Hsp90 mediates insulin-like growth factor 1 and interleukin-1beta signaling in an age-dependent manner in equine articular chondrocytes.
Abstract: Many metabolic processes in chondrocytes thought to contribute to age-related changes in the extracellular matrix are influenced by known roles of Hsp90. Age-related decreases in the level of Hsp90 have been documented in numerous cell types and could contribute to cartilage degeneration. The aim of this study was to investigate the roles of age and Hsp90 in insulin-like growth factor 1 (IGF-1) and interleukin-1beta (IL-1beta) signaling in chondrocytes. Methods: Levels of Hsp90 messenger RNA (mRNA) and protein, with respect to age, were determined by quantitative real-time polymerase chain reaction (PCR) and Western blot analysis, respectively. The Hsp90 inhibitor geldanamycin (50 nM, 100 nM, or 500 nM) was used to assess age-related responses to Hsp90 with concurrent IGF-1 or IL-1beta stimulation of chondrocytes. Quantitative real-time PCR was used to measure COL2A1 and matrix metalloproteinase 13 (MMP13) gene expression; Western blot analysis was performed to determine the phosphorylation status of p42/44 and Akt/protein kinase B. Results: The effects of Hsp90 inhibition with geldanamycin were concentration dependent. Inhibition of Hsp90 with 100 nM or 500 nM geldanamycin blocked IGF-1-induced cell proliferation, Akt and p42/44 activation, and COL2A1 expression. Basal and IL-1beta-induced up-regulation of MMP13 mRNA was blocked by all concentrations of geldanamycin tested. Gain-of-function assays with Hsp90 resulted in increased expression of MMP13 mRNA. Conclusions: These results suggest that Hsp90 is involved in opposing signaling pathways of cartilage homeostasis, and that catabolic responses are more sensitive to Hsp90 inhibition than are anabolic responses. Further studies are needed to determine the role of Hsp90 inhibition in osteoarthritis in order to assess its potential as a therapeutic target.
Publication Date: 2007-06-30 PubMed ID: 17599753DOI: 10.1002/art.22664Google Scholar: Lookup
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- Journal Article
- Research Support
- N.I.H.
- Extramural
Summary
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The research primarily focuses on how the protein Hsp90 affects aging-related changes in cartilage cells or chondrocytes, with special focus on how these interactions influence the signaling of insulin-like growth factor 1 and interleukin-1beta, factors linked to cellular growth and inflammation respectively.
Objective and Methodology
- The primary objective was to investigate the impact of age and the protein Hsp90 on signaling pathways of insulin-like growth factor 1 (IGF-1) and interleukin-1beta (IL-1beta) in chondrocytes, cells that are critical in cartilage health and maintenance.
- To complete this study, the researchers measured levels of Hsp90 mRNA and protein by conducting quantitative real-time polymerase chain reaction (PCR) and Western blot analysis respectively.
- Hsp90 inhibitor geldanamycin was used on the chondrocytes to assess how inhibition of Hsp90 affects the responses to IGF-1 or IL-1beta stimulation, studying concentrations of 50 nM, 100 nM, or 500 nM.
- Tests conducted also included measuring levels of COL2A1 and matrix metalloproteinase 13 (MMP13) gene expression using quantitative real-time PCR, with the protein expression measured using Western blot analysis.
Results and Conclusion
- The outcomes displayed that effects of Hsp90 inhibition through geldanamycin were concentration dependent.
- Specially, with 100 nM or 500 nM geldanamycin, IGF-1 induced cell growth, activation of Akt and p42/44, and COL2A1 expression were blocked.
- Baseline and IL-1beta-induced upregulation of MMP13 mRNA was obstructed by all concentrations of geldanamycin used in the study.
- The overexpression of Hsp90 resulted in an increase in MMP13 mRNA expression.
- The concluding message from the research was that Hsp90 is involved in both the growth and breakdown signaling pathways of cartilage homeostasis. Intriguingly, the breakdown pathways appeared more sensitive to Hsp90 inhibition than the growth pathways.
- This recognises the potential of further exploration into the role of Hsp90 inhibition in osteoarthritis, to evaluate it as a possible therapeutic target.
Cite This Article
APA
Boehm AK, Seth M, Mayr KG, Fortier LA.
(2007).
Hsp90 mediates insulin-like growth factor 1 and interleukin-1beta signaling in an age-dependent manner in equine articular chondrocytes.
Arthritis Rheum, 56(7), 2335-2343.
https://doi.org/10.1002/art.22664 Publication
Researcher Affiliations
- Cornell University, Veterinary Medical Center, Ithaca, New York 14853, USA.
MeSH Terms
- Aging
- Animals
- Benzoquinones / pharmacology
- Cartilage, Articular / growth & development
- Cartilage, Articular / physiology
- Chondrocytes / physiology
- Collagen Type II
- Gene Expression Regulation, Developmental
- HSP90 Heat-Shock Proteins / genetics
- Horses
- Insulin-Like Growth Factor I / physiology
- Interleukin-1beta / physiology
- Lactams, Macrocyclic / pharmacology
- Matrix Metalloproteinases / genetics
- Polymerase Chain Reaction
- RNA, Messenger / genetics
- Signal Transduction
Grant Funding
- AG-00905 / NIA NIH HHS
Citations
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