Differential expression of TGFβ isoforms by human articular chondrocytes in response to growth factors

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Abstract
Transforming growth factor β (TGFβ) is a family of important regulators of chondrocyte growth and differentiation. Although TGFβ has been detected in cartilage, the TGFβ isoforms expressed by chondrocytes and their regulation by growth factors are unknown. This study shows that human articular chondrocytes release TGFβ activity. Chondrocyte conditioned media contains active TGFβ and larger quantities in latent form. By neutralization with specific antibodies it is shown that all three isoforms (TGFβ1, TGFβ2, and TGFβ3) are secreted by chondrocytes. Analysis of the inducers of TGFβ gene expression demonstrates complex regulation of TGFβ production by growth factors. Basic fibroblast growth factor (bFGF) stimulates the release of TGFβ activity but has no effect on steady state TGFβ mRNA levels while platelet‐derived growth factor (PDGF) upregulates TGFβ1 and TGFβ3 mRNAs with a corresponding increase in protein secretion. The three TGFβ isoforms themselves differentially affect gene expression. While TGFβ1 and TGFβ2 show autoinduction, TGFβ3 upregulates TGFβ1 but does not affect TGFβ2 mRNA levels. These results demonstrate that human articular chondrocytes produce all three TGFβ isoforms. Induction of TGFβ expression is differentially regulated by various growth factors and occurs at the mRNA level and/or posttranscriptionally. Chondrocyte expression and the differential regulation of TGFβ1, TGFβ2, and TGFβ3 by growth factors suggest that all three isoforms of TGFβ are part of the network of cartilage regulatory factors.