title: Rapid and reliable healing of critical size bone defects with genetically modified sheep muscle.
abstract: Large segmental defects in bone fail to heal and remain a clinical problem. Muscle is highly osteogenic, and preliminary data suggest that autologous muscle tissue expressing bone morphogenetic protein-2 (BMP-2) efficiently heals critical size defects in rats. Translation into possible human clinical trials requires, inter alia, demonstration of efficacy in a large animal, such as the sheep. Scale-up is fraught with numerous biological, anatomical, mechanical and structural variables, which cannot be addressed systematically because of cost and other practical issues. For this reason, we developed a translational model enabling us to isolate the biological question of whether sheep muscle, transduced with adenovirus expressing BMP-2, could heal critical size defects in vivo. Initial experiments in athymic rats noted strong healing in only about one-third of animals because of unexpected immune responses to sheep antigens. For this reason, subsequent experiments were performed with Fischer rats under transient immunosuppression. Such experiments confirmed remarkably rapid and reliable healing of the defects in all rats, with bridging by 2 weeks and remodelling as early as 3-4 weeks, despite BMP-2 production only in nanogram quantities and persisting for only 1-3 weeks. By 8 weeks the healed defects contained well-organised new bone with advanced neo-cortication and abundant marrow. Bone mineral content and mechanical strength were close to normal values. These data demonstrate the utility of this model when adapting this technology for bone healing in sheep, as a prelude to human clinical trials.
authors.affiliation: Rehabilitation Medicine Research Center, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.evans.christopher@mayo.edu.
authors.forename: F
authors.initials: F
authors.lastname: Liu
authors.forename: E
authors.initials: E
authors.lastname: Ferreira
authors.forename: R M
authors.initials: RM
authors.lastname: Porter
authors.forename: V
authors.initials: V
authors.lastname: Glatt
authors.forename: M
authors.initials: M
authors.lastname: Schinhan
authors.forename: Z
authors.initials: Z
authors.lastname: Shen
authors.forename: M A
authors.initials: MA
authors.lastname: Randolph
authors.forename: C A
authors.initials: CA
authors.lastname: Kirker-Head
authors.forename: C
authors.initials: C
authors.lastname: Wehling
authors.forename: M S
authors.initials: MS
authors.lastname: Vrahas
authors.forename: C H
authors.initials: CH
authors.lastname: Evans
authors.forename: J W
authors.initials: JW
authors.lastname: Wells
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism*; D001861:Bone Regeneration / Q000235:genetics*; D001842:Bone and Bones / Q000293:injuries* / Q000378:metabolism*; D017102:Fracture Healing / Q000235:genetics*; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000627:therapeutic use; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism*; D051381:Rats; D012756:Sheep; D016212:Transforming Growth Factor beta / Q000235:genetics
chemical_list: D055396:Bone Morphogenetic Protein 2; D016212:Transforming Growth Factor beta