Dermal fibroblast-mediated BMP2 therapy to accelerate bone healing in an equine osteotomy model.
Abstract: This study evaluated healing of equine metacarpal/metatarsal osteotomies in response to percutaneous injection of autologous dermal fibroblasts (DFbs) genetically engineered to secrete bone morphogenetic protein-2 (BMP2) or demonstrate green fluorescent protein (GFP) gene expression administered 14 days after surgery. Radiographic assessment of bone formation indicated greater and earlier healing of bone defects treated with DFb with BMP2 gene augmentation. Quantitative computed tomography and biomechanical testing revealed greater mineralized callus and torsional strength of DFb-BMP2-treated bone defects. On the histologic evaluation, the bone defects with DFb-BMP2 implantation had greater formation of mature cartilage and bone nodules within the osteotomy gap and greater mineralization activity on osteotomy edges. Autologous DFbs were successfully isolated in high numbers by a skin biopsy, rapidly expanded without fastidious culture techniques, permissive to adenoviral vectors, and efficient at in vitro BMP2 protein production and BMP2-induced osteogenic differentiation. This study demonstrated an efficacy and feasibility of DFb-mediated BMP2 therapy to accelerate the healing of osteotomies. Skin cell-mediated BMP2 therapy may be considered as a potential treatment for various types of fractures and bone defects.
Publication Date: 2009-09-25 PubMed ID: 19777486DOI: 10.1002/jor.20978Google Scholar: Lookup
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- Journal Article
- Research Support
- N.I.H.
- Extramural
Summary
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The research evaluates how autologous dermal fibroblasts (cells sourced from the skin of a horse), which have been genetically modified to secrete bone morphogenetic protein-2 (BMP2), can improve the healing of bone fractures or defects in horses. The study shows that the application of these modified cells significantly accelerated bone healing.
Methodology and Results
- The examination carried out on horse metacarpal/metatarsal bone fracture repair, involved injection of genetically modified dermal fibroblasts, 14 days following bone surgery.
- These fibroblasts had been engineered to either secrete BMP2, a protein that stimulates bone growth, or to exhibit green fluorescent protein (GFP) gene expression, which enables the monitoring of gene activity.
- Radiographic analysis showed improved healing in bone defects that were treated with BMP2 gene-augmented dermal fibroblasts. The healing of these fractures appeared earlier and more defined compared to other cases.
- Advanced computerised tomography (CT) quantitatively backed up these findings by revealing larger mineralized calluses (hardened areas where the bone has been healed) in the treated fractures. Additionally, these bone defects demonstrated greater torsional strength, indicating that they were more resistant to twisting forces.
Biopsy and Histological Analysis
- By analyzing bone and skin cell samples, the researchers observed greater formation of mature cartilage and bone nodules in the gap caused by the osteotomy (a surgical procedure that cuts the bone) in bones treated with dermal fibroblasts modified with BMP2.
- This treatment also enhanced mineralization activity on the osteotomy edges, meaning the bone grew back more effectively.
- The fibroblast cells used for this therapy were obtained from a skin biopsy of the equines and were modified and multiplied successfully without the use of complex culture techniques. These cells were receptive to the viral vectors (vehicles for transferring genetic material) used for modification and effectively produced BMP2 protein and performed BMP2-induced osteogenic (bone-producing) differentiation in vitro (in a laboratory setting).
- This study, therefore, reveals the therapeutic efficacy and viability of using BMP2-enabled fibroblast treatment to speed up the healing of bone fractures.
Conclusions and Applications
- The researchers conclude that skin cell-mediated BMP2 therapy may serve as a potential treatment option for various types of fractures and bone defects. Such an approach could revolutionize treatments for bone repair, potentially leading to faster recovery times and improved outcomes for patients – whether human or animal.
Cite This Article
APA
Ishihara A, Zekas LJ, Litsky AS, Weisbrode SE, Bertone AL.
(2009).
Dermal fibroblast-mediated BMP2 therapy to accelerate bone healing in an equine osteotomy model.
J Orthop Res, 28(3), 403-411.
https://doi.org/10.1002/jor.20978 Publication
Researcher Affiliations
- Comparative Orthopedic Research Laboratories, Department of Veterinary Clinical Sciences, The Ohio State University, 601 Tharp Street, Columbus, Ohio 43210, USA.
MeSH Terms
- Animals
- Bone Morphogenetic Protein 2 / administration & dosage
- Bone Morphogenetic Protein 2 / genetics
- Bone Morphogenetic Protein 2 / metabolism
- Bone and Bones / physiopathology
- Cell Transplantation / methods
- Dermis / cytology
- Feasibility Studies
- Fibroblasts / metabolism
- Fibroblasts / transplantation
- Genetic Engineering
- Horses
- Injections
- Metacarpal Bones / surgery
- Metatarsal Bones / surgery
- Osteotomy
- Transduction, Genetic
- Wound Healing
Grant Funding
- K08 AR049201 / NIAMS NIH HHS
Citations
This article has been cited 18 times.- Hosseinkhani H, Domb AJ, Sharifzadeh G, Nahum V. Gene Therapy for Regenerative Medicine.. Pharmaceutics 2023 Mar 6;15(3).
- 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.
- Grzeskowiak RM, Alghazali KM, Hecht S, Donnell RL, Doherty TJ, Smith CK, Anderson DE, Biris AS, Adair HS. Influence of a novel scaffold composed of polyurethane, hydroxyapatite, and decellularized bone particles on the healing of fourth metacarpal defects in mares.. Vet Surg 2021 Jul;50(5):1117-1127.
- 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.
- Elangovan S, Gajendrareddy P, Ravindran S, Salem AK. Emerging local delivery strategies to enhance bone regeneration.. Biomed Mater 2020 Nov 21;15(6):062001.
- Liu L, Jiang X, Yu W. Dracohodin Perochlorate Stimulates Fibroblast Proliferation via EGFR Activation and Downstream ERK/CREB and PI3K/Akt/mTOR Pathways In Vitro.. Evid Based Complement Alternat Med 2019;2019:6027186.
- Alluri R, Song X, Bougioukli S, Pannell W, Vakhshori V, Sugiyama O, Tang A, Park SH, Chen Y, Lieberman JR. Regional gene therapy with 3D printed scaffolds to heal critical sized bone defects in a rat model.. J Biomed Mater Res A 2019 Oct;107(10):2174-2182.
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- Nyberg E, Holmes C, Witham T, Grayson WL. Growth factor-eluting technologies for bone tissue engineering.. Drug Deliv Transl Res 2016 Apr;6(2):184-94.
- Evans CH, Huard J. Gene therapy approaches to regenerating the musculoskeletal system.. Nat Rev Rheumatol 2015 Apr;11(4):234-42.
- 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).
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