Dual transduction of insulin-like growth factor-I and interleukin-1 receptor antagonist protein controls cartilage degradation in an osteoarthritic culture model.
Abstract: This study evaluated the potential of gene induced synoviocyte expression of a combination of insulin-like growth factor-I (AdIGF-I) and interleukin-1 receptor antagonist protein (AdIL-1Ra) to control articular cartilage degradation in vitro. Cartilage explants and synovial membrane were harvested from young mature horses. Synovial monolayers were established and either (1) maintained as untransduced controls; (2) transduced with AdIGF-I at 200 MOI in 500 microl serum-free medium; (3) transduced with AdIL-1Ra at 100 MOI; or (4) transduced with a combination of AdIGF-I (200 MOI) and AdIL-1Ra (100 MOI). Following transduction, cartilage explants were exposed to the synovial monolayer medium using co-culture inserts. Cultures were maintained for 6 days in either serum-free medium or medium containing 10 ng/ml recombinant human interleukin-1beta. At termination, synovial cell RNA was isolated for real-time PCR analysis, and cartilage explants were collected for H&E and toluidine blue staining, immunohistochemistry for type II collagen and IGF-I, in situ localization of IGF-I and type II collagen gene expression, and biochemical assays. Synovial monolayers were readily transduced with both AdIGF-I and AdIL-1Ra. IGF-I and IL-1Ra protein were secreted at beneficial levels throughout the experiment, having peak concentrations of 94.6 ng/ml and 33.0 ng/ml, respectively. Transduction with IGF-I promoted cartilage production of proteoglycan and type II collagen, suggesting a beneficial role for healing injured cartilage. Transduction with IL-1Ra decreased the synovial expression of IL-1alpha and IL-1beta and matrix metalloproteinases, indicating a mechanism for prevention of matrix degradation. The beneficial effects of the combination of anabolic growth factors and catabolic blockers were evident in improved preservation of proteoglycan content of cartilage explants exposed to the depleting effects of IL-1. These results show that gene therapy combining anabolic growth factors to stimulate matrix synthesis and catabolic blockers to prevent matrix degradation by IL-1, protects and causes partial restoration of cartilage matrix, and suggest a potential benefit of combination gene therapy for cartilage healing.
Publication Date: 2004-12-21 PubMed ID: 15607883DOI: 10.1016/j.orthres.2004.06.020Google Scholar: Lookup
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- Journal Article
- Research Support
- Non-U.S. Gov't
Summary
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The research examines the impact of introducing insulin-like growth factor-I and interleukin-1 receptor antagonist protein on controlling cartilage degradation using a laboratory model that replicates the conditions of osteoarthritis.
Research Methodology
- The researchers harvested cartilage explants and synovial membrane from young mature horses.
- There were four groups of synovial monolayers: untransduced controls, those introduced with AdIGF-I, those with AdIL-1Ra, and a combination of AdIGF-I and AdIL-1Ra.
- Post-transduction, the cartilage explants were exposed to a synovial monolayer medium via co-culture inserts.
- The cultures were maintained for six days, and some were exposed to a medium featuring recombinant human interleukin-1beta.
- Upon termination, synovial cell RNA was taken for real-time PCR analysis, and the cartilage explants underwent multiple tests and stains.
Findings
- The synovial monolayers successfully took in both AdIGF-I and AdIL-1Ra.
- IGF-I and IL-1Ra protein were observed in beneficial levels throughout the experiment, peaking at 94.6 ng/ml and 33.0 ng/ml, respectively.
- Transduction with IGF-I appeared to promote proteoglycan and type II collagen production in the cartilage, suggesting it supports cartilage healing.
- Transduction with IL-1Ra saw a decrease in the synovial expression of IL-1alpha, IL-1beta, and matrix metalloproteases, indicating that it can help prevent matrix degradation.
Conclusion
- The positive effects of combining anabolic growth factors and catabolic blockers were observed in the improved preservation of proteoglycan content in cartilage explants that were exposed to IL-1.
- The results demonstrate that gene therapy using both anabolic growth factors (to promote matrix synthesis) and catabolic blockers (to prevent matrix degradation by IL-1) can protect and partially restore the cartilage matrix. Therefore, these findings suggest that this combined gene therapy may be beneficial for cartilage healing.
Cite This Article
APA
Haupt JL, Frisbie DD, McIlwraith CW, Robbins PD, Ghivizzani S, Evans CH, Nixon AJ.
(2004).
Dual transduction of insulin-like growth factor-I and interleukin-1 receptor antagonist protein controls cartilage degradation in an osteoarthritic culture model.
J Orthop Res, 23(1), 118-126.
https://doi.org/10.1016/j.orthres.2004.06.020 Publication
Researcher Affiliations
- Comparative Orthopaedics Laboratory, College of Veterinary Medicine, Cornell University, C3-176 Veterinary Medical Center, Ithaca, NY 14853, USA.
MeSH Terms
- Animals
- Cartilage / metabolism
- Cartilage / pathology
- DNA / analysis
- Genetic Therapy
- Horses
- Insulin-Like Growth Factor I / genetics
- Interleukin 1 Receptor Antagonist Protein
- Osteoarthritis / therapy
- Proteoglycans / analysis
- RNA, Messenger / analysis
- Sialoglycoproteins / genetics
- Tissue Culture Techniques
Citations
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