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Osteogenic Plasmid Genes

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Osteogenic Plasmid Genes Proc. Natl. Acad. Sci. USA Vol. 93, pp. 5753-5758, June 1996 Medical Sciences Stimulation of new bone formation by direct transfer of osteogenic plasmid genes (gene transfer/rat osteotomy model/bone formation/repair fibroblast/wound healing) JIANMING FANG*, YAO-YAO ZHU*, ELIZABETH SMILEY*, JEFFREY BONADIO*, JEFFREY P. ROULEAUt, STEVEN A. GOLDSTEINt, LAURIE K. MCCAULEYt, BEVERLY L. DAVIDSON§, AND BLAKE J. ROESSLER§ Departments of *Pathology, tSurgery, and §Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109; and tDepartment of Periodontics/Prevention and Geriatrics, School of Dentistry, University of Michigan, Ann Arbor, MI 48109 Communicated by Hector F. DeLuca, University of Wisconsin, Madison, WI, February 2, 1996 (received for review November 22, 1995) ABSTRACT Degradable matrices containing expression and prolonged ambulatory impairment and often must be plasmid DNA [gene-activated matrices (GAMs)] were im- treated by operative procedure. External fixation devices may planted into segmental gaps created in the adult rat femur. stabilize fractures at risk for poor healing, but a lack of viable Implantation of GAMs containing 3-galactosidase or lucif- bone in the defect site can lead to structural instability and, at erase plasmids led to DNA uptake and functional enzyme times, infection and bony erosion. Bone grafts also may be expression by repair cells (granulation tissue) growing into used, but they may become infected or, for certain applica- the gap. Implantation of a GAM containing either a bone tions, may provide insufficient bone that is difficult to contour. morphogenetic protein-4 plasmid or a plasmid coding for a Microsurgical transfer of free bone grafts with attached soft fragment ofparathyroid hormone (amino acids 1-34) resulted tissue and blood vessels can mitigate against infection, but the in a biological response of new bone filling the gap. Finally, operation is arduous and highly specialized, and the morbidity implantation of a two-plasmid GAM encoding bone morpho- risk is high. Therefore, in general, current orthopedic practice genetic protein-4 and the parathyroid hormone fragment, lacks an effective therapy for fractures that heal with difficulty. which act synergistically in vitro, caused new bone to form As recombinant proteins, factors such as BMP and TGF-1p faster than with either factor alone. These studies demonstrate represent promising therapeutic alternatives for fracture re- for the first time that repair cells (fibroblasts) in bone can be pair (12, 13, 18, 19). However, relatively large doses (micro- genetically manipulated in vivo. While serving as a useful tool gram amounts) are required to stimulate significant new bone to study the biology of repair fibroblasts and the wound formation in animals, raising the concern that future human healing response, the GAM technology may also have wide therapies may be expensive and may possess an increased risk therapeutic utility. of toxicity. As an alternative, gene therapy may be more cost effective because ex vivo production of DNA for clinical use is Bone has a substantial capacity to regenerate following frac- inexpensive compared with traditional methods of protein ture. The complex but ordered fracture repair sequence in- production (22). Gene therapy may also be a more efficient cludes hemostasis, clot dissolution, granulation tissue in- way to deliver osteogenic factors in vivo-i.e., compared with growth, formation of a callus, and remodeling of the callus to traditional protein delivery, the cell-mediated synthesis and an optimized structure (1). Cells participating in this process delivery of bone growth factors in situ should be associated include platelets, inflammatory cells, fibroblasts, endothelial with efficient targeting to cell surface receptors, and, conse- cells, pericytes, osteoclasts, and osteogenic progenitors. Sev- quently, the need for less protein to achieve a clinically useful eral peptide growth and differentiation factors have been effect. To test these ideas, we developed a rat nonunion model identified that appear to control cellular events associated with system to study the in vivo delivery ofexpression plasmid DNA. bone formation and repair (2). Bone morphogenetic proteins We show for the first time that repair cells (fibroblasts) can be (BMPs), for example, are soluble extracellular factors that genetically manipulated in vivo to produce plasmid-encoded control osteogenic cell fate. BMP genes are normally ex- proteins capable of inducing bone growth. pressed by fetal osteoblasts in vitro (3) and in vivo (4-6). Recombinant BMP proteins initiate cartilage and bone pro- genitor cell differentiation (7-11); BMP delivery induces a MATERIALS AND METHODS bone formation sequence similar to endochondral bone for- Animal Model. To create a 5-mm osteotomy, four 1.2-mm mation (12, 13); BMP gene expression is upregulated early in diameter pins were screwed with intermittent irrigation into the process of fracture repair (14). Osteogenic protein-1, a the femoral diaphysis of normal adult Sprague-Dawley rats member of a family of molecules related to the BMPs (15), is under general anesthesia (23). A surgical template guided capable of similar effects in vitro and in vivo (16, 17). Finally, parallel pin placement (pins were set 3.5 mm from the edge of transforming growth factor-p (TGF-3) has been shown to the fixator plate and 2.5 mm apart), which could be confirmed stimulate cartilage and bone formation in vivo (18, 19). by fluorography. An external fixator plate (30 x 10 x 5 mm), Fracture repair in humans typically is robust, and medical fabricated with aluminum alloy on a computerized numerical treatment often involves only stabilization of the injured site control mill to ensure high tolerances, was then secured on the and pain management (20). However, a challenge arises with pins. All fixator parts were sterilized with ethylene oxide gas the -1 million fractures each year in the United States that prior to surgery. Segmental defects were created at midshaft heal with difficulty-e.g., fractures that occur at sites of with a Hall Micro 100 oscillating saw (Zimmer Inc., Warsaw, marginal vascularity, arise from metabolic or heritable bone IN). Collagen sponges + plasmid DNA were placed and held fragility syndromes, or are associated with large areas of tissue in the osteotomy gap until surrounded by clotted blood; a loss (21). Poor fracture healing is associated with chronic pain Abbreviations: BMP, bone morphogenetic protein; GAM, gene- The publication costs of this article were defrayed in part by page charge activated matrix; TGF-B, transforming growth factor-(8; 3-gal, 3-ga- payment. This article must therefore be hereby marked "advertisement" in lactosidase; PTH, parathyroid hormone; PTH1-34, peptide fragment accordance with 18 U.S.C. §1734 solely to indicate this fact. (amino acids 1-34) of parathyroid hormone; ROS, rat osteosarcoma. 5753 Downloaded by guest on September 26, 2021 5754 Medical Sciences: Fang et al. Proc. Natl. Acad. Sci. USA 93 (1996) preliminary time-course study showed that this maneuver fixed parathyroid hormone sequence (GenBank): upstream primer, the sponge within the osteotomy site prior to granulation tissue 5'-GCGGATCCGCGATGATACCTGCAAAAGA- ingrowth. The skin incision was closed with staples. The fixator CATG-3'; downstream primer, 5'-GCGGATCCGCGT- device provided necessary stability so that animal ambulation CAAAAATTGTGCACATCC-3'. This primer pair created was unlimited for a several week period. BamHI sites at both ends of the PCR fragment. The fragment Luciferase and B-Galactosidase (,-gal) Enzyme Assays. was digested with BamHI and ligated into a BamHI cloning site Luciferase and bacterial P-gal activity was determined using in the PLJ retrovirus vector (26). A clone with the insert in the the Luciferase Assay System (Promega) and 3-gal Enzyme coding orientation (pGAM2) eventually was isolated and Assay System (Promega) according to protocols supplied by characterized by DNA sequence analysis. the manufacturer. To assay the function of pGAM2-encoded PTH1-34, sp pGAM1 Expression Plasmid. To assemble pGAM1, mRNA CRIP packaging cells (26) were transfected with 10 txg of was prepared from day 13.5 postcoitus CD-1 mouse embryos plasmid DNA using the calcium phosphate method. After an using kit reagents and protocols (Poly(A)Tract mRNA Isola- overnight incubation, culture medium (Dulbecco's modified tion System I, Promega). An aliquot of mRNA was used to Eagle's medium, supplemented with 10% fetal bovine serum, generate cDNA using commercial reagents (Reverse Tran- penicillin (100 units/ml), and streptomycin (100 mg/ml; all scriptase System, Promega). A full-length mouse BMP-4 reagents from Gibco/BRL) containing retrovirion particles cDNA coding sequence was generated by PCR using the was harvested and applied to cultured Rat-1 cells. Independent following conditions: 94°C for 4 min, 1 cycle; 94°C for 1 min, clones of successfully transduced Rat-1 cells were obtained by 65°C for 1 min, 72°C for 1 min, 30 cycles; 72°C for 8 min, 1 standard infection and selection procedures. Briefly, cultured cycle. The sequence of the PCR primers was based on known Rat-1 cells were grown to confluence, split 1:10, and selected mouse BMP-4 sequence (GenBank): upstream primer, 5'- in G418 (1 mg/ml; GIBCO/BRL). Similar methods were used CCATGATTCCTGGTAACCGAATGCTG-3'; downstream to generate clones of Rat-1 cells transduced with the BAG primer, 5'-CTCAGCGGCATCCGCACCCCTC-3'. A single retrovirus, which encodes bacterial 3-gal. hPTH1-34 concen- PCR product of the expected size (1.3 kb) was purified by tration in cell culture media was estimated using a commercial agarose gel electrophoresis and cloned into the TA cloning radioimmunoassay kit (INS-PTH, Nichols) and according to vector (Invitrogen). The 5' end of the BMP-4 insert was further the manufacturer's protocol. The ability of the PTH1-34 modified by PCR addition of a sequence (CCACCATGG) to peptide to stimulate a cAMP response in rat osteosarcoma ensure correct initiation. The 3' end was also modified by PCR (ROS) 17/2.8 cells was evaluated as described (27).
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