Comparative efficacy of dermal fibroblast-mediated and direct adenoviral bone morphogenetic protein-2 gene therapy for bone regeneration in an equine rib model.
Abstract: Cell-mediated and direct adenoviral (Ad) vector gene therapies can induce bone regeneration, including dermal fibroblasts (DFbs). We compared two effective therapies, DFb-mediated and direct Ad vector delivery of bone morphogenetic protein-2 (BMP2), for relative efficacy in bone regeneration. Equine rib drill defects were treated by percutaneous injection of either DFb-BMP2 or an Ad-BMP2 vector. At week 6, both DFb-BMP2- and Ad-BMP2-treated rib defects had greater bone filling volume and mineral density, with DFb-BMP2 inducing greater bone volume and maturity in the cortical bone aspect of the defect than Ad-BMP2. The transplantation of DFb alone induced modest bone formation. Increased mineral density and bone turnover were evident in the cortical and cancellous bone directly adjacent to the healing drill defects treated with either DFb-BMP2 or Ad-BMP2. Using our cell/vector dosage and model, BMP2, whether delivered by the DFb vector or direct Ad vector, induced greater and robust bone regeneration. DFb-mediated BMP2 therapy promoted greater cortical bone regeneration than did direct gene delivery, possibly because of an increased cellularity of the bone healing site. BMP2 delivery, regardless of gene delivery method, increased the mineral density of the neighboring bone, which may be beneficial clinically in repairing or weak bone.
Publication Date: 2010-03-11 PubMed ID: 20220786DOI: 10.1038/gt.2010.13Google Scholar: Lookup
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- Comparative Study
- Journal Article
- Research Support
- N.I.H.
- Extramural
Summary
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The research article explores the comparative effectiveness of two methods—dermal fibroblast-mediated and direct adenoviral (Ad) vector gene therapies—in bone regeneration, with the application of bone morphogenetic protein-2 (BMP2). Trials were conducted in equine rib models, with both methods resulting in superior bone volume and mineral density. However, BMP2 therapy facilitated by dermal fibroblasts demonstrated a greater degree of cortical bone regeneration, potentially due to an increase in the cellular representation in the healing site.
Methods of Bone Regeneration Therapy
- The study focuses on comparing two main methods of bone regeneration induced by gene therapy, namely vector gene therapies mediated by dermal fibroblasts and direct adenoviral vectors.
- Both these methods employ the use of bone morphogenetic protein-2 (BMP2). BMP2 is a substance known to promote bone growth and repair, thus, it is integral to these therapies.
Procedure and Experimentation
- The trials were executed in an equine rib model and involved treating drill defects or induced damage to the ribs of horses.
- The treatment involved percutaneous injections of either Dermal Fibroblast-BMP2 (DFb-BMP2) or Ad-BMP2 vector.
- The effects were observed over a period of six weeks and measurements were taken of the extent of bone regeneration, bone filling volume, and mineral density.
Results and Findings
- The examination after six weeks showed that both delivery methods resulted in a noticeable increase in bone volume and mineral density within the treated rib defects.
- But, the therapy delivered via dermal fibroblasts resulted in a greater increase in bone volume and maturity, especially in cortical bone, which is the harder outer layer of bone.
- Gamma ray analysis further showed that the dermal fibroblast method yielded more robust cortical bone regeneration compared to direct gene therapy, possibly because it increased cellularity—meaning more active cells involved in the healing site.
Conclusion and Implications
- The study concludes that while both methods were effective in promoting bone growth, delivery of BMP2 via dermal fibroblasts led to superior bone regeneration, especially in cortical bone.
- This indicates that the method of gene delivery can have an influential role in the level and rate of bone restoration, which could have significant implications in bone repair treatment strategies.
- A valuable insight derived is that irrespective of the gene delivery method, the introduction of BMP2 increased the mineral density of the neighboring bone, which could be a valuable approach when repairing frail or weak bone structures.
Cite This Article
APA
Ishihara A, Zekas LJ, Weisbrode SE, Bertone AL.
(2010).
Comparative efficacy of dermal fibroblast-mediated and direct adenoviral bone morphogenetic protein-2 gene therapy for bone regeneration in an equine rib model.
Gene Ther, 17(6), 733-744.
https://doi.org/10.1038/gt.2010.13 Publication
Researcher Affiliations
- Department of Veterinary Clinical Sciences, The Ohio State University, Columbus, Ohio 43210, USA.
MeSH Terms
- Adenoviridae
- Animals
- Bone Morphogenetic Protein 2 / genetics
- Bone Regeneration / genetics
- Fibroblasts / transplantation
- Gene Transfer Techniques
- Genetic Therapy / methods
- Genetic Vectors
- Horses
- Osteogenesis / genetics
- Ribs / injuries
- Skin / cytology
- Transduction, Genetic
Grant Funding
- K08 AR049201 / NIAMS NIH HHS
Citations
This article has been cited 14 times.- Watson-Levings RS, Palmer GD, Levings PP, Dacanay EA, Evans CH, Ghivizzani SC. Gene Therapy in Orthopaedics: Progress and Challenges in Pre-Clinical Development and Translation.. Front Bioeng Biotechnol 2022;10:901317.
- Wilkinson P, Bozo IY, Braxton T, Just P, Jones E, Deev RV, Giannoudis PV, Feichtinger GA. Systematic Review of the Preclinical Technology Readiness of Orthopedic Gene Therapy and Outlook for Clinical Translation.. Front Bioeng Biotechnol 2021;9:626315.
- Ribitsch I, Oreff GL, Jenner F. Regenerative Medicine for Equine Musculoskeletal Diseases.. Animals (Basel) 2021 Jan 19;11(1).
- Taguchi T, Lopez MJ. An overview of de novo bone generation in animal models.. J Orthop Res 2021 Jan;39(1):7-21.
- Wang T, Zhu L, Pei M. Insight into skin cell-based osteogenesis: a review.. F1000Res 2017;6:291.
- Cohn Yakubovich D, Sheyn D, Bez M, Schary Y, Yalon E, Sirhan A, Amira M, Yaya A, De Mel S, Da X, Ben-David S, Tawackoli W, Ley EJ, Gazit D, Gazit Z, Pelled G. Systemic administration of mesenchymal stem cells combined with parathyroid hormone therapy synergistically regenerates multiple rib fractures.. Stem Cell Res Ther 2017 Mar 9;8(1):51.
- Ishihara A, Ohmine K, Weisbrode SE, Bertone AL. Effect of Intra-Medullar and Intra-Venous Infusions of Mesenchymal Stem Cells on Cell Engraftment by In-Vivo Cell Tracking and Osteoinductivity in Rabbit Long Bones: A Pilot Study.. Orthop Muscular Syst 2014 Nov;3(3).
- Ishihara A, Weisbrode SE, Bertone AL. Autologous implantation of BMP2-expressing dermal fibroblasts to improve bone mineral density and architecture in rabbit long bones.. J Orthop Res 2015 Oct;33(10):1455-65.
- Evans C. Using genes to facilitate the endogenous repair and regeneration of orthopaedic tissues.. Int Orthop 2014 Sep;38(9):1761-9.
- Huang C, Tang M, Yehling E, Zhang X. Overexpressing sonic hedgehog peptide restores periosteal bone formation in a murine bone allograft transplantation model.. Mol Ther 2014 Feb;22(2):430-439.
- Evans CH. Gene delivery to bone.. Adv Drug Deliv Rev 2012 Sep;64(12):1331-40.
- Kimelman Bleich N, Kallai I, Lieberman JR, Schwarz EM, Pelled G, Gazit D. Gene therapy approaches to regenerating bone.. Adv Drug Deliv Rev 2012 Sep;64(12):1320-30.
- Dalle Carbonare L, Innamorati G, Valenti MT. Transcription factor Runx2 and its application to bone tissue engineering.. Stem Cell Rev Rep 2012 Sep;8(3):891-7.
- Kimelman-Bleich N, Pelled G, Zilberman Y, Kallai I, Mizrahi O, Tawackoli W, Gazit Z, Gazit D. Targeted gene-and-host progenitor cell therapy for nonunion bone fracture repair.. Mol Ther 2011 Jan;19(1):53-9.
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