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The Journal of bone and joint surgery. British volume2007; 89(5); 672-685; doi: 10.1302/0301-620X.89B5.18343

Genetic modification of chondrocytes with insulin-like growth factor-1 enhances cartilage healing in an equine model.

Abstract: Gene therapy with insulin-like growth factor-1 (IGF-1) increases matrix production and enhances chondrocyte proliferation and survival in vitro. The purpose of this study was to determine whether arthroscopically-grafted chondrocytes genetically modified by an adenovirus vector encoding equine IGF-1 (AdIGF-1) would have a beneficial effect on cartilage healing in an equine femoropatellar joint model. A total of 16 horses underwent arthroscopic repair of a single 15 mm cartilage defect in each femoropatellar joint. One joint received 2 x 10(7) AdIGF-1 modified chondrocytes and the contralateral joint received 2 x 10(7) naive (unmodified) chondrocytes. Repairs were analysed at four weeks, nine weeks and eight months after surgery. Morphological and histological appearance, IGF-1 and collagen type II gene expression (polymerase chain reaction, in situ hybridisation and immunohistochemistry), collagen type II content (cyanogen bromide and sodium dodecyl sulphate-polyacrylamide gel electrophoresis), proteoglycan content (dimethylmethylene blue assay), and gene expression for collagen type I, matrix metalloproteinase (MMP)-1, MMP-3, MMP-13, aggrecanase-1, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and TIMP-3 were evaluated. Genetic modification of chondrocytes significantly increased IGF-1 mRNA and ligand production in repair tissue for up to nine weeks following transplantation. The gross and histological appearance of IGF-1 modified repair tissue was improved over control defects. Gross filling of defects was significantly improved at four weeks, and a more hyaline-like tissue covered the lesions at eight months. Histological outcome at four and nine weeks post-transplantation revealed greater tissue filling of defects transplanted with genetically modified chondrocytes, whereas repair tissue in control defects was thin and irregular and more fibrous. Collagen type II expression in IGF-1 gene-transduced defects was increased 100-fold at four weeks and correlated with increased collagen type II immunoreaction up to eight months. Genetic modification of chondrocytes with AdIGF-1 prior to transplantation improved early (four to nine weeks), and to a lesser degree long-term, cartilage healing in the equine model. The equine model of cartilage healing closely resembles human clinical cartilage repair. The results of this study suggest that cartilage healing can be enhanced through genetic modification of chondrocytes prior to transplantation.
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Publication Date: 2007-06-02 PubMed ID: 17540757DOI: 10.1302/0301-620X.89B5.18343Google Scholar: Lookup
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  • Journal Article
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  • Non-U.S. Gov't

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research is about using gene therapy to improve the healing of cartilage in horses. By altering chondrocytes (cartilage cells) with a gene coding for the Insulin-like Growth Factor-1 (IGF-1), the recovery of damaged cartilage is reportedly enhanced.

Objective and Methodology

  • The research aimed to observe whether chondrocytes genetically modified to produce Insulin-like Growth Factor-1 (IGF-1) would improve cartilage repair in horses.
  • 16 horses with single cartilage defects in their femoropatellar joint were chosen. One joint in each horse was treated with genetically modified chondrocytes while the opposite one was treated with unmodified cells for comparison.
  • The modified cells were altered using an adenovirus vector to encode for equine IGF-1. Adenovirus vectors are common tools in gene therapy, used to deliver the desired genes into cells.

Measurements and Analysis

  • The analysis took place at four weeks, nine weeks, and eight months after the surgery.
  • Aspects like the morphological and histological appearance, gene expression for IGF-1 and collagen type II, content of collagen type II and proteoglycans, and expressions for other genes related to cartilage health were evaluated.
  • The researchers used various laboratory techniques, such as Polymerase Chain Reaction (PCR), in situ hybridization, immunohistochemistry, cyanogen bromide and sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE), and dimethylmethylene blue assay.

Observations and Findings

  • The modified chondrocytes produced increased levels of IGF-1 mRNA and ligand for up to nine weeks, which suggests that the gene therapy was successful.
  • The genetically altered chondrocytes produced cartilage that was histologically and morphologically healthier than the control case.
  • Collagen type II expression was 100 times increased in the genetically enhanced cells at four weeks, also indicating healthier cartilage.
  • The experimental group showed significant enhancement in the cartilage healing process in four to nine weeks healing phases and a slight improvement in the long-term healing.

Implications and Conclusions

  • It is worth noting that the healing model of cartilage in horses closely matches human cartilage repair.
  • Thus, this study has implications for human health, potentially pointing to a gene therapy method that could accelerate and enhance cartilage repair.
  • The study concludes that genetically modifying chondrocytes with the IGF-1 gene before transplantation can improve cartilage healing.

Cite This Article

APA
Goodrich LR, Hidaka C, Robbins PD, Evans CH, Nixon AJ. (2007). Genetic modification of chondrocytes with insulin-like growth factor-1 enhances cartilage healing in an equine model. J Bone Joint Surg Br, 89(5), 672-685. https://doi.org/10.1302/0301-620X.89B5.18343

Publication

The Journal of bone and joint surgery. British volume
ISSN: 0301-620X
NlmUniqueID: 0375355
Country: England
Language: English
Volume: 89
Issue: 5
Pages: 672-685

Researcher Affiliations

Goodrich, L R
  • Colorado State University, College of Veterinary Medicine, Fort Collins, Colorado 80523, USA.
Hidaka, C
    Robbins, P D
      Evans, C H
        Nixon, A J

          MeSH Terms

          • Adenoviridae / genetics
          • Animals
          • Arthroscopy
          • Cartilage, Articular / injuries
          • Cartilage, Articular / metabolism
          • Cartilage, Articular / pathology
          • Cartilage, Articular / surgery
          • Chondrocytes / metabolism
          • Chondrocytes / transplantation
          • Collagen Type II / biosynthesis
          • Collagen Type II / genetics
          • Disease Models, Animal
          • Female
          • Gene Expression
          • Genetic Therapy / methods
          • Genetic Vectors
          • Horses
          • Insulin-Like Growth Factor I / biosynthesis
          • Insulin-Like Growth Factor I / genetics
          • Insulin-Like Growth Factor I / physiology
          • Male
          • Proteoglycans / metabolism
          • RNA, Messenger / genetics
          • Transduction, Genetic
          • Wound Healing

          Grant Funding

          • AR049159-02 / NIAMS NIH HHS

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