich-Vinther M, Abuzzahab F, Zhang X, Dougall WC, Anderson D, O’Keefe RJ, Schwarz EM (2003) Effects of receptor activator of NFkappaB (RANK) signaling blockade on fracture healing. J Orthop Res 21:676–684CrossRef
60.
Zurück zum Zitat Lieberman JR, Le LQ, Wu L, Finerman GA, Berk A, Witte ON, Stevenson S (1998) Regional gene therapy with a BMP-2-producing murine stromal cell line induces heterotopic and orthotopic bone formation in rodents. J Orthop Res 16:330–339 Lieberman JR, Le LQ, Wu L, Finerman GA, Berk A, Witte ON, Stevenson S (1998) Regional gene therapy with a BMP-2-producing murine stromal cell line induces heterotopic and orthotopic bone formation in rodents. J Orthop Res 16:330–339
61.
Zurück zum Zitat Lieberman JR, Daluiski A, Stevenson S, Wu L, McAllister P, Lee YP, Kabo JM, Finerman GA, Berk AJ, Witte ON (1999) 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 81:905–917PubMed Lieberman JR, Daluiski A, Stevenson S, Wu L, McAllister P, Lee YP, Kabo JM, Finerman GA, Berk AJ, Witte ON (1999) 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 81:905–917PubMed
62.
Zurück zum Zitat Dragoo JL, Choi JY, Lieberman JR, Huang J, Zuk PA, Zhang J, Hedrick MH, Benhaim P (2003) Bone induction by BMP-2 transduced stem cells derived from human fat. J Orthop Res 21:622–629CrossRefPubMed Dragoo JL, Choi JY, Lieberman JR, Huang J, Zuk PA, Zhang J, Hedrick MH, Benhaim P (2003) Bone induction by BMP-2 transduced stem cells derived from human fat. J Orthop Res 21:622–629CrossRefPubMed
63.
Zurück zum Zitat Gysin R, Wergedal JE, Sheng MH, Kasukawa Y, Miyakoshi N, Chen ST, Peng H, Lau KH, Mohan S, Baylink DJ (2002) Ex vivo gene therapy with stromal cells transduced with a retroviral vector containing the BMP4 gene completely heals critical size calvarial defect in rats. Gene Ther 9:991–999CrossRef Gysin R, Wergedal JE, Sheng MH, Kasukawa Y, Miyakoshi N, Chen ST, Peng H, Lau KH, Mohan S, Baylink DJ (2002) Ex vivo gene therapy with stromal cells transduced with a retroviral vector containing the BMP4 gene completely heals critical size calvarial defect in rats. Gene Ther 9:991–999CrossRef
64.
Zurück zum Zitat Lee JY, Peng H, Usas A, Musgrave D, Cummins J, Pelinkovic D, Jankowski R, Ziran B, Robbins P, Huard J (2002) Enhancement of bone healing based on ex vivo gene therapy using human muscle-derived cells expressing bone morphogenetic protein 2. Hum Gene Ther 13:1201–1211CrossRef Lee JY, Peng H, Usas A, Musgrave D, Cummins J, Pelinkovic D, Jankowski R, Ziran B, Robbins P, Huard J (2002) Enhancement of bone healing based on ex vivo gene therapy using human muscle-derived cells expressing bone morphogenetic protein 2. Hum Gene Ther 13:1201–1211CrossRef
65.
Zurück zum Zitat Viggeswarapu M, Boden SD, Liu Y, Hair GA, Louis-Ugbo J, Murakami H, Kim HS, Mayr MT, Hutton WC, Titus L (2001) Adenoviral delivery of LIM mineralization protein-1 induces new-bone formation in vitro and in vivo. J Bone Joint Surg Am 83:364–376CrossRef Viggeswarapu M, Boden SD, Liu Y, Hair GA, Louis-Ugbo J, Murakami H, Kim HS, Mayr MT, Hutton WC, Titus L (2001) Adenoviral delivery of LIM mineralization protein-1 induces new-bone formation in vitro and in vivo. J Bone Joint Surg Am 83:364–376CrossRef
66.
Zurück zum Zitat Krebsbach PH, Gu K, Franceschi RT, Rutherford RB (2000) Gene therapy-directed osteogenesis: BMP-7-transduced human fibroblasts form bone in vivo. Hum Gene Ther 11:1201–1210CrossRefPubMed Krebsbach PH, Gu K, Franceschi RT, Rutherford RB (2000) Gene therapy-directed osteogenesis: BMP-7-transduced human fibroblasts form bone in vivo. Hum Gene Ther 11:1201–1210CrossRefPubMed
67.
Zurück zum Zitat Zhang XS, Linkhart TA, Chen ST, Peng H, Wergedal JE, Guttierez GG, Sheng MH, Lau KH, Baylink DJ (2004) Local ex vivo gene therapy with bone marrow stromal cells expressing human BMP4 promotes endosteal bone formation in mice. J Gene Med 6:4–15CrossRef Zhang XS, Linkhart TA, Chen ST, Peng H, Wergedal JE, Guttierez GG, Sheng MH, Lau KH, Baylink DJ (2004) Local ex vivo gene therapy with bone marrow stromal cells expressing human BMP4 promotes endosteal bone formation in mice. J Gene Med 6:4–15CrossRef
68.
Zurück zum Zitat Turgeman G, Pittman DD, Muller R, Kurkalli BG, Zhou S, Pelled G, Peyser A, Zilberman Y, Moutsatsos IK, Gazit D (2001) Engineered human mesenchymal stem cells: a novel platform for skeletal cell mediated gene therapy. J Gene Med 3:240–251CrossRef Turgeman G, Pittman DD, Muller R, Kurkalli BG, Zhou S, Pelled G, Peyser A, Zilberman Y, Moutsatsos IK, Gazit D (2001) Engineered human mesenchymal stem cells: a novel platform for skeletal cell mediated gene therapy. J Gene Med 3:240–251CrossRef
69.
Zurück zum Zitat Tsuda H, Wada T, Ito Y, Uchida H, Dehari H, Nakamura K, Sasaki K, Kobune M, Yamashita T, Hamada H (2003) Efficient BMP2 gene transfer and bone formation of mesenchymal stem cells by a fiber-mutant adenoviral vector. Mol Ther 7:354–365CrossRef Tsuda H, Wada T, Ito Y, Uchida H, Dehari H, Nakamura K, Sasaki K, Kobune M, Yamashita T, Hamada H (2003) Efficient BMP2 gene transfer and bone formation of mesenchymal stem cells by a fiber-mutant adenoviral vector. Mol Ther 7:354–365CrossRef
70.
Zurück zum Zitat Abe N, Lee YP, Sato M, Zhang X, Wu J, Mitani K, Lieberman JR (2002) Enhancement of bone repair with a helper-dependent adenoviral transfer of bone morphogenetic protein-2. Biochem Biophys Res Commun 297:523–527CrossRef Abe N, Lee YP, Sato M, Zhang X, Wu J, Mitani K, Lieberman JR (2002) Enhancement of bone repair with a helper-dependent adenoviral transfer of bone morphogenetic protein-2. Biochem Biophys Res Commun 297:523–527CrossRef
71.
Zurück zum Zitat Park J, Ries J, Gelse K, Kloss F, von der MK, Wiltfang J, Neukam FW, Schneider H (2003) Bone regeneration in critical size defects by cell-mediated BMP-2 gene transfer: a comparison of adenoviral vectors and liposomes. Gene Ther 10:1089–1098CrossRefPubMed Park J, Ries J, Gelse K, Kloss F, von der MK, Wiltfang J, Neukam FW, Schneider H (2003) Bone regeneration in critical size defects by cell-mediated BMP-2 gene transfer: a comparison of adenoviral vectors and liposomes. Gene Ther 10:1089–1098CrossRefPubMed
72.
Zurück zum Zitat Tsuchida H, Hashimoto J, Crawford E, Manske P, Lou J (2003) Engineered allogeneic mesenchymal stem cells repair femoral segmental defect in rats. J Orthop Res 21:44–53CrossRefPubMed Tsuchida H, Hashimoto J, Crawford E, Manske P, Lou J (2003) Engineered allogeneic mesenchymal stem cells repair femoral segmental defect in rats. J Orthop Res 21:44–53CrossRefPubMed
73.
Zurück zum Zitat Li JZ et al (2003) Osteogenic potential of five different recombinant human bone morphogenetic protein (BMP) adenoviral vectors in the rat. Gene Ther 10(20):1735-1743CrossRef Li JZ et al (2003) Osteogenic potential of five different recombinant human bone morphogenetic protein (BMP) adenoviral vectors in the rat. Gene Ther 10(20):1735-1743CrossRef
74.
Zurück zum Zitat Helm GA, Alden TD, Beres EJ, Hudson SB, Das S, Engh JA, Pittman DD, Kerns KM, Kallmes DF (2000) Use of bone morphogenetic protein-9 gene therapy to induce spinal arthrodesis in the rodent. J Neurosurg 92:191–196 Helm GA, Alden TD, Beres EJ, Hudson SB, Das S, Engh JA, Pittman DD, Kerns KM, Kallmes DF (2000) Use of bone morphogenetic protein-9 gene therapy to induce spinal arthrodesis in the rodent. J Neurosurg 92:191–196
75.
Zurück zum Zitat Boden SD, Titus L, Hair G, Liu Y, Viggeswarapu M, Nanes MS, Baranowski C (1998) Lumbar spine fusion by local gene therapy with a cDNA encoding a novel osteoinductive protein (LMP-1). Spine 23:2486–2492CrossRef Boden SD, Titus L, Hair G, Liu Y, Viggeswarapu M, Nanes MS, Baranowski C (1998) Lumbar spine fusion by local gene therapy with a cDNA encoding a novel osteoinductive protein (LMP-1). Spine 23:2486–2492CrossRef
76.
Zurück zum Zitat Boden SD, Liu Y, Hair GA, Helms JA, Hu D, Racine M, Nanes MS, Titus L (1998) LMP-1, a LIM-domain protein, mediates BMP-6 effects on bone formation. Endocrinology 139:5125–5134CrossRefPubMed Boden SD, Liu Y, Hair GA, Helms JA, Hu D, Racine M, Nanes MS, Titus L (1998) LMP-1, a LIM-domain protein, mediates BMP-6 effects on bone formation. Endocrinology 139:5125–5134CrossRefPubMed
77.
Zurück zum Zitat Minamide A, Boden SD, Viggeswarapu M, Hair GA, Oliver C, Titus L (2003) Mechanism of bone formation with gene transfer of the cDNA encoding for the intracellular protein LMP-1. J Bone Joint Surg Am 85-A:1030–1039 Minamide A, Boden SD, Viggeswarapu M, Hair GA, Oliver C, Titus L (2003) Mechanism of bone formation with gene transfer of the cDNA encoding for the intracellular protein LMP-1. J Bone Joint Surg Am 85-A:1030–1039
78.
Zurück zum Zitat Kimble RB, Vannice JL, Bloedow DC, Thompson RC, Hopfer W, Kung VT, Brownfield C, Pacifici R (1994) Interleukin-1 receptor antagonist decreases bone loss and bone resorption in ovariectomized rats. J Clin Invest 93:1959–1967 Kimble RB, Vannice JL, Bloedow DC, Thompson RC, Hopfer W, Kung VT, Brownfield C, Pacifici R (1994) Interleukin-1 receptor antagonist decreases bone loss and bone resorption in ovariectomized rats. J Clin Invest 93:1959–1967
79.
Zurück zum Zitat Kitazawa R, Kimble RB, Vannice JL, Kung VT, Pacifici R (1994) Interleukin-1 receptor antagonist and tumor necrosis factor binding protein decrease osteoclast formation and bone resorption in ovariectomized mice. J Clin Invest 94:2397–2406 Kitazawa R, Kimble RB, Vannice JL, Kung VT, Pacifici R (1994) Interleukin-1 receptor antagonist and tumor necrosis factor binding protein decrease osteoclast formation and bone resorption in ovariectomized mice. J Clin Invest 94:2397–2406
80.
Zurück zum Zitat Ammann P, Rizzoli R, Bonjour JP, Bourrin S, Meyer JM, Vassalli P, Garcia I (1997) Transgenic mice expressing soluble tumor necrosis factor-receptor are protected against bone loss caused by estrogen deficiency. J Clin Invest 99:1699–1703 Ammann P, Rizzoli R, Bonjour JP, Bourrin S, Meyer JM, Vassalli P, Garcia I (1997) Transgenic mice expressing soluble tumor necrosis factor-receptor are protected against bone loss caused by estrogen deficiency. J Clin Invest 99:1699–1703
81.
Zurück zum Zitat Baltzer AW, Whalen JD, Wooley P, Latterman C, Truchan LM, Robbins PD, Evans CH (2001) Gene therapy for osteoporosis: evaluation in a murine ovariectomy model. Gene Ther 8:1770–1776CrossRef Baltzer AW, Whalen JD, Wooley P, Latterman C, Truchan LM, Robbins PD, Evans CH (2001) Gene therapy for osteoporosis: evaluation in a murine ovariectomy model. Gene Ther 8:1770–1776CrossRef
82.
Zurück zum Zitat Gerstenfeld LC, Cho TJ, Kon T, Aizawa T, Tsay A, Fitch J, Barnes GL, Graves DT, Einhorn TA (2003) Impaired fracture healing in the absence of TNF-alpha signaling: the role of TNF-alpha in endochondral cartilage resorption. J Bone Miner Res 18:1584–1592 Gerstenfeld LC, Cho TJ, Kon T, Aizawa T, Tsay A, Fitch J, Barnes GL, Graves DT, Einhorn TA (2003) Impaired fracture healing in the absence of TNF-alpha signaling: the role of TNF-alpha in endochondral cartilage resorption. J Bone Miner Res 18:1584–1592
83.
Zurück zum Zitat Bolon B, Carter C, Daris M, Morony S, Capparelli C, Hsieh A, Mao M, Kostenuik P, Dunstan CR, Lacey DL, Sheng JZ (2001) Adenoviral delivery of osteoprotegerin ameliorates bone resorption in a mouse ovariectomy model of osteoporosis. Mol Ther 3:197–205CrossRef Bolon B, Carter C, Daris M, Morony S, Capparelli C, Hsieh A, Mao M, Kostenuik P, Dunstan CR, Lacey DL, Sheng JZ (2001) Adenoviral delivery of osteoprotegerin ameliorates bone resorption in a mouse ovariectomy model of osteoporosis. Mol Ther 3:197–205CrossRef
84.
Zurück zum Zitat Kon T, Cho TJ, Aizawa T, Yamazaki M, Nooh N, Graves D, Gerstenfeld LC, Einhorn TA (2001) Expression of osteoprotegerin, receptor activator of NF-kappaB ligand (osteoprotegerin ligand) and related proinflammatory cytokines during fracture healing. J Bone Miner Res 16:1004–1014PubMed Kon T, Cho TJ, Aizawa T, Yamazaki M, Nooh N, Graves D, Gerstenfeld LC, Einhorn TA (2001) Expression of osteoprotegerin, receptor activator of NF-kappaB ligand (osteoprotegerin ligand) and related proinflammatory cytokines during fracture healing. J Bone Miner Res 16:1004–1014PubMed
85.
Zurück zum Zitat Peng H, Wright V, Usas A, Gearhart B, Shen HC, Cummins J, Huard J (2002) Synergistic enhancement of bone formation and healing by stem cell-expressed VEGF and bone morphogenetic protein-4. J Clin Invest 110:751–759CrossRefPubMed Peng H, Wright V, Usas A, Gearhart B, Shen HC, Cummins J, Huard J (2002) Synergistic enhancement of bone formation and healing by stem cell-expressed VEGF and bone morphogenetic protein-4. J Clin Invest 110:751–759CrossRefPubMed
Metadaten
Titel
The potential of gene therapy for fracture healing in osteoporosis
verfasst von
M. Egermann
E. Schneider
C. H. Evans
A. W. Baltzer
Publikationsdatum
01.03.2005
Verlag
Springer-Verlag
Erschienen in
Osteoporosis International / Ausgabe Sonderheft 2/2005
Print ISSN: 0937-941X
Elektronische ISSN: 1433-2965
DOI
https://doi.org/10.1007/s00198-004-1817-9

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