Ex vivo-transduced autologous skin fibroblasts expressing human Lim mineralization protein-3 efficiently form new bone in animal models.
Local gene transfer of the human Lim mineralization protein (LMP), a novel intracellular positive regulator of the osteoblast differentiation program, can induce efficient bone formation in rodents. To develop a clinically relevant gene therapy approach to facilitate bone healing, we have used primary dermal fibroblasts transduced ex vivo with Ad.LMP-3 and seeded on a hydroxyapatite/collagen matrix prior to autologous implantation. Here, we demonstrate that genetically modified autologous dermal fibroblasts expressing Ad.LMP-3 are able to induce ectopic bone formation following implantation of the matrix into mouse triceps and paravertebral muscles. Moreover, implantation of the Ad.LMP-3-modified dermal fibroblasts into a rat mandibular bone critical size defect model results in efficient healing, as determined by X-rays, histology and three-dimensional microcomputed tomography (3DmuCT). These results demonstrate the effectiveness of the non-secreted intracellular osteogenic factor LMP-3 in inducing bone formation in vivo. Moreover, the utilization of autologous dermal fibroblasts implanted on a biomaterial represents a promising approach for possible future clinical applications aimed at inducing new bone formation.
Lattanzi
W
W
Department of Anatomy and Cell Biology, Università Cattolica del Sacro Cuore School of Medicine, Rome, Italy.
Parrilla
C
C
Fetoni
A
A
Logroscino
G
G
Straface
G
G
Pecorini
G
G
Stigliano
E
E
Tampieri
A
A
Bedini
R
R
Pecci
R
R
Michetti
F
F
Gambotto
A
A
Robbins
P D
PD
Pola
E
E
D048868:Adaptor Proteins, Signal Transducing; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001847:Bone Diseases / Q000000981:diagnostic imaging / Q000378:metabolism / Q000628:therapy*; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000378:metabolism; D003598:Cytoskeletal Proteins; D005347:Fibroblasts / Q000378:metabolism / Q000637:transplantation*; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D060588:LIM Domain Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D010012:Osteogenesis / Q000235:genetics*; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D054457:Tissue Scaffolds; D014057:Tomography, X-Ray Computed; D014161:Transduction, Genetic / Q000379:methods*; D014182:Transplantation, Autologous
D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; C484380:PDLIM7 protein, human