DIFFERENTIAL EXPRESSION OF TGF-BETA ISOFORMS BY HUMAN ARTICULAR CHONDROCYTES IN RESPONSE TO GROWTH-FACTORS

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.