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Differential expression of TGF beta isoforms by human articular chondrocytes in response to growth factors
1Sam and Rose Stein Institute for Research on Aging, University of California San Diego, La Jolla 92093.
Abstract:
Transforming growth factor beta (TGF beta) is a family of important regulators of chondrocyte growth and differentiation. Although TGF beta has been detected in cartilage, the TGF beta isoforms expressed by chondrocytes and their regulation by growth factors are unknown. This study shows that human articular chondrocytes release TGF beta activity. Chondrocyte conditioned media contains active TGF beta and larger quantities in latent form. By neutralization with specific antibodies it is shown that all three isoforms (TGF beta 1, TGF beta 2, and TGF beta 3) are secreted by chondrocytes. Analysis of the inducers of TGF beta gene expression demonstrates complex regulation of TGF beta production by growth factors. Basic fibroblast growth factor (bFGF) stimulates the release of TGF beta activity but has no effect on steady state TGF beta mRNA levels while platelet-derived growth factor (PDGF) upregulates TGF beta 1 and TGF beta 3 mRNAs with a corresponding increase in protein secretion. The three TGF beta isoforms themselves differentially affect gene expression. While TGF beta 1 and TGF beta 2 show autoinduction, TGF beta 3 upregulates TGF beta 1 but does not affect TGF beta 2 mRNA levels. These results demonstrate that human articular chondrocytes produce all three TGF beta isoforms. Induction of TGF beta expression is differentially regulated by various growth factors and occurs at the mRNA level and/or posttranscriptionally. Chondrocyte expression and the differential regulation of TGF beta 1, TGF beta 2, and TGF beta 3 by growth factors suggest that all three isoforms of TGF beta are part of the network of cartilage regulatory factors.
Insights
Human articular chondrocytes produce all three transforming growth factor beta (TGF beta) isoforms. Growth factors differentially regulate TGF beta production, indicating its role in cartilage regulation.
Area of Science:
- Biochemistry
- Cell Biology
- Molecular Biology
Background:
- Transforming growth factor beta (TGF beta) is crucial for chondrocyte function.
- Previous studies detected TGF beta in cartilage, but its specific isoforms and regulation in chondrocytes were unknown.
Purpose of the Study:
- To investigate the TGF beta isoforms produced by human articular chondrocytes.
- To explore how growth factors regulate TGF beta production in these cells.
Main Methods:
- Analysis of TGF beta activity in conditioned media from human articular chondrocytes.
- Neutralization assays using specific antibodies to identify TGF beta isoforms.
- Quantitative analysis of TGF beta mRNA levels following growth factor stimulation.
- Assessment of TGF beta isoform-specific effects on gene expression.
Main Results:
- Human articular chondrocytes secrete active and latent TGF beta.
- All three TGF beta isoforms (TGF beta 1, TGF beta 2, TGF beta 3) are produced.
- Basic fibroblast growth factor (bFGF) increases TGF beta activity without altering mRNA levels.
- Platelet-derived growth factor (PDGF) upregulates TGF beta 1 and TGF beta 3 mRNA and protein.
- TGF beta 1 and TGF beta 2 exhibit autoinduction, while TGF beta 3 upregulates TGF beta 1.
Conclusions:
- Human articular chondrocytes express all three TGF beta isoforms.
- Growth factors differentially regulate TGF beta expression at the mRNA and/or post-transcriptional levels.
- TGF beta isoforms are integral components of cartilage regulatory networks.